Fetal Stages Research Articles

Shaping oral and intestinal microbiota and the immune system during the first 1,000 days of life.

The first 1, 000 days of life, from the fetal stage of a woman's pregnancy to 2 years of age after the baby is born, is a critical period for microbial colonization of the body and development of the immune system. The immune system and microbiota exhibit great plasticity at this stage and play a crucial role in subsequent development and future health. Two-way communication and interaction between immune system and microbiota is helpful to maintain human microecological balance and immune homeostasis. Currently, there is a growing interest in the important role of the microbiota in the newborn, and it is believed that the absence or dysbiosis of human commensal microbiota early in life can have lasting health consequences. Thus, this paper summarizes research advances in the establishment of the oral and intestinal microbiome and immune system in early life, emphasizing the substantial impact of microbiota diversity in the prenatal and early postnatal periods, and summarizes that maternal microbes, mode of delivery, feeding practices, antibiotics, probiotics, and the environment shape the oral and intestinal microbiota of infants in the first 1, 000 days of life and their association with the immune system.

Human epicardial organoids from pluripotent stem cells resemble fetal stage with potential cardiomyocyte- transdifferentiation

Epicardium, the most outer mesothelium, exerts crucial functions in fetal heart development and adult heart regeneration. Here we use a three-step manipulation of WNT signalling entwined with BMP and RA signalling for generating a self-organized epicardial organoid that highly express with epicardium makers WT1 and TCF21 from human embryonic stem cells. After 8-days treatment of TGF-beta following by bFGF, cells enter into epithelium-mesenchymal transition and give rise to smooth muscle cells. Epicardium could also integrate and invade into mouse heart with SNAI1 expression, and give birth to numerous cardiomyocyte-like cells. Single-cell RNA seq unveils the heterogeneity and multipotency exhibited by epicardium-derived-cells and fetal-like epicardium. Meanwhile, extracellular matrix and growth factors secreted by epicardial organoid mimics the ecology of subepicardial space between the epicardium and cardiomyocytes. As such, this epicardial organoid offers a unique ground for investigating and exploring the potential of epicardium in heart development and regeneration.

Maternal asthma imprints fetal lung ILC2s via glucocorticoid signaling leading to worsened allergic airway inflammation in murine adult offspring

The root of asthma can be linked to early life, with prenatal environments influencing risk. We investigate the effects of maternal asthma on the offspring’s lungs during fetal and adult life. Adult offspring of asthmatic mothers show an increase in lung group 2 innate lymphoid cell (ILC2) number and function with allergen-induced lung inflammation. Offspring of asthmatic mothers show phenotypic alteration of their lung ILC2s during fetal life, with increased expression of genes related to activation and glucocorticoid signaling. Furthermore, these offspring carry overlapping chromatin-accessible altered regions, including glucocorticoid receptor-binding regions in their lung ILC2s both at the fetal stage and adulthood, suggesting persistent prenatal epigenetic changes. Moreover, maternal exposure to glucocorticoids has similar effects on fetal lung ILC2s and contributes to allergen-induced lung inflammation during adulthood. Thus, asthma during pregnancy may have long-term effects on lung ILC2s in the offspring from the embryonic period, contributing to an increased risk of developing asthma.

Interplay of SHH, WNT and BMP4 signaling regulates the development of the lamina propria in the murine ureter.

In the mammalian ureters, the lamina propria presents as a prominent layer of connective tissue underneath the urothelium. Despite its important structural and signaling functions, little is known how the lamina propria develops. Here, we show that in the murine ureter, the lamina propria arises at late fetal stages and massively increases by fibrocyte proliferation and collagen deposition after birth. WNT, SHH, BMP4 and retinoic acid signaling are all active in the common mesenchymal progenitor of smooth muscle cells and lamina propria fibrocytes. However, around birth, the lamina propria becomes a target for epithelial WNT and SHH signals and a source of BMP4 and retinoic acid. SHH and WNT signaling promote lamina propria and smooth muscle cell differentiation and proliferation at fetal and early postnatal stages while BMP4 signaling is required for early smooth muscle cell differentiation but not for its later maintenance. Our findings suggest that in presence of SHH and WNT signaling it is the modulation of BMP4 signaling which is the major determinant for the segregation of lamina propria and smooth muscle cells.

