Search Results (151)

“Immature” or “late-maturing” neurons exist in layer II of the cerebral cortex (cortical immature neurons; cINs) and within the amygdaloid complex (subcortical immature neurons; scINs). These cells remain in a prolonged state of arrested development yet retain the ability to resume maturation and to functionally integrate into neural circuits. Both cINs and scINs are abundant in large-brained mammals with respect to small-brained, lissencephalic rodents. In previous reports, using a comparable method for quantification in diverse mammals, including mice, chimpanzees, and other species, we showed positive correlation of immature neuron cell density with brain size and gyrencephaly. Here, we quantified the cINs and scINs in the cerebral cortex and amygdala of young adult rhesus macaques to determine how they compare to phylogenetic variation. Our results further demonstrate the existence of covariance between cIN density and both increasing brain size and neocortical expansion, as well as the specialized increase of scINs in the amygdala of primates. These findings support the emerging view that immature neurons may represent a reservoir of undifferentiated (stem cell-independent) neuronal cells for the widely expanded cortices and amygdala of mammals endowed with high-order cognitive functions and complex sociality. The detailed mapping of cortical and subcortical immature neurons in a primate often used in translational research sets the foundation for deeper, functional studies aimed at understanding human brain plasticity. Full article

WEE2, an oocyte-specific kinase of the WEE family, is a core regulator of oocyte meiosis. It maintains germinal vesicle (GV) arrest and prevents premature meiotic resumption by phosphorylating cyclin-dependent kinase 1 (CDK1), thereby inhibiting maturation-promoting factor (MPF) activity. WEE2 also regulates exit from metaphase II (MII), ensuring orderly meiotic progression. Consequently, the functional integrity of WEE2 is essential for female reproduction. Homozygous or compound heterozygous mutations in the WEE2 gene represent a major genetic cause of total fertilization failure and primary infertility, as these mutations lead to reduced or abolished kinase activity, impair meiotic control, and disrupt oocyte maturation and embryonic development. This review systematically summarizes the protein structure, core functions, and mutation types of WEE2, along with its association with total fertilization failure and female primary infertility. It also highlights research advances in WEE2-targeted inhibitors and discusses the potential applications and future directions of WEE2 in the diagnosis and management of reproductive disorders. Full article

Granulosa cells (GCs), an element of the ovarian follicle, are crucial for oocyte maturation, folliculogenesis, and steroidogenesis. Granulosa cells play a crucial role in fertilization by providing metabolic and hormonal support to the oocyte, maintaining its quality and regulating its meiotic arrest. Oocyte quality and fertilization efficiency depend on the proper activity of GCs, especially their mutual communication, providing metabolic support and protecting against oxidative stress. When interrupted, they may take part in the pathogenesis of polycystic ovary syndrome, premature ovarian failure, primary ovarian insufficiency, and diminished ovarian reserve. GCs are enclosed in the antrum where they communicate with surrounding cells, create a dynamic microenvironment, and regulate hormone biosynthesis. To analyze molecular mechanisms regulating endogenous signaling, it is important to consider the dynamic transcriptomic response of porcine GCs during in vitro culturing over 48, 96, and 144 h. Transcriptomic analysis revealed a variable and dynamic transcriptional upregulation of genes associated with cellular response to endogenous and external stimuli, chemical compound metabolism, vascular development, and GCs migration. Also, proven by Gene Ontology (GO) enrichment analysis, the following terms were highlighted: “cellular response to chemical stimulus” and “cellular response to organic substance”. Specific genes, such as HSD3B1, POSTN, LOX, SERPINB2, ITGB3, ANKRD1, SLC1A1, and SFRP2, exhibited significant expression changes, suggesting extensive GCs self-regulation and metabolism changes. Further analysis indicates improvements in cellular response to a cytokine stimulus, growth factor response, hormone response, enzyme-linked receptor protein signaling, and positive regulation of cell migration. These findings suggest interweaving of regulatory mechanisms underlying intercellular communication in GCs during in vitro culturing, despite the lack of signals from the native ovarian environment. Further investigating interplays of detecting pathways will provide a more comprehensive understanding and even insights into the potential clinical use of the knowledge about the role of GCs in folliculogenesis, oocyte maturation and ovulation. Full article

