Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in-ovo inhibition in quail embryos of retinoic acid activity followed by single cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers indicating a failure in proper lineage segregation. Furthermore, separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their critical role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. Together, the implementation of scRNA sequencing facilitated the discovery and characterization of a molecular mechanism responsible for the segregation of dorsal neural fates during development.

Intercellular communication is indispensable across multicellular organisms, and any aberration in this process can give rise to significant anomalies in developmental and homeostatic processes. Thus, a comprehensive understanding of its mechanisms is imperative for addressing human health-related concerns. Recent advances have expanded our understanding of intercellular communication by elucidating additional signaling modalities alongside established mechanisms. Notably, cellular protrusion-mediated long-range communication, characterized by physical contact through thin and elongated cellular protrusions between cells involved in signal transmission and reception, has emerged as a significant intercellular signaling paradigm. This chapter delves into the exploration of a signaling cellular protrusion termed \'airinemes,\' discovered in the zebrafish skin. It covers their identified signaling roles and the cellular and molecular mechanisms that underpin their functionality.

Cancer stem cells (CSCs) possess a significant ability to renew themselves, which gives them a strong capacity to form tumors and expand to encompass additional body areas. In addition, they possess inherent resistance to chemotherapy and radiation therapies used to treat many forms of cancer. Scientists have focused on investigating the signaling pathways that are highly linked to the ability of CSCs to renew themselves and maintain their stem cell properties. The pathways encompassed are Notch, Wnt/β-catenin, hedgehog, STAT3, NF-κB, PI-3K/Akt/mTOR, sirtuin, ALDH, MDM2, and ROS. Recent studies indicate that directing efforts towards CSC cells is essential in eradicating the overall cancer cell population and reducing the likelihood of tumor metastasis. As our comprehension of the mechanisms that stimulate CSC activity, growth, and resistance to chemotherapy advances, the discovery of therapeutic drugs specifically targeting CSCs, such as small-molecule compounds, holds the potential to revolutionize cancer therapy. This review article examines and analyzes the novel anti-CSC compounds that have demonstrated effective and selective targeting of pathways associated with the renewal and stemness of CSCs. We also discussed their special drug metabolism and absorption mechanisms. CSCs have been the subject of much study in cancer biology. As a possible treatment for malignancies, small-molecule drugs that target CSCs are gaining more and more attention. This article provides a comprehensive review of the current state of key small-molecule compounds, summarizes their recent developments, and anticipates the future discovery of even more potent and targeted compounds, opening up new avenues for cancer treatment.

Drosophila Hey is a basic helix-loop-helix-orange (bHLH-O) protein with an important role in the establishment of distinct identities of postmitotic cells. We have previously identified Hey as a transcriptional target and effector of Notch signalling during the asymmetric division of neuronal progenitors, generating neurons of two types, and we have shown that Notch-dependent expression of Hey also marks a subpopulation of the newborn enteroendocrine (EE) cells in the midgut primordium of the embryo. Here, we investigate the transcriptional regulation of Hey in neuronal and intestinal tissues. We isolated two genomic regions upstream of the promoter (HeyUP) and in the second intron (HeyIN2) of the Hey gene, based on the presence of binding motifs for Su(H), the transcription factor that mediates Notch activity. We found that both regions can direct the overlapping expression patterns of reporter transgenes recapitulating endogenous Hey expression. Moreover, we showed that while HeyIN2 represents a Notch-dependent enhancer, HeyUP confers both Notch-dependent and independent transcriptional regulation. We induced mutations that removed the Su(H) binding motifs in either region and then studied the enhancer functionality in the respective Hey mutant lines. Our results provide direct evidence that although both enhancers support Notch-dependent regulation of the Hey gene, their role is redundant, as a Hey loss-of-function lethal phenotype is observed only after deletion of all their Su(H) binding motifs by CRISPR/Cas9.

