Model Of Early Development Research Articles

Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network.

Viable human aneuploidy can be challenging to model in rodents due to syntenic boundaries or primate-specific biology. Human monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in X-monosomic mice. To learn how monosomy-X may impact embryonic development, we turned to 45,X and isogenic euploid human induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because the neural crest (NC) is hypothesized to give rise to craniofacial and cardiovascular changes in TS, we assessed differential expression of hiPSC-derived anterior NC cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7+SOX10+ markers and disrupted expression of other NCC-specific genes relative to isogenic euploid controls. Additionally, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts with 5' terminal oligopyrimidine (TOP) motifs, including those of ribosomal and nuclear-encoded mitochondrial proteins. Such metabolic pathways are also over-represented in weighted co-expression modules that are preserved in monogenic neurocristopathy and reflect 28% of all TS-associated terms of the human phenotype ontology. We demonstrate that 45,X NCCs reduce protein synthesis despite activation of mammalian target of rapamycin (mTOR) but are partially rescued by mild mTOR suppression. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as powerful models of early NC development in TS and inform new hypotheses toward its etiology.

Analisis Kebijakan Pendidikan Diniyah dalam Implementasi Kurikulum Madrasah Diniyah di Lingkungan Pesantren

This research aims to analyze the Islamic education policy in implementing the Madrasah Islamic curriculum in the Islamic boarding school environment. The main focus of the research is to analyze the early education gap, adaptive early education curriculum, obstacles to early curriculum development and sustainable early education models. A qualitative approach is used with the case study method. Data was obtained through in-depth interviews, observation, and review of related documents. The research results show that there is a gap between the early education policy and the needs of traditional Islamic boarding schools, especially in maintaining local characteristics such as the yellow book curriculum. Islamic boarding schools face challenges in infrastructure, funding and human resource training, which hinder curriculum innovation. Manbaul Ulum Islamic Boarding School has combined religious values ??with modern skills, despite being constrained by technology and resources. This research proposes a sustainable, technology-based model of early education, teacher training, and collaboration with the business world to produce adaptive and relevant graduates without losing Islamic identity.

Diagnostics and Prognostics with High Dimensional Spatial-Temporal Data: From Structures to Human Brains

Diagnostics and prognostics with high-dimensional spatial-temporal data require innovative methodologies due to the inherent complexity of such datasets. This thesis explores the challenges of diagnostics and prognostics in high-dimensional spatial-temporal data, extending from physical structures to complex human brain analyses through resting-state functional magnetic resonance imaging (rs-fMRI). Drawing an analogy to engineering structural health monitoring using spatial-temporal vibration data, the approach leverages techniques from engineering diagnostics and prognostics data analytics to handle clinical problems with similar characteristics. A pioneering approach is developed to analyze multimodal datasets that not only include advanced rs-fMRI features—Amplitude of Low-frequency Fluctuations (ALFF), Regional Homogeneity (ReHo), Euler Characteristics (EC), and Fractal Analysis—but also encompass a wide array of clinical data. This integration includes infant developmental metrics such as birth weight and gestational age, maternal health factors like BMI and fat mass, and environmental influences including dietary intake and mental health during pregnancy. The study establishes a robust computational framework that uses advanced machine learning algorithms to analyze the interplay of these diverse data types, enhancing the precision and predictive power of our models for early childhood development. Initial validations have demonstrated the effectiveness of this comprehensive approach in identifying ADHD, with ongoing efforts aimed at expanding the methodology to address a broader range of developmental disorders. This work not only advances the diagnostic and prognostic capabilities in medical imaging but also significantly contributes to the field of Prognostics and Health Management (PHM). By providing a solid foundation for managing and understanding high-dimensional and multimodal spatial-temporal data across various disciplines, it bridges the gap between engineering and clinical diagnostics, demonstrating the potential for cross-disciplinary innovation.

Morphogen-driven differentiation is precluded by physical confinement in human iPSCs spheroids.

