Search Results (344)

Intercellular communication across cancer cells and the tumor microenvironment (TME) is essential for tumor growth, invasion, metastasis, and therapeutic resistance. Traditionally, these interactions have been viewed through the lens of diffusible signaling molecules and extracellular vesicles. However, growing evidence supports an additional paradigm in which specialized cytoskeleton-based membrane extensions, like tunneling nanotubes (TNTs), tumor microtubes (TMs), and cytonemes, mediate direct, contact-dependent communication between cells. This review examines the emerging roles of these cellular extensions in cancer biology, with a particular emphasis on cytonemes, long specialized signaling filopodia that facilitate transport and reception of signaling ligands and receptors. Cytonemes are interwoven with developmental signaling pathways, which are frequently reactivated in cancer, promoting tumor progression. We discuss cytoneme pathology in cancer, with specific examples in growth, stemness, invasion, and microenvironmental remodeling. These extensions represent an unexplored facet of tumor biology and a promising avenue for therapeutic intervention. Full article

Plant regeneration demonstrates the remarkable developmental plasticity of plants, enabling tissue repair, organ formation, and adaptation to environmental challenges through cellular reprogramming and redifferentiation. This capacity underpins numerous horticultural and biotechnological applications, including grafting, micropropagation, somatic embryogenesis, organogenesis, and genetic transformation. While regeneration has traditionally been explained by the coordinated actions of auxin and cytokinin together with key developmental regulators such as WUSCHEL, BABY BOOM, and WUSCHEL-related homeobox genes, recent studies indicate that regeneration is also influenced by stress signaling, metabolic reprogramming, reactive oxygen species, and epigenetic regulation. Among these regulatory components, polyamines have emerged as important modulators of cell division, differentiation, stress responses, and morphogenic competence during in vitro regeneration. Likewise, autophagy, a conserved intracellular recycling pathway, has gained increasing attention for its role in maintaining cellular homeostasis, facilitating metabolic adaptation, and supporting developmental transitions under tissue culture conditions. This review summarizes current knowledge on the independent roles of polyamines and autophagy in plant cell reprogramming and in vitro regeneration, with particular emphasis on wound responses, somatic embryogenesis, and organogenesis. In addition, it highlights common physiological processes through which these pathways may influence regeneration and identifies the limited understanding of their potential relationship as an important direction for future research. Full article

Soybean is a strategic crop for global protein and vegetable oil supply chains; however, genetic improvement remains constrained by genotype-dependent regeneration, variable transformation efficiency, and regulatory concerns regarding stable transgene integration. This review synthesizes emerging DNA-free and genotype-independent genome-editing frameworks for soybean, where genotype independence is defined as the ability to recover fertile, non-chimeric edited plants across elite germplasm. We critically examine the soybean genome-editing toolbox, including CRISPR-Cas9, Cas12a, multiplex editing systems, base editing, and prime editing, and discuss persistent bottlenecks associated with target selection, off-target assessment, editability, and plant recovery. Particular emphasis is placed on artificial intelligence (AI)-assisted approaches that integrate genomic, epigenomic, chromatin-accessibility, and multi-omics datasets to improve target prioritization, guide RNA design, off-target prediction, and locus- and genotype-specific editability assessment. We further evaluate DNA-free genome-editing technologies, including CRISPR-Cas ribonucleoproteins, transient RNA-based systems, and nanocarrier-mediated delivery platforms, highlighting their potential to generate non-integrative edits while reducing prolonged nuclease exposure. In addition, we discuss regeneration reprogramming strategies based on developmental regulators and morphogenic modules, including BBM-WUS, GRF-GIF, de novo meristem induction, and somatic embryogenesis, as enabling technologies for overcoming cultivar-dependent regeneration barriers. Importantly, this review proposes an integrated AI-to-field framework that connects target discovery, editability prediction, DNA-free editing, regeneration reprogramming, phenotypic validation, and breeding deployment into a unified soybean improvement pipeline. We further highlight emerging opportunities in multi-omics-guided target discovery, genotype-aware prediction models, regeneration-aware editing strategies, and closed-loop machine-learning systems that continuously improve editing decisions through experimental feedback. Collectively, these convergent innovations provide a practical foundation for accelerating the development of climate-resilient, nutritionally enhanced, and industry-ready soybean cultivars. Full article

