Fetal Stages Research Articles

Single-cell transcriptomic and cross-species comparison analyses reveal distinct molecular changes of porcine testes during puberty

The pig is an important model for studying human diseases and is also a significant livestock species, yet its testicular development remains underexplored. Here, we employ single-cell RNA sequencing to characterize the transcriptomic landscapes across multiple developmental stages of Bama pig testes from fetal stage through infancy, puberty to adulthood, and made comparisons with those of humans and mice. We reveal an exceptionally early onset of porcine meiosis shortly after birth, and identify a distinct subtype of porcine spermatogonia resembling transcriptome state 0 spermatogonial stem cells identified in humans, which were previously thought to be primate specific. We also discover the persistent presence of proliferating progenitors for myoid cells in postnatal testes. The regulatory roles of Leydig cell steroidogenesis and estrogen synthesis in supporting cell lineages are also explored, including the potential impact of estrogen on Sertoli cell maturation and spermatogenesis. Overall, this study offers valuable insights into porcine testicular development, paving the way for future research in reproductive biology, advancements in agricultural breeding, and potential applications in translational medicine.

The role of polyreactive memory B cells in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), the production of autoantibodies is a crucial characteristic, and B cells play a significant role in its pathogenesis. B cells are the immune cells most associated with the genetic predispositions of SLE, and recent clinical studies showing that anti-CD19 CAR-T cell therapy induces drug-free remission have underscored the importance of B cells in SLE. Meanwhile, various B cell subsets exist across different stages of differentiation, from naive B cells to plasma-cells, and identifying the important subpopulations within SLE remains a critical future challenge. Years of B cell repertoire analyses have revealed the importance of polyreactive B cell receptors (BCRs) and autoantibodies that react to a various self-antigens and microbial antigens. Particularly, memory B cells with polyreactive BCRs, which play a crucial role in biological defense during the fetal stage, are characteristically differentiated in SLE. Type I interferon-mediated expression of CXCL13 and IL21 in CD4+ T cells is associated with the development of polyreactive memory B cells. The expansion of the polyreactive B cell repertoire, vital for defending against infections such as viruses, may exert an intrinsic function in SLE.

Evaluating Maternal Risk Factors Impacting Fetal Intima-Media Thickness of the Abdominal Aorta Measured at 28 Weeks of Gestation.

Background and Objectives: Cardiovascular disease risk can exist in utero, influenced by maternal health factors. This study evaluates maternal characteristics and biochemical markers that correlate with the fetal intima-media thickness (IMT), aiming to identify interventions that could minimize prenatal influences on later cardiovascular disease. Methods: In this observational study approved by the Institutional Review Board at The Obstetrics and Gynecology Clinic of the Timisoara Municipal Emergency Hospital, we recruited pregnant women aged 15-40 years, divided into groups based on their lipid profiles and gestational diabetes risk. The data collection had, as its main focus, ultrasound measurements, along with demographic, clinical, and biochemical parameters. The IMT of the fetal abdominal aorta was measured at 28 weeks of gestation. Results: Notable differences were observed in the TNF-alpha levels (8.66 ± 3.87 pg/mL vs. 4.96 ± 3.37 pg/mL), hsCRP levels (0.94 ± 0.46 mg/L vs. 0.60 ± 0.52 mg/L), and the area under the curve (AUC) for hsCRP at 0.738 with a sensitivity of 84.41% and specificity of 79.01%. Compound score 2, integrating inflammatory markers and lipid profiles, exhibited a good diagnostic accuracy (AUC = 0.789) with a sensitivity of 86.35% and specificity of 81.42%. A regression analysis indicated strong associations of TNF-alpha and hsCRP with an increased fetal IMT, suggesting potential early markers of cardiovascular risk, presenting hazard ratios (HRs) of 2.21 (95% CI: 1.15-5.28) and 2.87 (95% CI: 1.11-4.23), respectively, both with p-values of less than 0.0001. Compound score 2 further indicated an increased risk (HR = 4.27; 95% CI: 1.19-8.32). Conclusions: Statistically significant correlations were found between an increased fetal IMT and elevated maternal inflammatory markers (TNF-alpha and hsCRP), suggesting that these could serve as early indicators of cardiovascular risk. This study supports the potential for targeted prenatal interventions to reduce cardiovascular risk factors from the fetal stage, emphasizing the importance of monitoring inflammatory markers in pregnant women at risk.

