PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models.

Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination. Our data show that this synergistic response is dependent on AHR/ARNT and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.

Nuclear translocation of nucleotide enzyme Phosphoglucomutase 2 governs DNA damage response and anti-tumor immunity.

Targeting nucleotide enzymes emerges as a promising avenue for impeding tumor proliferation and fortifying anti-tumor immunogenicity. The non-canonical role of nucleotide enzymes remains poorly understood. In this study, we have identified that Phosphoglucomutase 2 (PGM2) rapidly accumulates at the DNA damage site to govern the DNA damage response mediated by the phosphorylation at Serine 165 and by forming a complex with Rho-associated coiled-coil-containing protein kinase 2 (ROCK2). Silencing PGM2 in Glioblastoma Multiforme (GBM) cells heightens DNA damage in vitro and enhances the sensitivity of temozolomide (TMZ) treatment by activating anti-tumor immunity in vivo. Furthermore, we demonstrate that pharmacological inhibition of ROCK2 synergistically complements TMZ treatment and pembrolizumab (PD-L1) checkpoint immunotherapy, augmenting anti-tumor immunity. This study reveals the non-canonical role of the nucleotide enzyme PGM2 in the regulation of DNA damage response and anti-tumor immunity, with implications for the development of therapeutic approaches in cancer treatment.

Mirids secrete a TOPLESS targeting protein to enhance JA-mediated defense and gossypol accumulation for antagonizing cotton bollworms on cotton plants.

Most coexisting insect species exhibit stunted growth compared to the single species on plants. This phenomenon reflects an interspecific antagonism that draws extensive attention while the underlying mechanisms remain largely unknown. Mirids (Apolygus lucorum) and cotton bollworms (Helicoverpa armigera) are two common pests in cotton fields. We identified a secretory protein, ASP1, from the oral secretion of mirids, which was found in the nucleus of mirid-infested cotton leaves. ASP1 specifically targets the transcriptional corepressor TOPLESS (TPL) and inhibits NINJA-mediated recruitment of TPL, thereby promoting plant defense response and gossypol accumulation in cotton glands. ASP1-enhanced defense inhibits the growth of cotton bollworms on cotton plants, while having little impact on mirids. The mesophyll-feeding characteristic allows mirids to avoid most cotton glands, thereby invalidating cotton defense. Our investigation reveals the molecular mechanism by which mirids employ cotton defense to selectively inhibit the feeding of cotton bollworms.

Polysaccharides from Lanzhou Lily Attenuate Induced Nonalcoholic Fatty Liver Disease Modifying the Gut Microbiota and Metabolite Profile.

Nonalcoholic fatty liver disease (NAFLD) is closely related to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for treating NAFLD. However, the therapeutic effects and potential molecular mechanisms of Lanzhou Lily polysaccharides (LLP) on NAFLD remains unclear. Therefore, the alleviating effects of LLP on NAFLD induced by high-fat diet (HFD) were investigated. LLP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFD-induced NAFLD mice, as evidenced by decreased serum levels of TG, TC, HDL-C and LDL-C. Furthermore, LLP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. LLP also inhibited the TNF-α and IL-1ß expression, thereby reducing levels of hepatic proinflammatory cytokines. Furthermore, LLP restored gut microbiota dysbiosis, and regulated microbial metabolic pathways such as primary bile acid biosynthesis and amino acid metabolism. In addition, the resultes of Spearman's correlation analysis found that some key metabolites in these metabolic pathways were associated with intestinal microorganisms such as Desulfobacterota, Prevotellaceae-UCG-001, Colidextribacter and Alistipes. Therefore, our study suggests that LLP may has potential applications in the treatment of NAFLD by regulating gut microbiota and its metabolite profile.

mInsc coordinates Par3 and NuMA condensates for assembly of the spindle orientation machinery in asymmetric cell division.

As a fundamental process governing the self-renewal and differentiation of stem cells, asymmetric cell division is controlled by several conserved regulators, including the polarity protein Par3 and the microtubule-associated protein NuMA, which orchestrate the assembly and interplay of the Par3/Par6/mInsc/LGN complex at the apical cortex and the LGN/Gαi/NuMA/Dynein complex at the mitotic spindle to ensure asymmetric segregation of cell fate determinants. However, this model, which is well-supported by genetic studies, has been challenged by evidence of competitive interaction between NuMA and mInsc for LGN. Here, the solved crystal structure of the Par3/mInsc complex reveals that mInsc competes with Par6ß for Par3, raising questions about how proteins assemble overlapping targets into functional macromolecular complexes. Unanticipatedly, we discover that Par3 can recruit both Par6ß and mInsc by forming a dynamic condensate through phase separation. Similarly, the phase-separated NuMA condensate enables the coexistence of competitive NuMA and mInsc with LGN in the same compartment. Bridge by mInsc, Par3/Par6ß and LGN/NuMA condensates coacervate, robustly enriching all five proteins both in vitro and within cells. These findings highlight the pivotal role of protein condensates in assembling multi-component signalosomes that incorporate competitive protein-protein interaction pairs, effectively overcoming stoichiometric constraints encountered in conventional protein complexes.