Characterizing the In Utero Phenome of the Chiari II Malformation—A Network Medicine Approach, Using Fetal MRI

ABSTRACTObjectiveTo apply a network medicine‐based approach to analyze the phenome of the prenatal fetal MRI and biometric findings in the Chiari II malformation (CM II) to detect specific patterns and co‐occurrences.MethodA single‐center retrospective review of fetal MRI scans obtained in fetuses with CM II was performed. Co‐occurrence analysis was utilized to generate a phenotypic comorbidity matrix and visualized by Gephi software. Traditional univariate regression and geometric thin‐plate spline methodology were used to elucidate the mechanisms underlying the relationships between morphometric measurements and geometric landmarks of the spine, skull, and brain deformations.ResultsThe CM II phenome consists of 35 nodes interconnected by 979 edges with a density of 0.828. Key “hubs” identified within this network include spinal bony defects, reduced posterior fossa dimensions, and vermis ectopia. The brain edema phenotype appearing only in the fetal stage but disappearing after postnatal surgery, links to increased postnatal morbidity and demonstrates distinct shape patterns by geometric analysis. Traditional univariate regression reveals correlations among spinal defects, posterior fossa dimensions, and caudal extent of vermis ectopia. The degree of brain rearrangement versus spinal bony rearrangement shows a correlation (r = 0.721, p = 0.0023) by partial least‐squares analysis.ConclusionThe CM II prenatal phenome is a multifaceted network centered around three key elements—spinal bony defects, small posterior fossa, and vermis ectopia—with strong interconnections. Fetal brain edema emerged as an exclusively prenatally detectable and transient phenotype of prognostic relevance.

The effects of exposure to the Great Chinese Famine during the fetal stage and childhood on prevalence of hypertension in adulthood

IntroductionMany studies have found that famine exposure in early life was associated with higher prevalence of hypertension, but the results remain controversial. The aim was to examine the association of early life exposure to famine with hypertension in adulthood.Material and methodsThe cross-sectional study enrolled about 100,000 adults from Guangdong province, China, who were born between 1 October 1952 and 30 September 1964. Participants were classified as non-exposed, fetal exposed, early-childhood exposed, mid-childhood exposed, and late-childhood exposed group according to birth data. Multivariable logistic regression, subgroup analysis, and sensitivity analysis were used to estimate the odds ratios (ORs) and confidence intervals (CIs) for the association between famine exposure and hypertension.ResultsAmong the 28,804 participants, the prevalence of hypertension in non-exposed, fetal, early-childhood, mid-childhood, and late-childhood exposed groups were 2686 (41.2%), 1777 (44.5%), 2998 (49.0%), 3196 (51.1%), 3192 (53.9%), respectively. Compared with the non-exposed group, the fully adjusted ORs of subjects exposed to the famine in the fetal, early-childhood, mid-childhood and late-childhood exposed groups were 1.10 (95% CI: 0.97–1.24, p = 0.143), 1.23 (95% CI: 1.10–1.37, p < 0.001), 1.39 (95% CI: 1.24–1.55, p < 0.001), and 1.55 (95% CI: 1.38–1.73, p < 0.001), respectively (p for trend < 0.001), and for the age-balanced group it was 1.37 (95% CI: 1.13–1.59, p < 0.001). Subgroup analyses showed that the effect of famine on hypertension was more pronounced in women and in the rural and overweight population.ConclusionsExposure to famine at any stage in childhood, but not in the fetal stage, was significantly associated with higher prevalence of hypertension in adults, especially in women and in the rural and overweight population.

Deciphering the temporal transcriptional landscape of human fetal leptomeninges.