Background: The transfer of a nucleus from one oocyte to another offers patients harbouring high levels of mitochondrial DNA mutation and sufferers of frequent fertilisation failure or early embryonic arrest the potential to have healthy children. However, a small amount of mtDNA is carried over with the nucleus as the transfer takes place. Consequently, we still need to distinguish between the effects of the carryover and the transfer of a nucleus itself from a mature oocyte. Methods: To overcome this, we analysed a series of hatching stage blastocysts generated using metaphase II spindle transfer and mitochondrial supplementation. The latter approach also introduces a small amount of mtDNA into the oocyte as fertilisation takes place. For both manipulations, an autologous approach was used to overcome the effects of third-party transfer. Results: We then compared the changes in global gene expression between the two groups. We found that the nuclear transfer process affected a number of gene networks and pathways. These included metabolic, cell cycle, inflammatory and immune, and epigenetic responses. A comparison with earlier stage blastocysts did not suggest that the cause was due to developmental delay. Conclusions: Critically, these changes could affect offspring health and well-being as is the case following somatic cell nuclear transfer. Full article

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing Mycobacterium tuberculosis (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance. Full article

Periodontal ligament mesenchymal stem cells (PL-MSCs) are vital for both periodontal regeneration and alveolar bone maintenance, including their turnover during orthodontic therapy. Chronic periodontal inflammation, mainly caused by Gram-negative bacterial lipopolysaccharides (LPS), interferes with osteogenic differentiation and leads to bone loss. Increasing evidence indicates that long non-coding RNAs (lncRNAs) link inflammatory signaling to osteogenic regulation, but their specific role in LPS-driven modulation of PL-MSC osteogenesis is not well understood. The aim of this study was to assess the effects of LPS from two bacterial strains on PL-MSCs differentiation. Human PL-MSCs were cultured under standard stem cell or osteogenic conditions and treated with LPS from Escherichia coli or Porphyromonas gingivalis. Mineralization was assessed using Alizarin Red staining. Osteogenic differentiation was evaluated through immunocytochemical analysis of osteopontin, collagen type 1, osteocalcin, osteonectin, and dentin matrix protein-1 (DMP-1). Expression levels of lncRNAs growth arrest-specific transcript 5 (GAS5), Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), maternally expressed gene 3 (MEG3) and Nuclear Enriched Abundant Transcript 1 (NEAT1) were measured by real-time PCR at 6, 24 and 48 h of LPS exposure. Exposure to E. coli LPS significantly inhibited extracellular matrix mineralization and decreased the expression of key osteogenic markers, indicating impaired osteoblast maturation. In contrast, P. gingivalis LPS caused a partial, dysregulated osteogenic response, marked by increased expression of osteopontin, osteonectin, and dentin matrix protein-1 (DMP-1), but without complete differentiation. LPS types altered lncRNA expression profiles, suggesting that non-coding regulatory networks are involved in inflammation-induced osteogenic dysregulation. Multivariate analyses showed decreased expression of GAS5, MEG3, and MALAT1 in the LPS vs. CTR comparison, decreased COL1A1 in LPS-PG vs. CTR, and increased OSTEOPONTIN in LPS vs. CTR. Differentiation was significantly associated with reduced expression of XIST and NEAT1. Time exerted significant effects on GAS5, MEG3, XIST, and MALAT1, with lower expression at 48 h compared with 6 h, and on COL1A1, which was significantly reduced at both 24 h and 48 h relative to 6 h. Bacterial LPS disrupt osteogenic differentiation of PL-MSCs depending on the species, affecting matrix formation, mineralization, and lncRNA expression. These findings highlight lncRNA-mediated communication between inflammatory signals and osteogenic pathways, providing new insights into the molecular mechanisms of inflammation-related bone remodeling in periodontal disease and orthodontic movements. Targeting lncRNA-regulated pathways could be a promising strategy to enhance periodontal regeneration during inflammation and also ensure optimum outcomes in orthodontic therapy. Full article

