EIF4A3-Induced CircDHTKD1 regulates glycolysis in non-small cell lung cancer via stabilizing PFKL.

Lung cancer (LC) is one of the malignancies with the highest incidence and mortality in the world, approximately 85% of which is non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) exert multiple roles in NSCLC occurrence and development. The sequencing results in previous literature have illustrated that multiple circRNAs exhibit upregulation in NSCLC. We attempted to figure out which circRNA exerts an oncogenic role in NSLCL progression. RT-qPCR evaluated circDHTKD1 level in NSCLC tissue specimens and cells. Reverse transcription as well as RNase R digestion assay evaluated circDHTKD1 circular characterization in NSCLC cells. FISH determined circDHTKD1 subcellular distribution in NSCLC cells. Loss- and gain-of-function assays clarified circDHTKD1 role in NSCLC cell growth, tumour growth and glycolysis. Bioinformatics and RIP and RNA pull-down assessed association of circDHTKD1 with upstream molecule Eukaryotic initiation factor 4A-III (EIF4A3) or downstream molecule phosphofructokinase-1 liver type (PFKL) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) in NSCLC cells. Rescue assays assessed regulatory function of PFKL in circDHTKD1-meidated NSCLC cellular phenotypes. CircDHTKD1 exhibited upregulation and stable circular nature in NSCLC cells. EIF4A3 upregulated circDHTKD1 in NSCLC cells. CircDHTKD1 exerted a promoting influence on NSCLC cell malignant phenotypes and tumour growth. CircDHTKD1 exerted a promoting influence on NSCLC glucose metabolism. CircDHTKD1 exerts a promoting influence on NSCLC glucose metabolism through PFKL upregulation. RIP and RNA pull-down showed that circDHTKD1 could bind to IGF2BP, PFKL could bind to IGF2BP2, and circDHTKD1 promoted the binding of PFKL to IGF2BP2. In addition, RT-qPCR showed that IGF2BP2 knockdown promoted PFKL mRNA degradation, suggesting that IGF2BP2 stabilized PFKL in NSCLC cells. CircDHTKD1 exhibits upregulation in NSCLC. We innovatively validate that EIF4A3-triggered circDHTKD1 upregulation facilitates NSCLC glycolysis through recruiting m6A reader IGF2BP2 to stabilize PFKL, which may provide a new direction for seeking targeted therapy plans of NSCLC.

Quasi-Discrete Pore Engineering via Ligand Racemization in Metal-Organic Frameworks for Thermodynamic-Kinetic Synergistic Separation of Propylene and Propane.

The adsorptive separation of propylene and propane offers an energy-efficient alternative to the conventional cryogenic distillation technology. However, developing porous adsorbents with both high equilibrium and kinetic selectivity remains extremely challenging due to the similar size and physical properties of these gases. Herein, this work reports a ligand racemization strategy to construct quasi-discrete pores in MOFs for a synergistically enhanced thermodynamic and kinetic separation performance. The use of enantiopure l-malic acid versus racemic dl-malic acid as ligands afforded isoreticular Ni-based MOFs with contrasting one-dimensional channels (l-mal-MOF) and quasi-discrete cavities connected by small windows (dl-mal-MOF). The periodic pore constrictions in dl-mal-MOF significantly increased the differentiation in diffusion rates and binding energies between propylene and propane. dl-mal-MOF exhibited an exceptional propylene uptake of 1.82 mmol/g at 0.05 bar and 298 K along with an ultrahigh equilibrium-kinetic combined selectivity of 62.6. DFT calculations and MD simulations provided insights into the synergistic mechanism of preferential propylene adsorption and diffusion. Breakthrough column experiments demonstrated the excellent separation and high-purity recovery of propylene over propane on dl-mal-MOF. The robust stability and facile regeneration highlight its potential for propylene purification applications.

Nonlinear 3D Ligand-Based Metal-Organic Framework for Thermodynamic-Kinetic Synergistic Splitting of Mono-/Dibranched Hexane Isomers.

