Search Results (745)

RAC3 encodes a small Rho-family GTPase essential for cytoskeletal regulation and neurodevelopment, and de novo RAC3 variants typically act as gain-of-function alleles that cause severe neurodevelopmental disorders. In this study, we analyzed a fetus with multisystem congenital anomalies and identified a de novo RAC3 p.(T17R) variant by genome sequencing. To elucidate the pathogenicity of this variant, we combined in silico variant prioritization, structural and energetic modeling, and pathogenicity prediction with in vitro biochemical assays, including GDP/GTP exchange, GTP hydrolysis, effector pull-down, and luciferase reporter analyses in COS7 cells, as well as morphological analysis of primary hippocampal neurons. Furthermore, we performed in vivo analyses using a mouse in utero electroporation to assess cortical neuron migration, axon extension, and dendritic development. Our biochemical results suggest that RAC3-T17R exhibits markedly increased GDP/GTP exchange, with a preference for GDP binding, and undetectable GTP hydrolysis. The mutant displayed minimal binding to canonical RAC effectors (PAK1, MLK2, and N-WASP) and failed to activate SRF-, NFκB-, or AP1-dependent transcription. Neuronal overexpression of RAC3-T17R impaired axon formation in vitro, while in vivo expression delayed cortical neuron migration and axon extension and reduced dendritic arborization. Clinically, the fetus exhibited corpus callosum agenesis, microcephaly, organomegaly, and limb contractures. Collectively, these findings indicate that the RAC3 p.(T17R) variant may represent a signaling-deficient allele with pleiotropic, variant-specific mechanisms that disrupt corticogenesis and broader organogenesis. Our multi-tiered in silico–in vitro–in vivo approach demonstrates that noncanonical RAC3 variants can produce complex, multisystem developmental phenotypes beyond previously recognized RAC3-related neurodevelopmental disorders. Full article

Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the developing nervous system of the fetus. Any disturbances in the brain at embryonic and early postnatal stages might compromise its natural developmental trajectory, which could potentially increase the risk of developing neuropsychiatric disorders, such as schizophrenia, autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), major depressive and bipolar disorders, etc. Presumably, all these conditions could initiate the development of age-related cognitive impairment in late ontogenesis, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. As the main immune cell population in the CNS, microglia both mediate its proper development and receive pathological stimuli from the maternal organism. This could lead to microglia premature activation and could become a part of the mechanisms of the fetal CNS development alterations. In this review, we discuss the role of prenatal activation of microglia in neuropsychiatric disorders and neurodegenerative disease development. We highlight approaches to modeling MIA, as well as sex differences in the morphological and functional state of microglia in the context of physiological conditions. There is a hypothesis discussed regarding the contribution of these distinctions to neuropsychiatric disorders and neurodegenerative disease incidence, prevalence, and progression in males and females. Full article

Objectives: The present study aimed to analyze the growth dynamics of the ossification centers of the seventh cervical (C7) vertebra in the human fetus, focusing on linear, planar, and volumetric parameters of both the vertebral body and neural processes. Methods: The study was conducted on 55 human fetuses of both sexes (27 males and 28 females), aged 17–30 weeks’ gestation. High-resolution computed tomography, three-dimensional reconstruction, digital image analysis, and appropriate statistical modeling were used to obtain detailed morphometric measurements of the C7 ossification centers. Results: All morphometric parameters—length, cross-sectional area, and volume—of the vertebral body ossification center increased linearly with gestational age, except for the sagittal diameter, which followed a logarithmic growth pattern. Linear growth was likewise observed in all diameters of the neural process ossification centers, including length, width, cross-sectional area, and volume. No statistically significant sex-related or side-related differences were detected. Conclusions: The CT-based morphometric data and growth models for the ossification centers of C7 presented in this study offer preliminary reference values for the vertebra prominens during fetal development. Although limited by sample size, these results establish a baseline that may assist anatomists, radiologists, obstetricians, pediatricians, and spinal surgeons in assessing cervical-spine maturation and in detecting congenital anomalies prenatally. Further studies involving larger and more diverse fetal cohorts are warranted to validate and extend these observations. Full article