Cell lineage specification is tightly associated with profound morphological changes in the developing human embryo, particularly during gastrulation. The interplay between mechanical forces and biochemical signals is poorly understood. Here, we dissect the effects of biochemical cues and physical confinement on a 3D in vitro model based on spheroids formed from human induced pluripotent stem cells (hiPSCs). First, we compare self-renewing versus differentiating media conditions in free-floating cultures and observe the emergence of tri-germ layers. In these unconfined conditions, BMP4 exposure induces polarised expression of SOX17 in conjunction with spheroid elongation. We then physically confine spheroids using PEG-peptide hydrogels and observe dramatically reduced SOX17 expression, albeit rescued if gels that soften over time are used instead. Our study combines high-content imaging, synthetic hydrogels, and hiPSCs-derived models of early development to define the drivers that cause changes in the shape and the emergence of germ layers.

The development of aperiodic neural activity in the human brain.

The neurophysiological mechanisms supporting brain maturation are fundamental to attention and memory capacity across the lifespan. Human brain regions develop at different rates, with many regions developing into the third and fourth decades of life. Here, in this preregistered study (https://osf.io/gsru7), we analyzed intracranial EEG (iEEG) recordings from widespread brain regions in a large developmental cohort. Using task-based (i.e., attention to-be-remembered visual stimuli) and task-free (resting-state) data from 101 children and adults (5.93 - 54.00 years, 63 males; n electrodes = 5691), we mapped aperiodic (1/ƒ-like) activity, a proxy of excitation:inhibition (E:I) balance with steeper slopes indexing inhibition and flatter slopes indexing excitation. We reveal that aperiodic slopes flatten with age into young adulthood in both association and sensorimotor cortices, challenging models of early sensorimotor development based on brain structure. In prefrontal cortex (PFC), attentional state modulated age effects, revealing steeper task-based than task-free slopes in adults and the opposite in children, consistent with the development of cognitive control. Age-related differences in task-based slopes also explained age-related gains in memory performance, linking the development of PFC cognitive control to the development of memory. Last, with additional structural imaging measures, we reveal that age-related differences in gray matter volume are differentially associated with aperiodic slopes in association and sensorimotor cortices. Our findings establish developmental trajectories of aperiodic activity in localized brain regions and illuminate the development of PFC inhibitory control during adolescence in the development of attention and memory.

Artificial evolution summer school and winter camp: An organized early talent development model for innovation

Artificial evolution summer school and winter camp: An organized early talent development model for innovation

Age and provenance relationships between the basal Great Valley Group and its underlying basement: implications for initiation of the Great Valley forearc basin, California, U.S.A.

ABSTRACT The Great Valley forearc (GVf) basin, California, records deposition along the western margin of North America during active oceanic subduction from Jurassic through Paleogene time. Along the western GVf, its underlying basement, the Coast Range Ophiolite (CRO), is exposed as a narrow outcrop belt. CRO segments are overlain by the Great Valley Group (GVG), and locally, an ophiolitic breccia separates the CRO from basal GVG strata. New stratigraphic, petrographic, and geochronologic data (3865 detrital and 68 igneous zircon U-Pb ages) from the upper CRO, ophiolitic breccia, and basal GVG strata clarify temporal relationships among the three units, constrain maximum depositional ages (MDAs), and identify provenance signatures of the ophiolitic breccia and basal GVG strata. Gabbroic rocks from the upper CRO yield zircon U-Pb ages of 168.0 ± 1.3 Ma and 165.1 ± 1.2 Ma. Prominent detrital-zircon age populations of the ophiolitic breccia and GVG strata comprise Jurassic and Jurassic–Early Cretaceous ages, respectively, with pre-Mesozoic ages in both that are consistent with sources of North America affinity. Combined with petrographic modal analyses that show abundant volcanic grains (> 50%), we interpret the breccia to be mainly derived from the underlying CRO, with limited input from the hinterland of North America, and the basal GVG to be derived from Mesozoic igneous and volcanic rocks of the Sierra Nevada–Klamath magmatic arc and hinterland. Analysis of detrital-zircon grains from the lower and upper ophiolitic breccia yields MDAs of ∼ 166 Ma and ∼ 151 Ma, respectively. Along-strike variation in Jurassic and Cretaceous MDAs from basal GVG strata range from ∼ 148 to 141 Ma, which are interpreted to reflect diachronous deposition in segmented depocenters during early development of the forearc. The ophiolitic breccia was deposited in a forearc position proximal to North America < 4 Myr before the onset of GVG deposition. A new tectonic model for early development of the GVf highlights the role of forearc extension coeval with magmatic arc compression during the earliest stages of basin development.