The selective splitting of hexane isomers without the use of energy-intensive phase-change processes is essential for the low-carbon production of clean fuels and also very challenging. Here, we demonstrate a strategy to achieve a complete splitting of the high-RON dibranched isomer from the monobranched and linear isomers, by using a nonlinear 3D ligand to form pillar-layered MOFs with delicate pore architecture and chemistry. Compared with its isoreticular MOFs with the same ted pillar but different linear 3D or linear 2D in-layer ligands, the new MOF constructed in this work, Cu(bhdc)(ted)0.5 (ZUL-C5), exhibited an interesting "channel switch" effect which creates pore space with reduced window size and channel dimensionality together with unevenly distributed alkyl-rich adsorption sites, contributing to a greatly enhanced ability to discriminate between mono- and dibranched isomers. Evidenced by a series of studies including adsorption equilibrium/kinetics/breakthrough tests, guest-loaded single-crystal/powder XRD measurement, and DFT-D modeling, a thermodynamic-kinetic synergistic mechanism in the separation was proposed, resulting in a record production time for high-purity 2,2-dimethylbutane along with a high yield.

Investigating the prognostic role of lncRNAs associated with disulfidptosis-related genes in clear cell renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC). METHODS: Three sets of ccRCC cohorts, ICGC_RECA-EU (n = 91), GSE76207 (n = 32) and TCGA-KIRC (n = 607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups. RESULTS: A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy. CONCLUSION: We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.

Altered extracellular matrix-related pathways accelerate the transition from normal to prefibroid myometrium in Black women.

BACKGROUND: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive. OBJECTIVE: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women. STUDY DESIGN: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16). RESULTS: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women. CONCLUSION: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

The impact of stress on the risk decision-making process.

The effect of stress on risk-taking or risk-averse behavior in decision-making has been inconclusive in previous research, with few studies revealing the underlying neural mechanisms. This study employed event-related potentials technique and combined a social cold pressor assessment test with a mental arithmetic task to induce stress responses, aiming to investigate the influence of exogenous stress on the risk decision-making process. Stress induction results indicated that, in addition to raising heart rate and blood pressure, stress responses were accompanied by enhanced negative emotions, diminished positive emotions, and alterations in neural activity. The outcomes of risk decision-making showed that stress did not significantly affect risk preference or time of choice but did reduce the feedback-related negativity/reward positivity, with a particularly significant effect observed for large outcomes. Stress also altered the amplitude of the P3 component, with stress decreasing the P3 value for winning outcomes relative to losing outcomes. The study suggests that understanding how stress affects risk preference should consider the emotional valence induced by stress. Contrary to the reward sensitivity hypothesis, stress weakened reward sensitivity. Stress led to changes in the allocation of cognitive resources for outcome evaluation: compared to negative outcomes, stress reduced cognitive resources for positive outcomes, which might be related to the enhanced negative emotions induced by stress. The study highlights the importance of focusing on the subjective emotional experience induced by stress in future research on stress and risk decision-making.

Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.

BACKGROUND: The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs). METHODS: Developmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays. RESULTS: When exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity. CONCLUSION: Our studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.

TGFß signaling links early life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells.

Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Migration and transformation of Pb, Cu, and Zn during co-combustion of high-chlorine-alkaline coal and Si/Al dominated coal.

Shaerhu (SEH) coal is abundant in Xinjiang, China. The utilization of SEH suffers from severe ash deposition, slagging, and fouling problems due to its high-chlorine-alkaline characteristics. The co-combustion of high-alkaline coal and other type coals containing high Si/Al oxides has been proven to be a simple and effective method that will alleviate ash-related problems, but the risk of heavy metals (HMs) contamination in this process is nonnegligible. Hence, the volatilization rates and chemical speciation of Pb, Cu, and Zn in co-combusting SEH and a high Si/Al oxides coal, i.e., Yuanbaoshan (YBS) coal were investigated in this study. The results showed that the addition of SEH increased the volatilization rates of Pb, Cu, and Zn during the co-combustion at 800°C from 23.70%, 23.97%, and 34.98% to 82.31%, 30.01%, and 44.03%, respectively, and promoted the extractable state of Cu and Zn. In addition, the interaction between SEH and YBS inhibited the formation of the Pb residue state. SEM-EDS mapping results showed that compared to Zn and Cu, the signal intensity of Pb was extremely weak in regions where some of the Si and Al signal distributions overlap. The DFT results indicated that the O atoms of the metakaolin (Al2O3⋅2SiO2) (001) surface were better bound to the Zn and Cu than Pb atoms after adsorption of the chlorinated HMs. These results contribute to a better understanding of the effects of high-alkaline coal blending combustion on Pb, Cu, and Zn migration and transformation.