Adenoid cystic carcinoma (ACC) of head and neck origin is associated with slow but relentless progression and systemic metastasis, resulting in poor long-term survival rates. ACC does not respond to conventional chemotherapy. Determination of molecular drivers may provide a rational basis for personalized therapy. Herein, we investigate the clinical and detailed molecular genomic features of a cohort of patients treated in Ireland and correlate the site of origin, molecular features, and outcomes. Clinical and genomic landscapes of all patients diagnosed with ACC over a twenty-year period (2002-2022) in a single unit in Ireland were examined and analyzed using fluorescence in situ hybridization, DNA sequencing, and bioinformatic analysis. Fourteen patients were included for analysis. Eleven patients had primary salivary gland ACC and three primary lacrimal gland ACC; 76.9% of the analyzed tumors displayed evidence of NFIB-MYB rearrangement at the 6q23.3 locus; 35% had mutations in NOTCH pathway genes; 7% of patients had a NOTCH1 mutation, 14.3% NOTCH2 mutation, and 14.3% NOTCH3 mutation. The presence of epigenetic modifications in ACC patients significantly correlated with worse overall survival. Our study identifies genetic mutations and signaling pathways that drive ACC pathogenesis, representing potential molecular and therapeutic targets.

Alzheimer disease, the leading cause of dementia, and polycystic ovary syndrome, one of the most prevalent female endocrine disorders, appear to be unrelated conditions. However, studies show that both disease entities have common risk factors, and the amount of certain protein marker of neurodegeneration is increased in PCOS. Reports on the pathomechanism of both diseases point to the possibility of common denominators linking them. Dysregulation of the kynurenine pathway, insulin resistance, and impairment of the hypothalamic-pituitary-gonadal axis, which are correlated with amyloid-beta aggregation are these common areas. This article discusses the relationship between Alzheimer disease and polycystic ovary syndrome, with a particular focus on the role of disorders of tryptophan metabolism in both conditions. Based on a review of the available literature, we concluded that systemic changes occurring in PCOS influence the increased risk of neurodegeneration.

Retinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA sequencing of whole eyes from Xenopus at three embryonic stages and used differential expression analysis to define the transcriptomic profiles of optic tissues containing proliferating and differentiating RPCs during retinogenesis. Gene Ontology and KEGG pathway analyses showed that genes associated with developmental pathways (including Wnt and Hedgehog signaling) were upregulated during the period of active RPC proliferation in early retinal development (Nieuwkoop Faber st. 24 and 27). Developing eyes had dynamic expression profiles and shifted to enrichment for metabolic processes and phototransduction during RPC progeny specification and differentiation (st. 35). Furthermore, conserved adult eye regeneration genes were also expressed during early retinal development, including sox2, pax6, nrl, and Notch signaling components. The eye transcriptomic profiles presented here span RPC proliferation to retinogenesis and include regrowth-competent stages. Thus, our dataset provides a rich resource to uncover molecular regulators of RPC activity and will allow future studies to address regulators of RPC proliferation during eye repair and regrowth.

OBJECTIVE: Many individuals with healthy normal nasal anatomy and function exhibit a prominent notch indentation at the junction of the ala and sidewall, specifically around the anterior-superior region of the unilateral nasal vestibule up to the internal nasal valve. This study evaluates the influence of various sizes of notched indentations at the anterior nasal airway on local airflow pattern.
METHODS: A retrospective study involving 25 healthy individuals, each exhibiting at least one unilateral notched indentation (40 total airways). Each individual\'s notched indentation was quantified after subject-specific three-dimensional nasal airway reconstruction from radiographic images. Computational fluid dynamics modeling was used to simulate nasal inspiratory airflow in each nasal airway at 15 L/min. Localized airflow distributions passing through the inferior, middle, and superior regions were calculated at 15 cross sections.
RESULTS: Notched indentation size ranged 1.75-86.84 mm2 (average = 22.37 mm2). At the anterior airway, notched size significantly correlated with inferior airflow volume (R = 0.32, p = 0.04) but not in the middle (R = 0.21, p = 0.20) or superior (R = 0.06, p = 0.70) regions, whereas middle and superior regional resistance values were significantly correlated with notched size (middle: R = 0.54, p < 0.001; superior: R = 0.41, p = 0.009). Medially, resistance at the middle region significantly correlated with notched size (R = 0.56, p < 0.001). At the posterior airway, airflow distributions through the inferior, middle, and superior regions demonstrated weak correlation with notched size (inferior: R = 0.24, p = 0.14, middle: R = 0.24, p = 0.13; superior:R = 0.03, p = 0.83), whereas resistance was significantly correlated in the middle and inferior regions (middle: R = 0.56, p < 0.001;inferior: R = 0.43, p = 0.006).
CONCLUSIONS: Anterior nasal airway notched indentation size had significantly stronger influence on localized airflow volume through the anterior-inferior airway than other regions of the nasal passage.
METHODS: N/A Laryngoscope, 2024.