Kolmogorov–Sinai (KS) entropy is an indicator of the chaotic behavior of entire systems from an information-theoretic viewpoint. Here, we used KS entropy values derived from the heart sounds of four fetus–mother pairs to identify the changes in fetal and maternal informational patterns during the four phases of pregnancy (early, mid, late, and postnatal). Time-series data of the heart sounds were reconstructed in a five-dimensional phase space to obtain the Lyapunov spectrum, and KS entropy was calculated. Statistical analyses were then conducted separately for the fetus and mother for the four phases of pregnancy. The fetal KS entropy significantly increased from early pregnancy to the postnatal period (0.054 ± 0.007 vs. 0.097 ± 0.007; p < 0.001), whereas the maternal KS entropy decreased in late pregnancy and then significantly increased after birth (0.098 ± 0.002 vs. 0.133 ± 0.003; p < 0.001). The increase in KS entropy with the course of fetal gestation reflects an increase in information generation and adaptive capacity during the developmental process. Thus, changes in maternal KS entropy play a dual role, temporarily enhancing physiological stability to support fetal development and helping to rebuild the mother’s own adaptive capacity in the postpartum period. Full article

Background: While prenatal diagnosis of congenital heart disease is increasingly common, and communication is essential to minimizing familial stress, little is known about how the fetus is discussed in this setting. This study observed how clinicians and families refer to the fetus during initial fetal cardiology consultations. Methods: Initial fetal cardiology consultations from one institution were recorded and transcribed verbatim. A codebook was developed and used to code the transcripts. Codes included any reference to the fetus and any attribution of agency or mental states to the fetus. Results: Nineteen consultations performed by five clinicians from one academic institution were included. Clinicians and families most frequently referred to the fetus using personal terminology (e.g., third-person pronouns, a given name, or “son” or “daughter”). Impersonal terminology (e.g., “baby”) was used less frequently, followed by medical terminology (e.g., “fetus”), which was only used in two consultations. In about half of the consultations, clinicians conferred agency or mental states on the fetus by attributing actions, emotions, or knowledge to the fetus. Conclusions: Fetal cardiology clinicians primarily use personal terminology when referring to the fetus during initial consultations. Familial preferences need to be evaluated to optimize communication and support. Full article

During pregnancy, physiological adaptations occur in the respiratory and cardiovascular systems to support the increased metabolic needs of both mother and fetus. Key respiratory changes include mechanical adjustments of the chest wall and diaphragm to accommodate the growing uterus; decreases in functional residual capacity and its components—expiratory reserve volume and residual volume—with minimal or no change in total lung capacity; and an increase in minute ventilation. Major cardiovascular adaptations involve elevated cardiac output, stroke volume and heart rate, and decreased mean arterial pressure and systemic vascular resistance. During exercise in pregnancy, there is an increase in ventilation, alveolar diffusion, elevated oxygen consumption, greater carbon dioxide production and changes in respiratory volumes and capacities, as well as increases in cardiac output, stroke volume and heart rate. Understanding these normal physiological changes during pregnancy and exercise in pregnancy is essential for healthcare providers to develop and adapt exercise programs according to the gestational age and physical fitness level of the pregnant woman. Full article

(1) Background: Gestational diabetes mellitus (GDM) is a glucose metabolism disorder that typically develops in the second half of pregnancy, transforming a normal pregnancy into a high-risk condition, with both short- and long-term complications for the mother and the fetus. Achieving optimal glycaemic control during pregnancy is essential for preventing these outcomes and could be realized using continuous glucose monitoring systems (CGMSs). This systematic review aims to evaluate the role of the CGMS as a potential diagnostic aid and predictor of maternal and fetal outcomes in GDM. (2) Methods: Following the PRISMA guidelines (protocol ID: CRD42024559169), we performed a literature search using the terms “(continuous glucose monitoring system OR CGMS) AND (gestational diabetes mellitus OR GDM)” in the PubMed, Web of Science, and Scopus databases. (3) Results: Twelve studies were included, all reporting data on CGMS use in pregnancies complicated by GDM. The data included in our analysis are heterogeneous, the results suggesting that the CGMS may offer several advantages such as improved glycaemic control (by avoiding hyper- and hypoglycaemia), better gestational weight management, timely initiation of pharmacologic treatment, lower rates of preeclampsia, and improved neonatal outcomes. (4) Conclusions: the CGMS offers a more detailed assessment of both maternal and fetal exposure to high glucose levels, which could lead to earlier detection of those at risk for GDM complications and better guide treatment regimens, especially timely pharmacological intervention. While the current data are heterogeneous, reporting both limited or no benefits and superior benefits compared to the classic monitoring, larger longitudinal studies are mandatory to validate these findings and to better refine the role of CGMS in the monitoring and management of GDM. Full article