This paper examines the technological dimension of “handwritten time” a distinctive mode of existence of the Russian Avant-garde. By the mid-1930s, the avant-garde’s stylistic confrontation with Socialist Realism had effectively expelled it from the contemporary literary process, artificially arresting its development—an instance of “unfinished modernity.” The article offers a detailed analysis of the technology of self-archiving (“lit-recycling”) developed by Aleksei Kruchyonykh: a deliberately chosen strategy of uncensored writing oriented toward an implicit reader of the future. The conscious refusal to complete the conventional publishing cycle, together with the systematic archiving of materials, generated a new pragmatics of the Russian avant-garde, enabling continued work under conditions of total censorship. The study considers both the strengths of this pragmatics of self-isolation and its unavoidable costs, above all the rupture of author–reader communication. Drawing on workbooks and diary notebooks from the 1930s, it reconstructs an archiving technology that had fully matured by that decade: the balance between draft and fair copy, as well as the mechanisms of auto-communication and self-censorship. Each stage of textual work is shown to acquire a specific function within a single technological continuum. Special attention is paid to contemporary methods for reconstructing the avant-garde’s creative records. The article reconstructs successive versions of Kruchyonykh’s poems (“Irina in the Fog,” “Trash,” “All Dead Poets…,” “Mind You!,” “Grumbling,” etc.), and cites diaries and handwritten books. It also foregrounds Kruchyonykh’s “prophetic” texts—those marked by a premonition of the coming great war—which conclude his diary and creative notebooks of the 1930s. Full article

Early childhood caries (SECC) in children aged 3–4 years is a high-burden condition with consequences that extend beyond the dentition, including pain, infection, sleep disturbance, impaired nutrition, disrupted family functioning, and diminished quality of life. In contemporary pediatric practice, 38% silver diamine fluoride (SDF) and other minimally invasive approaches are widely used to stabilize disease while behavior matures, preventive strategies are intensified, or access to definitive care is secured. This perspective argues that SDF should be conceptualized not as a standalone solution, but as an evidence-supported interim stabilization strategy embedded within a defined, goal-directed care pathway. Its use is most appropriate when framed as a means of buying time under clear clinical intent, particularly in cases where teeth are expected to remain functional for years, symptoms are present, structural integrity is compromised, or follow up is uncertain. Although clinical guidelines and systematic reviews support SDF for arresting cavitated lesions in primary teeth, current evidence does not support its use as a universal long-term treatment for severe disease. Real-world data suggest that many SDF-treated teeth require additional intervention within approximately 2 years, and that delays to definitive care—including treatment under sedation or general anesthesia when indicated—are often relatively short. In response, this paper proposes a practical bridge-to-destination framework grounded in three principles: explicit treatment intent, child-centered outcomes, and predefined exit criteria to ensure a timely transition to definitive dental care. Rather than discouraging SDF use, this approach seeks to optimize its role within a continuum of dental care, emphasizing proportionality, transparency, and durable outcomes for children. Full article

Despite the growing interest in brain structural plasticity and the substantial body of knowledge that has accumulated over recent decades, some issues remain poorly defined, leading to confusion in the interpretation of results. In addition to stem cell-driven neurogenesis in adult neurogenic niches (adult neurogenesis), neuronal precursors in a state of arrested maturation have also been described, representing a form of neurogenesis without division based on so-called “immature” or late-maturing neurons. These processes occur in different brain regions yet share certain molecular markers and temporal windows. Recent advances in comparative neuroplasticity have further complicated our understanding. Studies reveal a reduction in adult neurogenesis in the olfactory bulb and hippocampus of large-brained, gyrencephalic mammals compared with small-brained species such as rodents. Conversely, a higher prevalence of immature neurons has been reported in the neocortex and amygdala of larger-brained mammals. It is becoming evident that evolutionary trade-offs took place in distinct plastic processes, resulting in the predominance of certain forms in particular species, while others coexist and share overlapping markers. Regardless of the approach employed (neuroanatomical, immunocytochemical, phylogenetic, or transcriptional), current evidence indicates substantial heterogeneity in cell types with different origins and fates across diverse mammalian species. These patterns appear to be sculpted by evolutionary pressures yet unified by shared transient maturational states. Full article