OBJECTIVE: Systemic therapy plays a major part in the cure of patients with early breast cancer (eBC). However, personalized treatment concepts are required to avoid potentially harmful overtreatment. Biomarkers are pivotal for individualized therapy. The Notch signalling pathway is widely considered as a suitable prognostic or predictive marker in eBC. This study aimed primarily at assessing the relationship between NOTCH1 mRNA expression levels and histopathological features of breast cancer tumors, as well as clinical characteristics of the correspondent eBC patients. As a secondary aim, we investigated the prognostic and predictive value of NOTCH1 by assessing possible associations between NOTCH1 mRNA expression and recurrence-free interval (RFI) and overall survival after five years of observation.
METHODS: The relative NOTCH1 mRNA expression was determined in 414 tumour samples, using quantitative PCR in a prospective, multicenter cohort (Prognostic Assessment in Routine Application (PiA), 2009-2011, NCT01592825) of 1,270 female eBC patients.
RESULTS: High NOTCH1 mRNA expression was detected in one-third of the tumours and was associated with negative hormone receptor status and high uPA/PAI-1 status. In addition, high NOTCH1 mRNA expression was found to be associated with more RFI related events (adjusted hazard ratio 2.1, 95% CI 1.077-4.118). Patients who received adjuvant chemotherapy and had high NOTCH1 mRNA expression in the tumour (n = 86) were three times more likely to have an RFI event (adjusted hazard ratio 3.1, 95% CI 1.321-7.245, p = 0.009).
CONCLUSIONS: In this cohort, NOTCH1 mRNA expression had a prognostic and predictive impact. Tumours with high NOTCH1 mRNA expression may be less sensitive to cytotoxic treatment and downregulation of the Notch signalling pathway (e.g. by γ-secretase inhibitors) may be valuable for eBC therapy as an individualised treatment option.

BACKGROUND: Papillary thyroid carcinoma (PTC) accounts for about 85% of thyroid cancer cases. Transmembrane protein 252 (TMEM252) is a gene encoding a transmembrane protein that has only been reported to be associated with triple-negative breast cancer. Herein, we first elucidated the physiological roles and possible regulatory proteins of TMEM252 in PTC pathogenesis.
METHODS: Quantitative real-time polymerase chain reaction, western blot, and immunohistochemical analyses were utilized to ascertain the relative TMEM252 expression in PTC and surrounding normal tissues. Functional investigations involved CCK-8 viability assay, EdU incorporation assay for proliferation, transwell assays for migration and invasion, and an in vivo tumor development assessment to evaluate the TMEM252-mediated regulation of tumor formation.
RESULTS: Our results first revealed diminished TMEM252 transcript and protein expressions in PTC tissues and cell lines. TMEM252 overexpression suppressed cell proliferation through reducing p53, p21, and p16 expression. Conversely, TMEM252 depletion has opposite effects in PTC cells both in vivo. Additionally, the upregulation of TMEM252 demonstrated cell migration and invasion suppression by impeding the epithelial-mesenchymal transition (EMT) process via inhibition of the Notch pathway. Furthermore, overexpression of TMEM252 suppressed tumor growth in vivo.
CONCLUSIONS: Our study elucidates that TMEM252 suppresses PTC progression by modulating the Notch pathway. These findings underscore TMEM252 is a potential therapeutic target in managing PTC.