Estimation of the Global Disease Burden of Depression and Anxiety between 1990 and 2044: An Analysis of the Global Burden of Disease Study 2019.

(1) Background: Depression and anxiety are the most common and severe mental disorders. This research estimated the prevalence and disease burden of depression and anxiety from 1990 to 2044. (2) Methods: Data on disease burden, population, and risk factors were identified and gathered from the Global Health Data Exchange database. The time trends, sex and age differences, key factors, and regional variations in and predictions of depression and anxiety were analyzed based on the age-standardized incidence rate, prevalence rate, and DALY rate. (3) Results: Our findings revealed that the burden of depression and anxiety was heavy. Specifically, the age-standardized DALY rate of depression started to decrease compared with trends related to anxiety disorders. Meanwhile, females bear a heavier burden for both depression and anxiety. Seniors and the middle-aged population carry the highest burden regarding mental disorders. Both high- and low-socio-demographic-index countries were found to be high-risk regions for depressive disorders. The disease burden attributed to childhood sexual abuse, bullying victimization, and intimate partner violence has increased since 1990. Finally, projections regarding depression and anxiety revealed geographic and age variations. (4) Conclusions: Public health researchers, officers, and organizations should take effective age-, sex-, and location-oriented measures.

The Association of Myopia Progression with Changes in Retinal Thickness among Primary School Students with Myopia.

Purpose: To observe the relationship between myopia progression and changes in retinal thickness during one year of follow-up among primary school children. Methods: The study included 1161 eyes of 708 myopic children, with 616 (53.06%) right eyes and 545 (46.94%) left eyes. The participants underwent a comprehensive ophthalmic examination, including visual acuity, axial length (AL), autorefraction, and optical coherence tomography (OCT) examination in 2016 and in 2017. An analysis was conducted on the differences in retinal thickness between different genders and between high myopia and nonhigh myopia. Furthermore, the study delved into the correlation between the progression of myopia and the changes of retinal thickness. Results: The average diopter was -1.83 ± 1.29D, average AL was 23.78 ± 0.94 mm, and average foveal thickness was 228.02 ± 23.00 µm. For the inner retina, the median value [the lower quartile value, the upper quartile value] of the foveal thickness was thicker in the high myopia group than the nonhigh myopia group (67 [64; 74] µm vs. 63 [56; 70] µm), while the parafoveal region and perifoveal region were thinner in the high myopia group than the nonhigh myopia group (106 [100; 123] µm vs. 124 [117; 130] µm; 95.0 [93; 102] µm vs. 104 [100; 108] µm). Among all the children with myopia, 67.53% (784/1161) of them have a diopter progression within one year. The AL progression was 95.43% (1108/1161). The retinal thickness of all children has slightly increased in various regions. As the AL of the eye increased and the diopter decreased, the progression degree of inner retinal thickness and full retinal thickness (exclusive of full fovea) decreased. Conclusion: For the school-age myopic children, the inner foveal retinal thickness were thicker in highly myopic students than in the nonhighly myopic students, while the parafoveal and perifoveal retina were thinner in highly myopic students. The inner and full retinal thicknesses of male students were thicker than that of females. The progression of myopia mainly affected the changes of the inner retinal thickness in the one-year follow-up.

Optical Coherence Tomography-Guided Stenting for Common Carotid Free-Floating Thrombus.

CLINICAL IMPACT: Digital subtraction angiography (DSA) has traditionally been considered an effective method for visualizing carotid free-floating thrombus (CFFT), but it falls short in providing detailed structures of the lumen and the composition of thrombi, making it challenging to determine the etiology. Intravascular optical coherence tomography (OCT) is a valuable adjunct to DSA that can precisely evaluate the characteristics of the intrinsic vessel wall and accurately distinguish between red and white thrombus, providing clues to the etiology of CFFTs. Moreover, OCT not only precisely determined the scope of a floating thrombus but also provided guidance for decision-making in endovascular treatment.