Female reproductive aging is associated with a progressive decline in oocyte competence and reduced success in assisted reproductive technologies. While chromosomal abnormalities, mitochondrial dysfunction, and DNA damage have been extensively studied, these mechanisms do not fully explain developmental arrest in chromosomally euploid embryos or the variability in embryo competence. Human oocytes enter a transcriptionally quiescent state during meiotic maturation and rely almost entirely on the regulated translation of stored maternal messenger RNAs to support fertilization and early embryonic development until zygotic genome activation. In this context, translational fidelity becomes a critical determinant of proteome integrity and cellular function. Age-related alterations affecting ribosomal RNA integrity, transfer RNA modification, aminoacylation accuracy, and translational regulatory networks may impair the precision, timing, and coordination of protein synthesis. These defects can disrupt essential processes such as spindle assembly, cytoskeletal organization, and early cleavage dynamics, ultimately compromising embryo viability despite chromosomal normality. In addition, the follicular microenvironment, including redox balance, metabolic support, and signaling pathways, plays a crucial upstream role in maintaining translational integrity. This review integrates mechanistic evidence from molecular, cellular, and developmental studies to propose that progressive decline in translational fidelity represents a fundamental and previously underrecognized driver of reproductive aging. Understanding translational control as a central regulator of oocyte competence may provide new insights into unexplained IVF failure and support the development of novel biomarkers and therapeutic strategies aimed at preserving reproductive potential. Full article

Time delays are intrinsic to mitotic regulation, particularly within the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). These delays emerge from multi-step protein activation, molecular transport, force-dependent conformational transitions, and spatial redistribution of regulatory complexes. They span seconds to minutes and strongly influence checkpoint activation, maintenance, and silencing. Increasing evidence shows that such delayed processes shape mitotic timing, checkpoint robustness, and cell-fate decisions. While classical ordinary differential equation (ODE) models assume instantaneous biochemical responses, delay differential equations (DDEs) provide a natural framework for representing these finite timescales by explicitly incorporating system history. Recent DDE-based studies have revealed how delayed signaling contributes to bistability, oscillatory responses, prolonged mitotic arrest, and variability in checkpoint outputs. This review summarizes the biological origins of delays in SAC and SPOC, including Mad2 activation, MCC assembly and turnover, APC/C reactivation, tension maturation at kinetochores, and Bfa1–Bub2 regulation of Tem1. The article further discusses how mechanistic models with explicit delays improve our understanding of SAC–SPOC ordering, error-correction dynamics, and mitotic exit control. Finally, open challenges and future directions are outlined for integrative delay-aware modeling that unifies biochemical, mechanical, and spatial processes to better explain checkpoint function and chromosomal stability. Full article

Two rearing systems are used for Plectropomus leopardus: sea-cage culture and the land-based flow-through aquaculture system. Cages approximate natural conditions and yield many high-quality eggs but offer limited control over ovarian development; the land-based system is highly controllable yet ovaries develop slowly and seldom reach full maturity. We compared these systems by analyzing growth–gonad relationships, monthly hormone profiles (GnRH, E2, GnIH), and hypothalamic transcriptomes in 14- and 18-month-old females. Within each system, body weight did not predict gonadal stage and energy allocation was size-independent. In cages, ovaries reached full maturity with normal histology; in tanks, gonads of all sizes remained at stage III, indicating arrested development. Serum GnRH and E2 displayed parallel increases from 12 to 14 months, declined at 16 months and surged at 18 months in both systems, while GnIH fluctuated inversely, suggesting antagonistic control. Transcriptome analysis identified fshr, cyp11a1 and sox17 as key down-regulated genes in tank-reared fish. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment implicated GnRH, oxidative phosphorylation, ribosome and Wnt pathways in ovarian progression. These findings elucidate reproductive constraints under artificial conditions and provide molecular targets for controllable breeding of P. leopardus. Full article