Prenatal alcohol exposure (PAE) is recognized as a major public health concern due to its profound and lasting effects on the central nervous system (CNS) and its ability to induce fetal alcohol spectrum disorders (FASD), which encompass a wide range of cognitive, behavioural, and neuropsychiatric disorders that persist throughout life. Experimental and clinical studies have identified several mechanisms underlying ethanol impairing brain development, including apoptosis, oxidative stress, disruption of morphogen and growth factor signalling pathways, impaired neuronal proliferation and migration, neurotransmitter systems’ dysfunction, glial cells damage associated with deficient myelination, vascular and blood–brain barrier (BBB) alterations, and lasting epigenetic reprogramming. However, to date no widely accepted integrative framework explaining how these impairments underline the heterogeneous phenotype observed in FASD is available. The present brings together developmental neurobiology and computational neuroscience to conceptualize PAE as a disorder of emerging neural and functional architecture. Here, we summarize the pharmacokinetics of ethanol in pregnancy, critical windows of vulnerability, and the classical pathways of alcohol teratogenesis affecting neuronal survival, migration, synaptogenesis, myelination, and gene regulation. We have also reviewed MRI, diffusion imaging, and EEG/MEG evidence showing altered brain volumes, white matter microstructure, functional connectivity, and network organization in individuals with PAE. Finally, we propose a systems-level model that conceptualizes PAE as a disorder of emerging neuro-computational architecture, in which ethanol-induced cellular and molecular perturbations collectively alter the building blocks and self-organization rules of brain network assembly. Full article

Micropropagation of Selenicereus hybrids is a key tool for breeding and conservation; however, further refining the balance between high multiplication rates and morphological quality remains a complex challenge within conventional protocols. This study explores targeted signaling modulation using nine bioactive small molecules—including three mammalian glycogen synthase kinase 3 (GSK3) inhibitors (TDZD-9, VP3.15 and VP0.7), three leucine rich repeat kinase 2 (LRRK2) inhibitors (JZ1.24, JZ1.3 and IGS4.75), and three phosphodiesterase (PDE) inhibitors—to complement traditional micropropagation. Explants were evaluated in two distinct contexts: a hormone-free basal medium (BM) and a plant growth regulator-supplemented medium (PIT2) and the response rates, yield, and quality were measured and integrated using a Global Efficiency Index (GEI). Results demonstrate that inhibitor efficacy is strictly context-dependent; while most molecules repressed budding in BM, they acted as response modulators by determining the specific type of morphogenic pathway in PIT2. Notably, the GSK3 inhibitor TDZD-9 reached the highest GEI (0.85) by maximizing productivity, whereas LRRK2 inhibitors effectively preserved architectural integrity. Flow cytometry confirmed cytogenetic stability across all treatments, with a 98.5% plantlet survival rate during acclimatization. In conclusion, the strategic integration of targeted signaling modulators and multi-parametric indices offers a refined and objective framework to enhance the efficiency of mass propagation protocols in pitahaya and other recalcitrant species. Furthermore, our findings provide new evidence of the strong potential of these small molecules as novel tools to improve plant micropropagation beyond traditional plant growth regulators. Full article