Effects of multiple stress events at different stages of life on the incidence of metabolic syndrome.

To investigate the effects of multiple stress events in different stages of life on the incidence of metabolic syndrome (MetS). Miners from Tangshan, China, were recruited for this study. Workers of the Kailuan Mining Group were evaluated to investigate whether exposure to Tangshan earthquakes during the fetal period in 1976. Adult life events and childhood trauma were assessed separately via the Life Event Scale and Childhood Trauma Questionnaire. The subjects were physically examined and general demographic data such as waist circumference were collected. Blood samples were collected for measurement of metabolic parameters. Corticotropin releasing hormone(CRH) levels was measured by enzyme-linked immunosorbent assay (ELISA). The subjects were divided into four groups according to their exposure to traumatic events in different stages of life: no exposure group, 1-exposure group, 2-exposures group, and 3-exposures group. The incidence of MetS, metabolic parameters and CRH levels in each of the four groups was compared. In all, 626 people were enrolled; of these, 183, 262, 150, and 31 were in the no exposure, 1-exposure, 2-exposures, and 3-exposure groups, respectively. A remarkable variation in the incidence of MetS was observed among the four groups (x2 = 16.462, P<0.001). MetS incidence increased with the increasing number of traumatic events, except for in the no exposure group (17.9% in 1-exposure group, 24.7% in 2-exposure group, and 48.4% in the 3-exposure group). Multivariate logistic regression analysis showed that exposure to multiple stress during the fetal, childhood, and adult stages of life represent independent risk factors for developing MetS (OR=3.134, 95%CI=1.042-9.429). Smoking increased the risk of developing MetS (OR=1.809, 95%CI=1.140-2.871). Exposure to multiple traumatic events in distinct life stages increases the risk of developing MetS. Smoking is a risk factor for developing MetS.

The Study of Dermatoglyphic Patterns in Females with Primary Infertility: A Case-Control Study in the Maharashtra Population

Introduction: Dermatoglyphics is a widely known technique applied in genetic and medical research for the examination of finger, palm, and sole patterns. Dermatoglyphic characters are formed in the fetal stage and remain unaltered throughout their life. Some previous studies have indicated that dermatoglyphic patterns are linked with some reproductive disorders, like primary infertility. This study focuses on the evaluation and comparison of the dermatoglyphic patterns of females with primary infertility and healthy controls in the Maharashtra population. Methods: It involves a case-control study on two hundred females diagnosed with primary infertility and two hundred age-matched healthy controls. Several dermatoglyphic patterns were found, including total ridge count (TRC), atd angles, loops, whorls, and arches, which were assessed and compared among the groups. Results: When compared to the control group, the dermatoglyphic patterns of the infertility group were significantly different. Whorls and arches were more common in this group, and loops were less common. Furthermore, the infertility group exhibited a higher mean atd angle value and a lower total ridge count in comparison to the control group. Conclusion: Certain dermatoglyphic features correlated with female primary infertility in Maharashtra have been identified. These results can be taken as a precursor to further research work on the genetic basis of infertility and also with regard to whether dermatoglyphics can be used as a diagnostic tool.

12246 The Stage-Dependent Transcriptome And Methylome Reveal Significance Of The Neonatal Period In Postnatal Metabolic Maturation Of The Mouse Liver

Abstract Disclosure: S. Yano: None. N. Sato: None. H. Araki: None. F. Miura: None. T. Ito: None. Y. Ogawa: None. The mammalian liver serves as an extramedullary hematopoietic organ during the fetus and matures into a metabolic organ after birth, adapting to changes in the nutritional environment. DNA demethylation upregulates fatty acid β-oxidation (FAO) genes in the postnatal mouse liver to produce energy from breast milk lipids. However, the detailed interactions between DNA methylation (DNAme) and gene expression through the perinatal stages remain poorly understood. Here, we perform an integrative analysis of the transcriptome and methylome of the mouse liver at the fetal, neonatal, and postweaning stages. We found a drastic loss of DNAme at the neonatal stage in specific regions associated with metabolic pathways such as FAO and gluconeogenesis in concordance with the activation of metabolic processes. Moreover, in silico analysis predicted transcription factors including HNF4α, PPARα, and NR1H2 as key epigenetic regulators within the neonatal period. We also observed an inactivation of erythrocyte development with a concordant gain of DNAme. This analysis extends the epigenetic landscape of postnatal hepatic maturation, suggesting the importance of the nutritional environment during the neonatal period for epigenetic regulation. Presentation: 6/3/2024

CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia

The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy. Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling. Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities. CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD.