Endoscopic Endonasal Approach to the Ventral Petroclival Fissure: Anatomical Findings and Surgical Techniques.

Objective The endoscopic endonasal approach has emerged as an excellent option for the treatment of lesions involving the petroclival fissure (PCF). Here, we investigate the surgical anatomy of the ventral PCF and its application in endoscopic endonasal surgery. Methods Sixteen head specimens were used to investigate the anatomical features of PCF and relevant technical nuances in translacerum, extreme medial, and contralateral transmaxillary (CTM) approaches. Two representative endoscopic endonasal surgeries involving the PCF were selected to illustrate the clinical application. Results From the endoscopic endonasal view, the ventral PCF is presented as a lazy L sign, which is divided into two distinct segments: (1) upper (or petrosphenoidal) segment, which extends vertically from the foramen lacerum inferiorly to the junction of the petrosal process of sphenoid bone and petrous apex superiorly, and (2) lower (or petroclival) segment, which extends inferolaterally from the foramen lacerum to the ventral jugular foramen. Approaching both segments of the ventral PCF first requires full exposure of the foramen lacerum, followed either by exposure of the anterior wall of cavernous sinus and paraclival internal carotid artery for upper segment access, or transection of pterygosphenoidal fissure and Eustachian tube mobilization for lower segment access. Combined with a CTM approach, the lateral extension of the surgical access can be improved for both upper and lower segment PCF approaches. Conclusion This study provides a detailed investigation of the microsurgical anatomy of the ventral part of PCF, relevant surgical approaches, and technical nuances that may facilitate its safe exposure intraoperatively.

Whole-exome sequencing identifies protein-coding variants associated with brain iron in 29,828 individuals.

Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson's (STAB1, KCNA10), Alzheimer's (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson's. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Branch Chain Amino Acid Metabolism Promotes Brain Metastasis of NSCLC through EMT Occurrence by Regulating ALKBH5 activity.

Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.

Prognostic Capability of Clinical SYNTAX Score in Patients with Complex Coronary Artery Disease and Chronic Renal Insufficiency Undergoing Percutaneous Coronary Intervention.

Background: The SYNTAX score (SS) is useful for predicting clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). The clinical SYNTAX score (CSS), developed by combining clinical parameters with the SS, enhances the risk model's ability to predict clinical outcomes. However, prior research has not yet evaluated the prognostic capacity of CSS in patients with complex coronary artery disease (CAD) and chronic renal insufficiency (CRI) who are undergoing PCI. We aimed to demonstrate the prognostic potential of CSS in assessing long-term adverse events in this high-risk patient cohort. Methods: A total of 962 patients with left main and/or three-vessel CAD and CRI were enrolled in the study spanning from January 2014 to September 2017. The CSS was calculated by multiplying the SS by the modified age, creatinine, and left ventricular ejection fraction (ACEF) score (age/ejection fraction + 1 for each 10 mL of creatinine clearance < 60 mL/min per 1.73 m 2 ). The patients were categorized into three groups based on their CSS values: low-CSS group (CSS < 18.0, n = 321), mid-CSS group (18.0 ≤ CSS < 28.3, n = 317), and high-CSS group (CSS ≥ 28.3, n = 324) as per the tertiles of CSS. The primary endpoints were all-cause mortality (ACM) and cardiac mortality (CM). The secondary endpoints included myocardial infarction (MI), unplanned revascularization, stroke, and major adverse cardiac and cerebrovascular events (MACCE). Results: At the median 3-year follow-up, the high-CSS group exhibited higher rates of ACM (19.4% vs. 6.6% vs. 3.6%, p < 0.001), CM (15.6% vs. 5.1% vs. 3.2%, p = 0.003), and MACCE (33.8% vs. 29.0% vs. 20.0%, p = 0.005) in comparison to the low and mid-CSS groups. Multivariable Cox regression analysis revealed that CSS was an independent predictor for all primary and secondary endpoints (p < 0 .05). Moreover, the C-statistics of CSS for ACM (0.666 vs. 0.597, p = 0.021) and CM (0.668 vs. 0.592, p = 0.039) were significantly higher than those of SS. Conclusions: The clinical SYNTAX score substantially enhanced the prediction of median 3-year ACM and CM in comparison with SS in complex CAD and CRI patients following PCI.

Aluminum hydroxide and immunostimulatory glycolipid adjuvant combination for enhanced COVID-19 subunit vaccine immunogenicity.