The role of type 3 deiodinase in a human model for early brain development

The role of type 3 deiodinase in a human model for early brain development

Retinoic acid induces human gastruloids with posterior embryo-like structures

Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis.

MÔ HÌNH PHÁT TRIỂN CHUYÊN MÔN GIÁO VIÊN MẦM NON: NGHIÊN CỨU TRƯỜNG HỢP TRÊN MÔ HÌNH STEMSMART

This article presents the STEMsmart early childhood teacher professional development model. The model is developed based on Clarke and Hollingsworth’s Interconnected Model and focuses on early childhood STEM education. The model includes components contributing to teachers’ change in four main domains: (1) Personal domain, (2) External domain, (3) Domain of practice, and (4) Domain of consequence. Initial trials of the model have significantly improved teachers’ knowledge and pedagogical practices related to STEM education. This model needs further research to gather convincing evidence confirming its suitability and effectiveness, providing a basis for scaling up and applying it to develop other professional competencies of early childhood teachers. Keywords: Professional development; early childhood teacher; professional development model; STEMsmart.

A brief chronicle of research on human pluripotent stem cells.

Today, human pluripotent stem cell technologies find widespread application across biomedical research, as models for early human development, as platforms for functional human genomics, as tools for the study of disease, drug screening and toxicology, and as a renewable source of cellular therapeutics for a range of intractable diseases. The foundations of this human pluripotent stem cell revolution rest on advances in a wide range of disciplines, including cancer biology, assisted reproduction, cell culture and organoid technology, somatic cell nuclear transfer, primate embryology, single-cell biology, and gene editing. This review surveys the slow emergence of the study of human pluripotency and the exponential growth of the field during the past several decades.

Symbolic recording of signalling and cis-regulatory element activity to DNA.

Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here we demonstrate an alternative paradigm in which such biological activities are stably recorded to the genome. Enhancer-driven genomic recording of transcriptional activity in multiplex (ENGRAM) is based on the signal-dependent production of prime editing guide RNAs that mediate the insertion of signal-specific barcodes (symbols) into a genomically encoded recording unit. We show how this strategy can be used for multiplex recording of the cell-type-specific activities of dozens to hundreds of cis-regulatory elements with high fidelity, sensitivity and reproducibility. Leveraging signal transduction pathway-responsive cis-regulatory elements, we also demonstrate time- and concentration-dependent genomic recording of WNT, NF-κB and Tet-On activities. By coupling ENGRAM to sequential genome editing via DNA Typewriter1, we stably record information about the temporal dynamics of two orthogonal signalling pathways to genomic DNA. Finally we apply ENGRAM to integratively record the transient activity of nearly 100 transcription factor consensus motifs across daily windows spanning the differentiation of mouse embryonic stem cells into gastruloids, an in vitro model of early mammalian development. Although these are proof-of-concept experiments and much work remains to fully realize the possibilities, the symbolic recording of biological signals or states within cells, to the genome and over time, has broad potential to complement contemporary paradigms for how we make measurements in biological systems.

Genetic and non-genetic factors in prediction of early pubertal development in Chinese girls.