Newborn piglets in intensive pig farms are often prone to pulmonary diseases due to underdeveloped fetal lung neural systems, and ATRA is often regarded as an important morphogen that displays pleiotropic functions during embryonic development. However, information about the effect of maternal administration with ATRA on the peripheral neural system of fetal lungs is still scare. Fifteen pregnant sows were assigned to the ATRA0 (0 mg/kg diet), ATRA4, ATRA8, ATRA16 and ATRA32 treatment groups and offered their own feed from d12 to d95 after artificial insemination; then two neonatal pigs with birth weights similar to the average birth weight were taken out from each litter for the collection of lung samples, and samples were subjected to immunofluorescence staining, RNA-seq and RT-qPCR assays. Results indicated that compared to newborn piglets from the ATRA0 treatment group, newborn piglets from the ATRA4 treatment group had higher percentages of GFAP-positive astrocyte cells (p < 0.05) and GFAP-TUBB3 colocalization (p < 0.05) in the lungs. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that differential expressed genes are mainly enriched in the pathways of neuroactive ligand–receptor interaction, GABAergic synapses and cell adhesion molecules. Addition of ATRA at 4 mg/kg to the diet of pregnant sows can enhance the healthy development of the pulmonary nervous systems of fetal pigs. Full article

Polygonatum cyrtonema is a medicinally and edible perennial herb, yet functional studies in this species are constrained by limited knowledge of regeneration-associated developmental regulators. Here, we performed a genome-wide characterization of the WUSCHEL-related homeobox (WOX) gene family in P. cyrtonema. Eleven PcWOX genes were identified and classified into the ancient, intermediate, and modern/WUS clades. Comparative phylogenetic, syntenic, structural, and chromosomal analyses indicated that the PcWOX family retains a conserved evolutionary framework but also exhibits clear lineage-specific diversification. Tissue- and stage-specific expression profiling, promoter cis-element analysis, and subcellular localization further supported functional differentiation among PcWOX members, particularly between PcWOX5 and PcWUS. Weighted gene co-expression network analysis identified 33 co-expression modules, including six key modules strongly associated with PcWOX abundance patterns, and prioritized 49 candidate transcription factors (TFs) to construct PcWOX-centered regulatory networks. These TFs showed marked tissue- and stage-dependent heterogeneity. Heterologous assays in Nicotiana benthamiana showed that both PcWUS and PcWOX5 enhanced regeneration competence but produced distinct developmental outputs. These findings support PcWUS and PcWOX5 as promising candidate morphogenic regulators and provide a useful framework for future mechanistic studies, homologous validation, and regeneration improvement in P. cyrtonema. Full article

Butterfly wing color patterns are determined in pupal wing tissues, in which the prospective eyespot focus functions as a developmental organizer. Here, we investigated the microscopic structures of pupal wing tissues containing an eyespot organizer in line with the physical distortion hypothesis. Histochemical staining revealed that the pupal cuticle and epidermis were wavy and thin at 6 h but smooth and thick at 12 h postpupation. The eyespot organizer was associated with the thickest cuticle layer, called the cuticle focal spot. Transmission election microscopy (TEM) revealed that the intervening space (IVS) between the cuticle layer and the cellular apical end was wide at 6 h but narrow at 12 h postpupation. The spatial relationship between cuticle thickness and IVS width was indicative of mechanical buckling of the region adjacent to the cuticle focal spot. Live in vivo imaging revealed that the IVS at and near the eyespot organizer trapped orange fluorescent protein (OFP) injected into hemolymph. Dynamic distortions of the pupal wing epidermis and cuticular surface were detected in live individuals over time. These results suggest that physical distortions of the wing tissue induced by differential cuticle synthesis and subsequent buckling may function as mechanical morphogenic signals from eyespot organizers. Full article

Physalis peruviana exhibits highly variable and poorly reproducible morphogenic responses under in vitro conditions, limiting the development of reliable regeneration systems. This study evaluated how the interaction between thidiazuron (TDZ), naphthaleneacetic acid (NAA), and explant type influences shoot regeneration in the Colombiano ecotype of Physalis peruviana. A factorial design (2 × 3 × 2) revealed that morphogenic responses were primarily driven by interaction effects rather than by individual plant growth regulators. Hypocotyl explants cultured in 4.54 µM TDZ combined with 0.6 µM NAA showed the highest shoot production, shoot formation capacity, and elongation. In contrast, TDZ alone induced limited shoot production, did not support efficient and organized shoot development, and was associated with abnormal morphologies. The response to NAA was non-linear, with intermediate concentrations maximizing shoot regeneration response, indicating that morphogenic competence operates within a narrow hormonal range. Overall, regeneration in the Colombiano ecotype of P. peruviana evaluated here was governed by the interaction between hormonal balance and explant type, identifying favorable conditions for shoot regeneration under the conditions tested. Full article