The leptomeninges play a pivotal role in the central nervous system (CNS), serving both as a barrier and as a conduit for fluid and cellular transport. Despite their critical functions, our understanding of leptomeningeal development and maturation during human embryogenesis remains limited. This study seeks to bridge this gap. We conducted single-nucleus RNA sequencing on leptomeningeal tissues from eight human embryos, capturing developmental stages from early fetal to late mid-fetal phases. Our bioinformatic analyses encompassed cell type classification, identification of layer-specific markers, mapping of the arachnoid barrier maturation trajectory, and joint analyses with mouse and aged human leptomeningeal scRNA datasets. Key bioinformatic findings were validated through immunostaining in selected samples. Our study revealed a complex cellular heterogeneity within the developing leptomeninges, identifying distinct subpopulations of fibroblasts, immune cells, and vascular cells. We mapped the transcriptomic dynamics of fibroblast cell types throughout fetal brain development, highlighting a clear maturation process from early fetal to late mid-fetal stages. Comparative analysis with mouse data allowed us to distinguish human-specific layer markers while confirming several conserved markers shared between humans and mice. Joint analysis with aged human datasets identified two unique arachnoid clusters specific to aging leptomeninges. Moreover, we traced the developmental trajectory of the arachnoid barrier, detailing the transcriptomic shifts associated with its gradual formation. Notably, immune cells in early fetal stages were predominantly M2-type macrophages, underscoring a distinctive immune environment. Finally, we explored the molecular interactions between fibroblasts and other cell types, highlighting their coordinated roles in orchestrating leptomeningeal development. Together, our findings provide a comprehensive overview of the cellular and molecular landscape of the developing human leptomeninges.

Cell-type specific, inducible and acute degradation of targeted protein in mice by two degron systems

Despite its broad application in in vitro studies, the application of targeted protein degradation (TPD) to animal models faces considerable challenges. Here, we develop inducible and cell-type specific TPD systems in mice using two degron systems: Oryza sativa TIR1F74G (OsTIR1)-auxin-inducible degron 2 (AID2) and human cereblon (hCRBN)-SALL4 degron (S4D). Efficient degradation of Satb1Venus protein by these systems recapitulates phenotypes observed in the Satb1-deficient mice. These TPD are successfully applied in both the fetal and neonatal stages. The OsTIR1-AID2 system proves to be effective for membrane proteins such as PD-1, emulating the effects of the anti-PD-1 antibody. Degradation of Bcl11b reveals a role of Bcl11b which was not characterized by the Cre-loxP system. Collectively, in vivo TPD technologies developed in this study enable inducible, temporal, and cell type-specific depletion of target proteins with high efficacy in mice. These technologies have a wide range of applications in the diverse fields of biological and medical research.

Neurodevelopment of Autism: Critical Periods, Stress and Nutrition.

Autism spectrum disorder (ASD) is a neurodevelopmental disability that presents significant challenges in communication and behavior. ASD prevalence exceeds 2% among eight-year-old children and is at similar levels globally. We propose that critical periods during fetal development and early postnatal years establish the conditions for either neurotypical development or the emergence of autism through mechanisms that influence immune function or delay neuronal development. One critical period is characterized by the requirement for folate, a crucial methyl donor needed for DNA regulation. Insufficient folate availability has been linked to the risk of developing ASD. Another critical period may be affected by oxidative stress or inflammation of the fetal brain, potentially due to inadequate microglial immunity, which can lead to CNS inflammatory changes that disrupt typical neurodevelopment. We suggest that early supplementation with reduced folate and taurine during both the fetal and postnatal stages may be effective in mitigating the severity of ASD symptoms by promoting neurotypical development through these critical neurodevelopmental periods.

Development of hybrid models by the integration of the read-across hypothesis with the QSAR framework for the assessment of developmental and reproductive toxicity (DART) tested according to OECD TG 414

The governing laws mandate animal testing guidelines (TG) to assess the developmental and reproductive toxicity (DART) potential of new and current chemical compounds for the categorization, hazard identification, and labeling. In silico modeling has evolved as a promising, economical, and animal-friendly technique for assessing a chemical's potential for DART testing. The complexity of the endpoint has presented a problem for Quantitative Structure-Activity Relationship (QSAR) model developers as various facets of the chemical have to be appropriately analyzed to predict the DART. For the next-generation risk assessment (NGRA) studies, researchers and governing bodies are exploring various new approach methodologies (NAMs) integrated to address complex endpoints like repeated dose toxicity and DART. We have developed four hybrid computational models for DART studies of rodents and rabbits for their adult and fetal life stages separately. The hybrid models were created by integrating QSAR features with similarities-derived features (obtained from read-across hypotheses). This analysis has identified that this integrated method gives a better statistical quality compared to the traditional QSAR models, and the predictivity and transferability of the model are also enhanced in this new approach.

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.

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

BackgroundThe 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. MethodsTrios-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. ResultsHemizygous 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. SignificanceCCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD.

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

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.