29P Temporal requirement of dystroglycan glycosylation during brain development and rescue of cortical dysplasia via gene delivery in the fetal stage

29P Temporal requirement of dystroglycan glycosylation during brain development and rescue of cortical dysplasia via gene delivery in the fetal stage

Impact of health education on stunting knowledge among mothers with children aged 1-5 years

Background: Stunting remains an unresolved nutritional issue, particularly affecting the first 1,000 days of life, from the fetal stage to 23 months of age. This condition can negatively impact a child's intelligence and overall health. According to the World Health Organization (WHO), stunting becomes a public health concern when its prevalence exceeds 20%. Parents, especially mothers, play a crucial role in ensuring adequate nutrition for their children. Purpose: To find out the effect of health education on stunting knowledge among mothers with children aged 1-5 years. Method: A pre-experimental "one group pretest-posttest" design was employed. The sample consisted of 35 mothers with children aged 1 to 60 months, selected using the non-probability sampling technique through total sampling. Results: Before the health education intervention, 40.0% of mothers had moderate knowledge about stunting. After the intervention, this figure increased to 60.0%, indicating a good level of understanding. A paired simple t-test showed a statistically significant improvement with a p-value of 0.000 (&lt;0.05). Conclusion: Health education has a positive impact on increasing mothers' knowledge about stunting in Sumberwungu village, Tepus sub-district, Gunung Kidul regency. It is recommended that health workers enhance their efforts to educate the community on stunting prevention.

Gray matter based spatial statistics framework in the 1-month brain: insights into gray matter microstructure in infancy.

The neurodevelopmental epoch from fetal stages to early life embodies a critical window of peak growth and plasticity in which differences believed to be associated with many neurodevelopmental and psychiatric disorders first emerge. Obtaining a detailed understanding of the developmental trajectories of the cortical gray matter microstructure is necessary to characterize differential patterns of neurodevelopment that may subserve future intellectual, behavioral, and psychiatric challenges. The neurite orientation dispersion density imaging (NODDI) Gray-Matter Based Spatial Statistics (GBSS) framework leverages information from the NODDI model to enable sensitive characterization of the gray matter microstructure while limiting partial volume contamination and misregistration errors between images collected in different spaces. However, limited contrast of the underdeveloped brain poses challenges for implementing this framework with infant diffusion MRI (dMRI) data. In this work, we aim to examine the development of cortical microstructure in infants. We utilize the NODDI GBSS framework and propose refinements to the original framework that aim to improve the delineation and characterization of gray matter in the infant brain. Taking this approach, we cross-sectionally investigate age relationships in the developing gray matter microstructural organization in infants within the first month of life and reveal widespread relationships with the gray matter architecture.

Proteomics reveals dynamic metabolic changes in human hematopoietic stem progenitor cells from fetal to adulthood