Alcohol consumption during pregnancy and lactation remains a significant global issue. Preventive policies have proven insufficient, and consumption rates remain high, mainly due to a lack of awareness, the misconception that only high alcohol intake harms the fetus, inconsistent medical advice, and pre-existing alcohol use disorders. Alcohol consumption is linked to child harm during critical stages of development. Using a recently published model of fetal alcohol spectrum disorder (FASD) developed by our group, we analyzed brain changes in mothers who consumed alcohol during pregnancy and lactation and the behavioral consequences at the emotional-cognitive level and in caring for their offspring. We also considered the previous drinking history, using the paradigm of voluntary pre-gestational alcohol consumption. In addition, from gestational day 7 (GD7) until the day of sacrifice, mothers received a 3 g/kg dose of alcohol every 12 h via gavage. Our findings revealed deficiencies in maternal care, anxiety and depressive-like behavior, and aversive stimulus learning disturbances. These were associated with changes in gene targets linked to stress-axis regulation, reward circuits, and neuroplasticity. Additionally, we observed increased microgliosis and astrogliosis, indicating neuroinflammation in brain regions involved in cognition and emotional states’ regulation. Full article

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age. Full article

Toxoplasma gondii is responsible for the disease toxoplasmosis and has the broadest host range among apicomplexan parasites, as it infects virtually all warm-blooded vertebrates. Toxoplasmosis is a zoonotic and emerging public health concern with considerable morbidity and mortality, especially in the developing world, affecting approximately one-third of the world’s human population. Clinical presentation varies among species, and the infection establishes lifelong chronicity in hosts. Most of the host species (including healthy humans) are asymptomatic on the one hand, it is fatal to marsupials, neotropical primates and some marine mammals on the other hand. In immunocompetent humans, infection is typically asymptomatic, whereas immunocompromised individuals may develop disseminated disease affecting virtually any organ system—most commonly reproductive, cerebral, and ocular systems. Toxoplasmosis spreads by ingestion of food or water contaminated with T. gondii oocysts, consumption of undercooked/raw meat containing tissue cysts, transplacental transmission from mother to fetus, or by receiving infected organ/blood from the infected individual. Toxoplasmosis is mainly diagnosed by serologic tests and polymerase chain reaction (PCR). It is treated with pyrimethamine combined with sulfadiazine or clindamycin, often supplemented with leucovorin, atovaquone, and dexamethasone. Despite having many potent anti-T. gondii antigenic candidates, there is no commercially available vaccine for humans due to many factors, including the complex life cycle of the parasite and its evasion strategies. To date, the only commercially available anti-T. gondii vaccine is for sheep, licensed for veterinary use to prevent ovine abortions. In this review, we have summarized the current understanding of toxoplasmosis. Full article

Background: Epigenetic mechanisms and RNA signalling profoundly impact body growth during the early stages of embryonic development. RNA molecules, like microRNAs, play a vital role in early embryonic development, laying the groundwork for future growth and function. miR-124-3p microinjected into mouse fertilised eggs (miR-124-3p*) exhibited a significantly overgrowth phenotype. Behavioural test results showed that miR-124-3p mice were more physically active, as indicated by total distance and movement velocity. However, the molecular mechanism leading to these phenotypic changes mediated by miR-124-3p remains a mystery. This study aimed to investigate the role of epidermal growth factor (EGF) in developing an overgrowth phenotype in miR-124-3p* mice. Results: In this research, we preferred to work with neurospheres (NSs) due to the challenges of handling a single embryo, as NSs exhibit similar features, especially regarding cell growth, differentiation, and capacity for self-renewal. We examined the mRNA expression levels of Sox8, Sox9, Sox10, Doublecortin (Dcx), and Neurod1 genes, which are linked to a tiny phenotype in knockout mice, in total embryos at E7.5 and hippocampal cells isolated from E19.5-day fetus and neurospheres aged 12 and 21 days, which were derived from these hippocampal cells through primary cell culture. These genes are significantly overexpressed in miR-124-3p* NSs, but not in the E7.5 total embryos or the hippocampus of the E19.5 fetus. Conclusions: These findings suggest a possible link between miR-124-3p microinjection and EGF activation, which may be associated with early neurogenesis and neuronal differentiation in embryos. This molecular shift might contribute to the development of mice exhibiting increased physical activity and enlarged body size, although these observations remain correlative and require further validation. Full article