Protein-based subunit vaccines like RBD-Fc are promising tools to fight COVID-19. RBD-Fc fuses the receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein with the Fc region of human IgG1, making it more immunogenic than RBD alone. Earlier work showed that combining RBD-Fc with iNKT cell agonists as adjuvants improved neutralizing antibodies but did not sufficiently enhance T cell responses, a limitation RBD-Fc vaccines share with common adjuvants. Here we demonstrate that aluminum hydroxide combined with α-C-GC, a C-glycoside iNKT cell agonist, significantly improved the RBD-Fc vaccine's induction of RBD-specific T-cell responses. Additionally, aluminum hydroxide with α-GC-CPOEt, a phosphonate diester derivative, synergistically elicited more robust neutralizing antibodies. Remarkably, modifying αGC with phosphate (OPO3H2) or phosphonate (CPO3H2) to potentially enhance aluminum hydroxide interaction did not improve efficacy over unmodified αGC with aluminum hydroxide. These findings underscore the straightforward yet potent potential of this approach in advancing COVID-19 vaccine development and provide insights for iNKT cell-based immunotherapy.

Application of individual brain connectome in chronic ischemia: mapping symptoms before and after reperfusion.

How brain functions in the distorted ischemic state before and after reperfusion is unclear. It is also uncertain whether there are any indicators within ischemic brain that could predict surgical outcomes. To alleviate these issues, we applied individual brain connectome in chronic steno-occlusive vasculopathy (CSOV) to map both ischemic symptoms and their postbypass changes. A total of 499 bypasses in 455 CSOV patients were collected and followed up for 47.8 ± 20.5 months. Using multimodal parcellation with connectivity-based and pathological distortion-independent approach, areal MR features of brain connectome were generated with three measurements of functional connectivity (FC), structural connectivity, and PageRank centrality at the single-subject level. Thirty-three machine-learning models were then trained with clinical and areal MR features to obtain acceptable classifiers for both ischemic symptoms and their postbypass changes, among which, 11 were deemed acceptable (AUC > 0.7). Notably, the FC feature-based model for long-term neurological outcomes performed very well (AUC > 0.8). Finally, a Shapley additive explanations plot was adopted to extract important individual features in acceptable models to generate "fingerprints" of brain connectome. This study not only establishes brain connectomic fingerprint databases for brain ischemia with distortion, but also provides informative insights for how brain functions before and after reperfusion.

Effects of airflow superfine pulverization on the structure, functional properties, and flavor quality of wheat bran.

BACKGROUND: Wheat bran (WB) is a byproduct of refined wheat flour production with poor edible taste and low economic value. Herein, the WB was micronized via airflow superfine pulverization (ASP), and the effects of the ASP conditions on its particle size, nutritive compositions, whiteness, hydration characteristics, moisture distribution, microstructure, cation exchange capacity, volatile flavor components, and other characteristics were investigated. RESULTS: Reducing the rotational speed of the ASP screw and increasing the number of pulverizations significantly decreased the median particle size Dx(50) of WB to a minimum of 12.97 ± 0.19 µm (P < 0.05), increased the soluble dietary fiber content from 55.05 ± 2.94 to 106.86 ± 1.60 mg g-1, and improved the whiteness and water solubility index. In addition, the water holding capacity and oil holding capacity were significantly reduced (P < 0.05), while the cation exchange and swelling capacities first increased and then decreased. Up to about 70% of water in WB exists as bound water. As the Dx(50) of WB decreased, the content of bound and immobile water increased, while the free water decreased from 14.37 ± 1.21% to 7.59 ± 1.03%. Furthermore, WB was micronized and the particles became smaller and more evenly distributed. Using gas chromatography-ion mobility spectrometry, a total of 37 volatile compounds in micronized WB (including 10 aldehydes, 9 esters, 7 alcohols, and several acids, furans, ethers, aldehydes, esters, and alcohols) were identified as the main volatile compounds of WB. CONCLUSION: Collectively, ASP improved the physicochemical properties of WB. This study provides theoretical references for the use of ASP to improve the utilization and edibility of WB. © 2024 Society of Chemical Industry.

Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.

The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.

Study on the Structure and Properties of Silk Fibers Obtained from Factory All-Age Artificial Diets.