BackgroundHematopoietic stem progenitor cells (HSPCs) undergo phenotypical and functional changes during their emergence and development. Although the molecular programs governing the development of human hematopoietic stem cells (HSCs) have been investigated broadly, the relationships between dynamic metabolic alterations and their functions remain poorly characterized.MethodsIn this study, we comprehensively described the proteomics of HSPCs in the human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM). The metabolic state of human HSPCs was assessed via a Seahorse assay, RT‒PCR, and flow cytometry-based metabolic-related analysis. To investigate whether perturbing glutathione metabolism affects reactive oxygen species (ROS) production, the metabolic state, and the expansion of human HSPCs, HSPCs were treated with buthionine sulfoximine (BSO), an inhibitor of glutathione synthetase, and N-acetyl-L-cysteine (NAC).ResultsWe investigated the metabolomic landscape of human HSPCs from the fetal, perinatal, and adult developmental stages by in-depth quantitative proteomics and predicted a metabolic switch from the oxidative state to the glycolytic state during human HSPC development. Seahorse assays, mitochondrial activity, ROS level, glucose uptake, and protein synthesis rate analysis supported our findings. In addition, immune-related pathways and antigen presentation were upregulated in UCB or aBM HSPCs, indicating their functional maturation upon development. Glutathione-related metabolic perturbations resulted in distinct responses in human HSPCs and progenitors. Furthermore, the molecular and immunophenotypic differences between human HSPCs at different developmental stages were revealed at the protein level for the first time.ConclusionThe metabolic landscape of human HSPCs at three developmental stages (FL, UCB, and aBM), combined with proteomics and functional validations, substantially extends our understanding of HSC metabolic regulation. These findings provide valuable resources for understanding human HSC function and development during fetal and adult life.

Early-life famine exposure and risk of osteoporosis and low bone mineral density: a systematic review and meta-analysis.

Early-life exposure to famine has been hypothesized to influence long-term bone health, potentially increasing the risk of osteoporosis and fractures in later life. This systematic review and meta-analysis aimed to investigate the association between early-life famine exposure and the risk of osteoporosis, bone mineral density (BMD) loss, and fractures. A comprehensive literature search was conducted across MEDLINE/PubMed, Scopus, Web of Science, and Embase, supplemented by manual searches on Google Scholar. Observational studies examining the impact of early-life famine exposure on osteoporosis, BMD, and fracture risk were included. Data were extracted and quality assessed independently by two reviewers, and meta-analyses were performed using the Mantel-Haenszel method for odds ratios (OR) and Hedges' g for standardized mean differences (SMD). Heterogeneity was assessed using the I2 statistic, and meta-regression analyses were conducted to explore potential sources of heterogeneity. From 6147 initial studies, 10 met the inclusion criteria, with 8 included in the meta-analysis. The early-life famine-exposed group showed a significantly higher incidence of osteoporosis (OR = 2.12, 95%CI [1.35, 3.34], I2 = 88%) and fractures (OR = 1.58, 95%CI [1.07, 2.33], I2 = 92%) compared to non-exposed individuals. Meta-regression indicated that higher female prevalence in studies made the association with osteoporosis stronger, while higher ages strengthened the association with fractures. Exposure during fetal and childhood stages was particularly associated with increased risks of osteoporosis and fractures. Additionally, famine exposure correlated with lower BMD, particularly in the heels, femoral neck, and total hip regions. Early-life famine exposure is significantly associated with an increased risk of osteoporosis, fractures, and lower BMD in later life. These results emphasize the lasting effects on bones from early lack of nutrition and stress the importance of specific interventions for bone health in groups with past famine experiences. Future studies should investigate the reasons behind these connections and assess preventative approaches to reduce the negative effects on bone health in those impacted.

Single-cell sequencing of the vermiform appendix during development identifies transcriptional relationships with appendicitis in preschool children

BackgroundThe development of the human vermiform appendix at the cellular level, as well as its function, is not well understood. Appendicitis in preschool children, although uncommon, is associated with a high perforation rate and increased morbidity.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on the human appendix during fetal and pediatric stages as well as preschool-age inflammatory appendices. Transcriptional features of each cell compartment were discussed in the developing appendix. Cellular interactions and differentiation trajectories were also investigated. We compared scRNA-seq profiles from preschool appendicitis to those of matched healthy controls to reveal disease-associated changes. Bulk transcriptomic data, immunohistochemistry, and real-time quantitative PCR were used to validate the findings.ResultsOur analysis identified 76 cell types in total and described the cellular atlas of the developing appendix. We discovered the potential role of the BMP signaling pathway in appendiceal epithelium development and identified HOXC8 and PITX2 as the specific regulons of appendix goblet cells. Higher pericyte coverage, endothelial angiogenesis, and goblet mucus scores together with lower epithelial and endothelial tight junction scores were found in the preschool appendix, which possibly contribute to the clinical features of preschool appendicitis. Preschool appendicitis scRNA-seq profiles revealed that the interleukin-17 signaling pathway may participate in the inflammation process.ConclusionsOur study provides new insights into the development of the appendix and deepens the understanding of appendicitis in preschool children.Graphical

Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids

The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with invivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

Embryonic and Fetal Mortality in Dairy Cows: Incidence, Relevance, and Diagnosis Approach in Field Conditions

Pregnancy loss (PL) in dairy cattle results in animal health and welfare disruption and has a great economic impact on farms, with decreases in fertility and increased culling. It can occur at any stage of embryonic or fetal development. Abortion occurring from the second half of pregnancy has a more negative impact on dairy farms. There are several infectious and non-infectious factors that can lead to PL and vary according embryonic or fetal stages. As this is a multifactorial or multi-etiological occurrence, it is important to identify the risk factors and the best diagnostic tools to approach these reproductive losses that can occur sporadically or by outbreaks. Reaching a final diagnosis can be challenging, especially when it occurs at a very early stage of pregnancy, where losses may not be detected and neonatal deaths may be related to alterations in the fetus in utero. Also, laboratorial results from animal samples should be interpreted according to the full clinical approach. This review aimed to highlight all these essential aspects, identifying the main infectious and non-infectious causes leading to PL, as well as the best veterinary practices for diagnosing it, mainly through transrectal palpation, ultrasound, and laboratory methods, in bovine dairy farms.

Detailed delineation of the fetal brain in diffusion MRI via multi-task learning.

Diffusion-weighted MRI is increasingly used to study the normal and abnormal development of fetal brain inutero. Recent studies have shown that dMRI can offer invaluable insights into the neurodevelopmental processes in the fetal stage. However, because of the low data quality and rapid brain development, reliable analysis of fetal dMRI data requires dedicated computational methods that are currently unavailable. The lack of automated methods for fast, accurate, and reproducible data analysis has seriously limited our ability to tap the potential of fetal brain dMRI for medical and scientific applications. In this work, we developed and validated a unified computational framework to (1) segment the brain tissue into white matter, cortical/subcortical gray matter, and cerebrospinal fluid, (2) segment 31 distinct white matter tracts, and (3) parcellate the brain's cortex and delineate the deep gray nuclei and white matter structures into 96 anatomically meaningful regions. We utilized a set of manual, semi-automatic, and automatic approaches to annotate 97 fetal brains. Using these labels, we developed and validated a multi-task deep learning method to perform the three computations. Our evaluations show that the new method can accurately carry out all three tasks, achieving a mean Dice similarity coefficient of 0.865 on tissue segmentation, 0.825 on white matter tract segmentation, and 0.819 on parcellation. The proposed method can greatly advance the field of fetal neuroimaging as it can lead to substantial improvements in fetal brain tractography, tract-specific analysis, and structural connectivity assessment.

Early-life malnutrition exposure associated with higher osteoporosis risk in adulthood: a large-scale cross-sectional study.

Evidence on the association between early-life malnutrition exposure at different developmental stages and the subsequent risk of osteoporosis and fractures in adulthood remains sparse and equivocal. This study sought to elucidate the relationship between malnutrition exposure in early life and the occurrence of osteoporosis and fractures later in life. This research is a cross-sectional analysis carried out within the framework of the China Community-based Cohort of Osteoporosis (CCCO), an ongoing community-based cohort study. Participants were stratified by birthdate into several categories: non-exposed, fetal, early childhood, mid-childhood, late childhood, and adolescence exposure groups. The non-exposure and adolescence exposure groups were consolidated into an "age-matched group" to provide a robust comparative framework for analyzing the probability of developing osteoporosis (defined as a T-score ≤ -2.5 in bone mineral density) and the frequency of self-reported fracture. Multiple logistic regression models were utilized to investigate the association between early-life malnutrition exposure and the risks of osteoporosis and fracture. Additionally, we validated our findings using the China Northwest Cohort (CNC). A total of 12,789 participants were included into the final analysis. After adjusting for various covariates, individuals exposed to malnutrition during their fetal and childhood stages (early, middle, and late) increased the likelihood of developing osteoporosis in adulthood, compared to their age-matched counterparts. In these four groups, the ORs (95% CI) for osteoporosis risk were 1.223 (1.035 to 1.445), 1.208 (1.052 to 1.386), 1.249 (1.097 to 1.421), and 1.101 (1.001 to 1.210), respectively (all P values < 0.05). Specifically, the late childhood exposure group showed a heightened risk of fracture, with an OR (95% CI) of 1.155 (1.033 to 1.291) and a P-value of 0.01127. Stratified analyses further found a significant correlation between early-life exposure to malnutrition and an elevated risk of osteoporosis in participants with lower educational attainment, overweight or obese participants. Additionally, corroborating evidence from the CNC confirmed the influence of malnutrition exposure on osteoporosis risk. Early-life exposure to malnutrition had a detrimental impact on bone health. Individuals who had experienced malnutrition during fetal and childhood stages (early, middle, and late) exhibited a high susceptibility to osteoporosis in adulthood, compared to age-matched cohorts. This susceptibility was particularly pronounced in women, and individuals who were overweight or obese, or had lower levels of education.