GATA transcription factors, defined by their zinc finger DNA-binding domains, are central regulators of tissue development. They modulate gene expression by activating or repressing transcription, thereby coordinating cellular differentiation and cell cycle exit to maintain homeostasis. In progenitor cells, GATA factors promote proliferation, whereas in differentiating cells, they drive maturation and induce cell cycle arrest. Dysregulation of GATA factors has been linked to tumorigenesis and contributes significantly to cancer progression and metastasis. Mutations in GATA factor genes correlate with poor prognosis in multiple cancers, where they influence key oncogenic processes, including sustained proliferative signaling, activation of epithelial–mesenchymal transition, angiogenesis, resistance to cell death, and immune escape. Importantly, their context-dependent roles across tumor types highlight the complexity of their functions in malignancies. Meanwhile, non-coding RNAs have emerged as critical regulators of gene expression, acting as either tumor suppressors or oncogenes by modulating chromatin dynamics, transcription factor activity, and mRNA stability. Despite this, the regulation of GATA transcriptional activity by non-coding RNAs remains largely unexplored. This review highlights the role of GATA factors in regulating EMT and metastasis and focuses on the interplay between non-coding RNAs and GATA transcription factors in cancer progression, proposing a novel regulatory axis with potential implications for biomarker discovery and therapeutic targeting. Full article

Preterm birth has evolved from being an acute neonatal challenge to a lifelong health determinant, as advances in neonatal care have markedly improved the survival of very and extremely preterm infants. This narrative review synthesizes epidemiological and mechanistic evidence linking preterm birth with heightened cardiometabolic risk across the life course. In adulthood, individuals born preterm demonstrate increased rates of heart failure, ischemic heart disease, stroke, atrial fibrillation, and diabetes. Beneath these overt clinical outcomes lies a distinct phenotype characterized by increased adiposity, insulin resistance, dyslipidemia, hypertension, and atypical growth trajectories, with rapid catch-up growth amplifying long-term risk. Mechanistic pathways highlight adipose tissue maldevelopment, predisposing to metabolic syndrome, alongside cardiac maldevelopment with reduced ventricular size, impaired diastolic function, and diminished exercise capacity. Furthermore, vascular growth arrest, impaired elastin synthesis, and nephron deficiency contribute to sustained elevations in blood pressure, establishing an early substrate for hypertension and cardiovascular remodeling. These alterations reflect the developmental origins of health and disease, whereby early-life disruption of growth and maturation exerts lasting effects on organ structure and function. Collectively, the evidence identifies adults born preterm as a growing yet under-recognized patient population with a unique clinical and biochemical profile and accelerated vulnerability to non-communicable diseases. Greater awareness among pediatric and adult physicians, structured transition of care, and targeted prevention strategies are urgently needed to mitigate early cardiometabolic morbidity and optimize long-term health outcomes in this high-risk group. Full article

Acinetobacter baumannii (A. baumannii) is an opportunistic pathogen associated with healthcare-related infections and is of particular concern due to its high level of antibiotic resistance and its ability to form biofilms. The global emergence of carbapenem-resistant A. baumannii highlights the urgent need for alternative therapeutic strategies. This study investigated the antibacterial and antibiofilm activities of two scorpion venom-derived peptides, pantinin-1 and pantinin-2, against a reference strain and a clinical isolate of A. baumannii. We found that both peptides, in the non-cytotoxic concentration range, have strong bactericidal activity, showing a minimum inhibitory concentration (MIC) of 6.25 μM and 12.5 μM for pantinin 1 and 2, respectively. Scanning electron microscopy (SEM) analysis showed that the peptides cause extensive damage to the bacterial membrane. Furthermore, both peptides showed potent antibiofilm activity, inhibiting adhesion and maturation, arresting biofilm expansion, and reducing the expression of key biofilm-associated genes (bap, pgaA, and smpA). Altogether, these findings indicate that pantinin-1 and pantinin-2 act through a dual mechanism, combining bactericidal and antivirulence activities. Their strong efficacy at low micromolar concentrations, together with low cytotoxicity, underscores their potential as innovative therapeutic candidates against infections caused by carbapenem-resistant, biofilm-forming A. baumannii. Full article