The traditional production mode of the sericulture industry is no longer suitable for the development requirements of modern agriculture; to facilitate the sustainable development of the sericulture industry, factory all-age artificial diet feeding came into being. Understanding the structural characteristics and properties of silk fibers obtained from factory all-age artificial diet feeding is an important prerequisite for application in the fields of textiles, clothing, biomedicine, and others. However, there have been no reports so far. In this paper, by feeding silkworms with factory all-age artificial diets (AD group) and mulberry leaves (ML group), silk fibers were obtained via two different feeding methods. The structure, mechanical properties, hygroscopic properties, and degradation properties were studied by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Structurally, no new functional groups appeared in the AD group. Compared with the ML group, the structure of the two groups was similar, and there was no significant difference in mechanical properties and moisture absorption. The structure of degummed silk fibers is dominated by crystalline regions, but α-chymotrypsin hydrolyzes the amorphous regions of silk proteins, so that after 28 d of degradation, the weight loss of both is very small. This provides further justification for the feasibility of factory all-age artificial diets for silkworms.

Regulation of Glandular Size and Phytoalexin Biosynthesis by a Negative Feedback Loop in Cotton.

Plants have evolved diverse defense mechanisms encompassing physical and chemical barriers. Cotton pigment glands are known for containing various defense metabolites, but the precise regulation of gland size to modulate defense compound levels remains enigmatic. Here, it is discovered that the VQ domain-containing protein JAVL negatively regulates pigment gland size and the biosynthesis of defense compounds, while the MYC2-like transcription factor GoPGF has the opposite effect. Notably, GoPGF directly activates the expression of JAVL, whereas JAVL suppresses GoPGF transcription, establishing a negative feedback loop that maintains the expression homeostasis between GoPGF and JAVL. Furthermore, it is observed that JAVL negatively regulates jasmonate levels by inhibiting the expression of jasmonate biosynthetic genes and interacting with GoPGF to attenuate its activation effects, thereby maintaining homeostatic regulation of jasmonate levels. The increased expression ratio of GoPGF to JAVL leads to enlarged pigment glands and elevated jasmonates and defense compounds, enhancing insect and pathogen resistance in cotton. These findings unveil a new mechanism for regulating gland size and secondary metabolites biosynthesis, providing innovative strategies for strengthening plant defense.

Single-Cell Chromatin Accessibility Analysis Reveals Subgroup-Specific TF-NTR Regulatory Circuits in Medulloblastoma.

Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the regulatory program driving malignancy in MB cells and their interactions with the microenvironment remains insufficiently understood. Leveraging the capabilities of single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq), the chromatin accessibility landscape is unveiled across 59,015 distinct MB cells. This expansive dataset encompasses cells belonging to discrete molecular subgroups, namely SHH, WNT, Group3, and Group4. Within these chromatin accessibility profiles, specific regulatory elements tied to individual subgroups are uncovered, shedding light on the distinct activities of transcription factors (TFs) that likely orchestrate the tumorigenesis process. Moreover, it is found that certain neurotransmitter receptors (NTRs) are subgroup-specific and can predict MB subgroup classification when combined with their associated transcription factors. Notably, targeting essential NTRs within tumors influences both the in vitro sphere-forming capability and the in vivo tumorigenic capacity of MB cells. These findings collectively provide fresh insights into comprehending the regulatory networks and cellular dynamics within MBs. Furthermore, the significance of the TF-NTR regulatory circuits is underscored as prospective biomarkers and viable therapeutic targets.

Employment of diverse in vitro systems for analyzing multiple aspects of disease, hereditary hemorrhagic telangiectasia (HHT).

BACKGROUND: In vitro disease modeling enables translational research by providing insight into disease pathophysiology and molecular mechanisms, leading to the development of novel therapeutics. Nevertheless, in vitro systems have limitations for recapitulating the complexity of tissues, and a single model system is insufficient to gain a comprehensive understanding of a disease. RESULTS: Here we explored the potential of using several models in combination to provide mechanistic insight into hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder. Genome editing was performed to establish hPSCs (H9) with ENG haploinsufficiency and several in vitro models were used to recapitulate the functional aspects of the cells that constitute blood vessels. In a 2D culture system, endothelial cells showed early senescence, reduced viability, and heightened susceptibility to apoptotic insults, and smooth muscle cells (SMCs) exhibited similar behavior to their wild-type counterparts. Features of HHT were evident in 3D blood-vessel organoid systems, including thickening of capillary structures, decreased interaction between ECs and surrounding SMCs, and reduced cell viability. Features of ENG haploinsufficiency were observed in arterial and venous EC subtypes, with arterial ECs showing significant impairments. Molecular biological approaches confirmed the significant downregulation of Notch signaling in HHT-ECs. CONCLUSIONS: Overall, we demonstrated refined research strategies to enhance our comprehension of HHT, providing valuable insights for pathogenic analysis and the exploration of innovative therapeutic interventions. Additionally, these results underscore the importance of employing diverse in vitro systems to assess multiple aspects of disease, which is challenging using a single in vitro system.