The objective of this study is to develop a combined predictive model for early pubertal development (EPD) in girls based on both non-genetic and genetic factors. The case-control study encompassed 147 girls diagnosed with EPD and 256 girls who exhibited normal pubertal development. The non-genetic risk score (NGRS) was calculated based on 6 independent biochemical predictors screened by multivariate logistic regressions, and the genetic risk score (GRS) was constructed using 28 EPD related single-nucleotide polymorphisms (SNPs). Area under receiver operator characteristic curve (AROC), net reclassification optimization index (NRI) and integration differentiation index (IDI) were used to evaluate the improvement of adding genetic variants to the non-genetic risk model. Overweight (OR=2.74), longer electronic screen time (OR=1.79) and higher ratio of plastic bottled water (OR=1.01) were potential risk factors, and longer exercise time (OR=0.51) and longer day sleeping time (OR=0.97) were protective factors for EPD, and the AROC of NGRS model was 83.6% (79.3-87.9%). The GRS showed a significant association with EPD (OR=1.90), and the AROC of GRS model was 65.3% (59.7-70.8%). After adding GRS to the NGRS model, the AROC significantly increased to 85.7% (81.7-89.6%) (P=0.020), and the reclassification significantly improved, with NRI of 8.19% (P= 0.023) and IDI of 4.22% (P <0.001). We established a combined prediction model of EPD in girls. Adding genetic variants to the non-genetic risk model brought modest improvement. However, the non-genetic factors such as overweight and living habits have higher predictive utility.

Efficiency of embryo complementation and pluripotency maintenance following multiple passaging of in vitro-derived bovine embryos.

Context Current methods to obtain bovine embryos of high genetic merit include approaches that require skilled techniques for low-efficiency cloning strategies. Aims The overall goal herein was to identify the efficacy of alternative methods for producing multiple embryos through blastomere complementation while determining maintenance of cell pluripotency. Methods Bovine oocytes were fertilised in vitro to produce 4-cell embryos from which blastomeres were isolated and cultured as 2-cell aggregates using a well-of-the-well system. Aggregates were returned to incubation up to 7days (Passage 1). A second passage of complement embryos was achieved by splitting 4-cell Passage 1 embryos. Passaged embryos reaching the blastocyst stage were characterised for cell number and cell lineage specification in replicate with non-reconstructed zona-intact embryos. Key results Passage 1 and 2 embryo complements yielded 29% and 25% blastocyst development, respectively. Passage 1 embryos formed blastocysts, but with a reduction in expression of SOX2 and decreased size compared to non-reconstructed zona-intact embryos. Passage 2 embryos had a complete lack of SOX2 expression and a reduction in transcript abundance of SOX2 and SOX17, suggesting loss of pluripotency markers that primarily affected inner cell mass (ICM) and hypoblast formation. Conclusions In vitro fertilised bovine embryos can be reconstructed with multiple passaging to generate genetically identical embryos. Increased passaging drives trophectoderm cell lineage specification while compromising ICM formation. Implications These results may provide an alternative strategy for producing genetically identical bovine embryos through blastomere complementation with applications towards the development of trophoblast and placental models of early development.

Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.

Multiplex profiling of developmental cis-regulatory elements with quantitative single-cell expression reporters.

The inability to scalably and precisely measure the activity of developmental cis-regulatory elements (CREs) in multicellular systems is a bottleneck in genomics. Here we develop a dual RNA cassette that decouples the detection and quantification tasks inherent to multiplex single-cell reporter assays. The resulting measurement of reporter expression is accurate over multiple orders of magnitude, with a precision approaching the limit set by Poisson counting noise. Together with RNA barcode stabilization via circularization, these scalable single-cell quantitative expression reporters provide high-contrast readouts, analogous to classic in situ assays but entirely from sequencing. Screening >200 regions of accessible chromatin in a multicellular in vitro model of early mammalian development, we identify 13 (8 previously uncharacterized) autonomous and cell-type-specific developmental CREs. We further demonstrate that chimeric CRE pairs generate cognate two-cell-type activity profiles and assess gain- and loss-of-function multicellular expression phenotypes from CRE variants with perturbed transcription factor binding sites. Single-cell quantitative expression reporters can be applied in developmental and multicellular systems to quantitatively characterize native, perturbed and synthetic CREs at scale, with high sensitivity and at single-cell resolution.

XPC Protects against Carcinogen-Induced Histologic Progression to Lung Squamous Cell Carcinoma by Reduced Basal Epithelial Cell Proliferation.