Maternal health has a profound impact on fetal development, influencing the risk of pediatric endocrine disorders both directly and indirectly through various biological and environmental mechanisms. Throughout pregnancy, several endocrine disorders can arise or be exacerbated due to the physiological changes that occur. An in-depth review of articles with evidence-based research discussing the significant effects of maternal endocrinopathies and endocrine disruptors on fetal development and infant health was conducted in this review paper. The most common endocrine disorder during pregnancy is gestational diabetes mellitus, which has an incidence rate of 2–16%, depending on ethnic origin. Maternal diabetes, apart from macrosomia and hypoglycemia, increases the risk for several pregnancy and neonatal complications such as stillbirth, perinatal mortality, and congenital malformations. Other endocrine issues occurring in pregnancy include alterations in thyroid hormone levels, obesity-related insulin resistance, Cushing syndrome, or polycystic ovarian syndrome, which all may negatively influence the fetus, as well as offspring development. Additionally, environmental exposure to harmful substances during pregnancy can disrupt endocrine function. Bisphenol A is the most common endocrine disruptor, which is particularly detrimental during gestation. Bisphenol A exposure is related to low birth weight, preterm birth, or developmental delays. Also, its exposition could be associated with an increased risk of obesity, metabolic disorders, and certain cancers later in life. Endocrinopathies and exposure to endocrine disruptors during pregnancy represent a challenging problem, being widespread and demanding appropriate management to reduce fetal and newborn complications. Full article

Introduction: Gestational diabetes mellitus (GDM) is a form of hyperglycemia that develops during pregnancy and poses risks to both the mother and fetus. In other words, it is a glucose intolerance disorder first recognized during pregnancy, specifically in the second and third trimesters, with approximately 7–14% of pregnancies worldwide being affected. Methodology: A systematic literature search was conducted across three major well-established databases; PubMed, Scopus, and ScienceDirect. The search was conducted with the aim of identifying the most suitable studies for the evaluation of fetal cardiac function using Doppler ultrasound techniques in pregnancies affected by GDM. Results: Following a comprehensive full-text assessment, 186 papers were excluded, mainly due to discrepancies in the population, unsuitable study design, publishing type, or unavailability of full-text access. Ultimately, 12 studies met all the inclusion criteria and were incorporated into the scoping review. From the studies included it was found that the conventional pulsed-wave Doppler was the most frequently used modality, assessing parameters such as the E/A ratios, myocardial performance index (MPI), and the isovolumic relaxation time (IVRT). The advanced techniques of choice included tissue Doppler imaging (TDI), speckle-tracking echocardiography (STE), dual-gate Doppler, and automated MPI. Conclusions: Doppler ultrasound techniques, particularly the advanced modalities like TDI and STE, provide valuable insights into fetal cardiac function in GDM pregnancies. Their integration into routine prenatal surveillance may enhance the early detection of cardiac dysfunction and inform timely clinical interventions. Full article

The maturation of brain regions involved in emotion regulation—particularly the amygdala and prefrontal cortex—from fetal life to age two is a dynamic process shaped by genetic and environmental factors. Early experiences, especially responsive caregiving, promote the growth of neural circuits supporting emotional expression and regulation. In contrast, early adversity such as neglect or chronic stress may disrupt these circuits and increase vulnerability to emotional difficulties. Elevated levels of placental CRH are linked to alterations in fetal brain development related to emotion. Neurodevelopmental processes like synaptic pruning and myelination, active during the first years, further shape emotional circuitry. These findings underscore the importance of early caregiving and timely interventions in fostering healthy emotional development. The present article proposes an integrative conceptual framework for early emotional and cognitive development, combining neurobiological models with contemporary theories in developmental psychology. Full article

IgG Fc binding protein (FcGBP) is a mucin-like protein that binds strongly to IgG and IgG–antigen complexes in intestinal mucus. FcGBP presence and its altered expression levels in meconium accumulating in the fetal intestine and amniotic fluid flowing in the intestine may provide new knowledge of the mechanisms responsible for the immune adaptation of the fetus to extrauterine life. FcGBP concentrations were measured by ELISA in the first-pass meconium and amniotic fluid samples collected from 120 healthy neonates delivered by either vaginal birth (n = 35) or cesarean section (n = 85) at 36 to 41 weeks gestation. The meconium FcGBP concentrations (405.78 ± 145.22 ng/g) decreased (r = −0.241, p = 0.007) over the course of 36 to 41 weeks gestation, but there were no significant changes (p > 0.05) in the amniotic fluid FcGBP (135.70 ± 35.83 ng/mL) in the same period. Both meconium and amniotic fluid FcGBP concentrations were higher (p < 0.05) in neonates delivered by cesarean section. Decreases in the meconium FcGBP concentrations correlated (r = −0.37, p = 0.027) with the gestational age in neonates delivered by vaginal birth but not in those delivered by cesarean section (p > 0.05). No association was found between the FcGBP concentrations in meconium and amniotic fluid and the birth weight (p > 0.05). With the development of the mucosal immune system in the fetal intestine over the course of the third trimester of gestation, the meconium FcGBP concentrations decrease. Increased FcGBP concentrations measured in the meconium and amniotic fluid of neonates delivered by cesarean section may possibly indicate altered intestinal mucosal function. Intrauterine growth is not associated with the intestinal mucosal barrier maturation involving FcGBP. Full article