Background/Objectives: Congenital heart malformations (CHDs) are not rare diseases, and, in many cases, their pathogenic mechanisms are well established. Several conotruncal defects are associated with genetic syndromes such as DiGeorge syndrome and RASopathies, reflecting shared developmental pathways affecting cardiac outflow tract formation. However, even common CHDs may occur within complex syndromic contexts, making early diagnosis essential for optimal management. This review aims to provide a unifying framework linking ciliary dysfunction to CHD phenotypes. Methods: We performed an integrative narrative review of genetic, experimental, and developmental studies focusing on the role of primary and motile cilia in cardiac morphogenesis. Particular attention was given to signaling pathways regulated by cilia and their contribution to disease phenotypes. Results: Emerging evidence indicates that primary and motile cilia act as central regulators of cardiac development, integrating morphogen gradients and mechanical cues into transcriptional programs. Dysfunctions in ciliary structure or signaling are increasingly recognized as important contributors to selected complex CHD phenotypes, particularly in syndromic forms and laterality-associated defects. This cilia-centered model may help explain part of the phenotypic heterogeneity observed in CHD and highlights shared mechanisms across distinct clinical entities. Conclusions: Understanding cilia-dependent mechanisms provides a unifying conceptual framework linking genetic defects to disrupted morphogenesis. This perspective may refine disease interpretation and support future development of precision diagnostics and pathway-informed therapeutic strategies in CHD. Full article

Hydroxyapatite–calcium sulfate (HACaS) bone cements have been clinically established. Combining HACaS with an antiresorptive (zoledronic acid, ZA) and osteoanabolic agent (bone morphogenic protein 2; BMP-2) may enhance the performance of HACaS bone cements in challenging indications, but it must be ensured that this does not impair their setting and mechanical properties. This study established a Vicat/Gillmore-inspired indentation protocol to quantify force-based endpoints and the setting of HACaS with biological adjuvants. HACaS was mixed with or without ZA and/or BMP-2 at 0 min and after a 2 min pre-setting phase with reduced NaCl content (lower liquid-to-powder ratio). For each time point (3–90 min), three cylindrical pellets (Ø 4 mm, height 6 mm) underwent single indentation. Setting was defined as the maximum force at needle penetration, and endpoint hardness was defined as peak force at failure. For 24 h endpoints, specimens were incubated in blood at 37 °C. One-way ANOVA with Tukey’s H post hoc test was performed per time point (n = 3; 24 h endpoints n = 5). All 2 min protocols showed accelerated setting, consistent with the initial lower liquid-to-powder ratio. ZA significantly delayed setting and remained lowest at 90 min and after 24 h in blood. Mixing sequence and vehicle composition critically influenced early mechanical properties and should be considered in the further preclinical evaluation of HACaS with osteoanabolic or antiresorptive agents. Full article