Lung squamous cell carcinoma (LUSC) is the second leading cause of lung cancer. Although characterized by high DNA mutational burdens and genomic complexity, the role of DNA repair in LUSC development is poorly understood. We sought to better understand the role of the DNA repair protein Xeroderma Pigmentosum Group C (XPC) in LUSC development. XPC knock-out (KO), heterozygous, and wild-type (WT) mice were exposed topically to N-nitroso-tris-chloroethylurea (NTCU), and lungs were evaluated for histology and pre-malignant progression in a blinded fashion at various time-points from 8-24 weeks. High-grade dysplasia and LUSC were increased in XPC KO compared with XPC WT NTCU mice (56% vs. 34%), associated with a higher mean LUSC lung involvement (p < 0.05). N-acetylcysteine pre-treatment decreased bronchoalveolar inflammation but did not prevent LUSC development. Proliferation, measured as %Ki67+ cells, increased with NTCU treatment, in high-grade dysplasia and LUSC, and in XPC deficiency (p < 0.01, ANOVA). Finally, pre-LUSC dysplasia developed earlier and progressed to higher histologic classification sooner in XPC KO compared with WT mice. Overall, this supports the protective role of XPC in squamous dysplasia progression to LUSC. Mouse models of early LUSC development are limited; this may provide a valuable model to study mechanisms of LUSC development and progression.

Precise and scalable self-organization in mammalian pseudo-embryos.

Gene expression is inherently noisy, posing a challenge to understanding how precise and reproducible patterns of gene expression emerge in mammals. Here we investigate this phenomenon using gastruloids, a three-dimensional in vitro model for early mammalian development. Our study reveals intrinsic reproducibility in the self-organization of gastruloids, encompassing growth dynamics and gene expression patterns. We observe a remarkable degree of control over gene expression along the main body axis, with pattern boundaries positioned with single-cell precision. Furthermore, as gastruloids grow, both their physical proportions and gene expression patterns scale proportionally with system size. Notably, these properties emerge spontaneously in self-organizing cell aggregates, distinct from many in vivo systems constrained by fixed boundary conditions. Our findings shed light on the intricacies of developmental precision, reproducibility and size scaling within a mammalian system, suggesting that these phenomena might constitute fundamental features of multicellularity.

Time-integrated BMP signaling determines fate in a stem cell model for early human development

How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discover that measured BMP signaling history correlates strongly with fate in individual cells. We find that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, both the level and duration of signaling activity control cell fate choices only by changing the time integral. Therefore, signaling duration and level are interchangeable in this context. In a stem cell model for patterning of the human embryo, we show that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Our data suggest that mechanistically, BMP signaling is integrated by SOX2.

Apically localized PANX1 impacts neuroepithelial expansion in human cerebral organoids

Dysfunctional paracrine signaling through Pannexin 1 (PANX1) channels is linked to several adult neurological pathologies and emerging evidence suggests that PANX1 plays an important role in human brain development. It remains unclear how early PANX1 influences brain development, or how loss of PANX1 alters the developing human brain. Using a cerebral organoid model of early human brain development, we find that PANX1 is expressed at all stages of organoid development from neural induction through to neuroepithelial expansion and maturation. Interestingly, PANX1 cellular distribution and subcellular localization changes dramatically throughout cerebral organoid development. During neural induction, PANX1 becomes concentrated at the apical membrane domain of neural rosettes where it co-localizes with several apical membrane adhesion molecules. During neuroepithelial expansion, PANX1−/− organoids are significantly smaller than control and exhibit significant gene expression changes related to cell adhesion, WNT signaling and non-coding RNAs. As cerebral organoids mature, PANX1 expression is significantly upregulated and is primarily localized to neuronal populations outside of the ventricular-like zones. Ultimately, PANX1 protein can be detected in all layers of a 21–22 post conception week human fetal cerebral cortex. Together, these results show that PANX1 is dynamically expressed by numerous cell types throughout embryonic and early fetal stages of human corticogenesis and loss of PANX1 compromises neuroepithelial expansion due to dysregulation of cell-cell and cell-matrix adhesion, perturbed intracellular signaling, and changes to gene regulation.