Developmental Changes in the Excitation-Contraction Mechanisms of the Ventricular Myocardium and Their Sympathetic Regulation in Small Experimental Animals.

The developmental changes in the excitation-contraction mechanisms of the ventricular myocardium of small animals (guinea pig, rat, mouse) and their sympathetic regulation will be summarized. The action potential duration monotonically decreases during pre- and postnatal development in the rat and mouse, while in the guinea pig it decreases during the fetal stage but turns into an increase just before birth. Such changes can be attributed to changes in the repolarizing potassium currents. The T-tubule and the sarcoplasmic reticulum are scarcely present in the fetal cardiomyocyte, but increase during postnatal development. This causes a developmental shift in the Ca2+ handling from a sarcolemma-dependent mechanism to a sarcoplasmic reticulum-dependent mechanism. The sensitivity for beta-adrenoceptor-mediated positive inotropy decreases during early postnatal development, which parallels the increase in sympathetic nerve innervation. The alpha-adrenoceptor-mediated inotropy in the mouse changes from positive in the neonate to negative in the adult. This can be explained by the change in the excitation-contraction mechanism mentioned above. The shortening of the action potential duration enhances trans-sarcolemmal Ca2+ extrusion by the Na+-Ca2+ exchanger. The sarcoplasmic reticulum-dependent mechanism of contraction in the adult allows Na+-Ca2+ exchanger activity to cause negative inotropy, a mechanism not observed in neonatal myocardium. Such developmental studies would provide clues towards a more comprehensive understanding of cardiac function.

Non-immune hydrops fetalis is associated with bi-allelic pathogenic variants in the MYB Binding Protein 1a (MYBBP1A) gene.

Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.

Transplacental delivery of factor IX Fc-fusion protein ameliorates bleeding phenotype of newborn hemophilia B mice

Hemophilia B is an inherited hemorrhagic disorder characterized by a deficiency of blood coagulation factor IX (FIX) that results in abnormal blood coagulation. The blood coagulation is already evident in hemophiliacs at the fetal stage, and thus intracranial hemorrhage and other bleeding complications can occur at birth, leading to sequelae. Therefore, it is important to develop effective treatments for hemophiliacs in utero. In this study, in order to transplacentally deliver FIX from pregnant mice to their fetuses, an improved adenovirus (Ad) vector expressing human FIX fused with the IgG Fc domain (FIX Fc fusion protein), which plays a crucial role in neonatal Fc receptor (FcRn)-mediated transcytosis across the placenta, was intravenously administered to E13.5 pregnant mice. Significant levels of FIX Fc fusion protein were detected in 0-day-old newborn mice whose mothers were administered an Ad vector expressing FIX Fc fusion protein. Wild-type FIX overexpressed in the pregnant mice was not delivered to the fetuses. Plasma FIX levels in the newborn mice were relatively well correlated with those in their mothers, although transplacental delivery efficiencies of FIX Fc fusion protein were slightly reduced when the FIX Fc fusion protein was highly expressed in the mother mice. Plasma FIX levels in the newborn mice were about 3.6–6.4% of those in their mothers, Transplacental delivery of FIX Fc fusion protein to their fetuses successfully improved the blood clotting ability in the newborn mice.