Traditional analyses of transport phenomena rely on prescribed geometric boundaries, yet natural flow systems dynamically evolve their architecture to maximize access to currents. To address this disparity, we propose a field-theoretic framework for the constructal law that treats physical geometry as a dynamic state variable, represented by a time-dependent conductivity tensor. Using a variational approach grounded in non-equilibrium thermodynamics, we derive a general tensor evolution equation. Within this framework, macroscopic flow architecture emerges deterministically from the continuous competition between non-linear flux-induced accretion, linear entropic relaxation, and spatial smoothing. Scaling analysis reduces this dynamic to a tri-parameter dimensionless phase space: a morphogenic number driving structural growth, a structural diffusion number governing spatial coherence, and a stochastic intensity number providing the microscopic seeds for symmetry breaking. Our principal result is the analytical prediction of a critical bifurcation. When the local morphogenic number strictly exceeds unity, the system escapes its stable, isotropic configuration and branches into highly conductive, anisotropic architectures. We demonstrate the predictive validity and trans-scalar applicability of this continuum theory by mapping it to highly diverse phase transitions, successfully capturing phenomena ranging from microscopic aerosol agglomeration and microbial resistance, to macroscopic coral plasticity and crystal growth instabilities, and finally to the astrophysical launching of relativistic jets from black holes. Full article

Background/Objectives: Craniofacial malformations such as orofacial clefts affect ~1 in 700 births; 40–60% lack clear genetic etiology, and many exhibit asymmetry and variable expressivity unexplained by classical Sonic Hedgehog (SHH) morphogen gradient models. We investigated whether integrated molecular modules linking morphogen signaling with metabolic stress responses may better account for craniofacial developmental outcomes. Methods: Sequential UniProt gene set integration identified 186 candidate craniofacial regulators. STRING network analysis revealed modular architecture. Molecular docking profiled 17 compounds against SMO, CK1δ, PINK1, and TIE2 (control). Pathway reconstruction integrated the SHH–CK1δ–HIF1A–HEY1–PINK1 axis with in-silico-predicted CK1δ phosphorylation sites on SMO (S615, T593, S751), HIF1A (Ser247), and GLI1/2/3 transcription factors. A developmental decision tree mapped affinity profiles to node-specific phenotype hypotheses. Results: CK1δ and PINK1 emerged as candidate nodes coupling morphogen signaling with mitochondrial quality control. Cross-docking showed preferential binding to developmental kinases (CK1δ: −8.34 kcal/mol; PINK1: −8.80 kcal/mol) versus TIE2 control (−6.76 kcal/mol; p < 0.001). Pathway reconstruction suggested that CK1δ-mediated Ser247 phosphorylation of HIF1A disrupts ARNT dimerization, redirecting HIF1A toward ARNT-independent HEY1 induction and consequent PINK1 suppression. Based on computed profiles, node-specific associations were proposed as computational hypotheses: SMO perturbation → midline defects; CK1δ → facial asymmetry/clefting; PINK1 → mandibular hypoplasia. Multi-target compounds (e.g., purmorphamine, taladegib) generated composite phenotype predictions consistent with clinical complexity. Conclusions: This strictly in silico study identifies candidate integrated morphogenic modules whose multi-node perturbation may underlie anatomically specific craniofacial malformation patterns. Node–phenotype associations are prioritized computational hypotheses requiring experimental validation; if confirmed, the framework could inform developmental toxicity assessment, therapeutic design, and reclassification of idiopathic craniofacial anomalies. Full article

Human cerebral organoids, derived from pluripotent stem cells, are powerful models for studying human brain development. The understanding of how morphogens can be used to guide patterning and differentiation has matured rapidly; however, the influence of basal media components on organoid development remains unclear. Standard organoid media frequently contain non-physiological concentrations of nutrients, including glucose, a central regulator of cellular metabolism and signaling. Here, we examine how glucose availability shapes cerebral organoid growth, morphology, and cell type composition by comparing conventional hyperglycemic media to media with glucose levels more closely resembling normoglycemic conditions. We find that organoids derived from multiple human pluripotent stem cell lines can grow in low glucose, but they exhibit altered growth rates, structural features, and lineage distributions. In H9 embryonic stem cell-derived organoids, inhibition of the mammalian target of rapamycin pathway under low glucose restores neurodevelopmental cell types otherwise diminished in these conditions. These findings highlight glucose as a key determinant of organoid lineage specification and cellular signaling. Importantly, however, glucose modulation does not reduce variability across organoids or cell lines, underscoring the need to better understand and control sources of heterogeneity to improve organoid models. Full article