Interlayer Symmetry Control in Flexible-Robust Layered Metal-Organic Frameworks for Highly Efficient C2H2/CO2 Separation.

Removal of the CO2 impurities from C2H2/CO2 mixtures is an essential process to produce high-purity C2H2. Fabricating an adsorbent capable of discriminating these species, which have close kinetic diameters, is critical for developing advanced adsorption processes. Herein, we demonstrate a strategy to exploit the tunability of interlayer and intralayer spaces of two-dimensional (2D) layered metal-organic frameworks to achieve high performance for C2H2/CO2 separation. This indicates that interlayer symmetrical control can achieve more efficient packing of C2H2 into Ni(4-DPDS)2CrO4, with a high C2H2 capacity of 45.7 cm3·g-1 at 0.01 bar and a selectivity of 67.7 (298 K, 1 bar), which strikes a good balance between working capacity and separation selectivity compared to other isostructural Ni(4-DPDS)2MO4 (M = Mo, W). Crystallographic studies and DFT-D calculations reveal that such a C2H2-selective adsorbent possesses strong binding interactions due to the tailored pore confinement provided by the angular anions and rich electronic environment. Experimental breakthrough results comprehensively demonstrate the efficient C2H2/CO2 separation performance of this unique material.

Vertex Strategy in Layered 2D MOFs: Simultaneous Improvement of Thermodynamics and Kinetics for Record C2H2/CO2 Separation Performance.

Developing adsorbents with multiple merits in capacity, selectivity, mass transfer, and stability toward C2H2/CO2 separation is crucial and challenging for producing high-purity C2H2 for advanced polymers and the electronic industry. Here, we demonstrate a vertex strategy to create adsorbents combining these merits through rationally designing the vertex groups of a wavy-shaped framework in layered 2D metal-organic frameworks (MOFs) to finely regulate the local conformation and stacking interactions, which creates the optimal inter- and intralayer space to realize simultaneous improvement of adsorption thermodynamics and kinetics. Two new hydrolytically stable MOFs, ZUL-330 and ZUL-430, were prepared, and diverse experiments and modeling on both adsorption equilibrium and diffusion were performed. Record separation selectivities coupled with extraordinary dynamic C2H2 capacities were achieved for C2H2/CO2 mixtures with different proportions (50/50 or 10/5, v/v), along with a small diffusion barrier and fast mass transfer. Consequently, polymer-grade (99.9%) and electronic-grade (99.99%) C2H2 were obtained with excellent productivities of up to ∼6 mmol cm-3.

Blending Aryl Ketone in Covalent Organic Frameworks to Promote Photoinduced Electron Transfer.

Aryl-ketone derivatives have been acknowledged as promising organic photocatalysts for photosynthesis. However, they are limited by their photostability and have been less explored for photoinduced electron transfer (PET) applications. Herein we demonstrate a novel strategy to cover the shortage of aryl-ketone photocatalysts and control the photoreactivity by implanting symmetric aryl ketones into the conjugated covalent organic frameworks (COFs). To prove the concept, three comparative materials with the same topology and varied electronic structures were built, adopting truxenone knot and functionalized terephthalaldehyde linkers. Spectroscopic investigation and excited carrier dynamics analysis disclosed improvements in the photostability and electronic transfer efficiency as well as the structure-performance relationships toward N-aryl tetrahydroisoquinoline oxidation. This system provides a robust rule of thumb for designing new-generation aryl-ketone photocatalysts.

Customizing Metal-Organic Frameworks by Lego-Brick Strategy for One-Step Purification of Ethylene from a Quaternary Gas Mixture.

One-step purification of ethylene (C2 H4 ) from a quaternary gas mixture of C2 H6 /C2 H4 /C2 H2 /CO2 by adsorption is a promising separation process, yet developing adsorbents that synergistically capture various gas impurities remains challenging. Herein, a Lego-brick strategy is proposed to customize pore chemistry in a unified framework material. The ethane-selective MOF platform is further modified with customized binding sites to specifically adsorb acetylene and carbon dioxide, thus one-step purification of C2 H4 with high productivity of polymer-grade product (134 mol kg-1 ) is achieved on the assembly of porous coordination polymer-2,5-furandicarboxylic acid (PCP-FDCA) and PCP-5-aminoisophthalic acid (IPA-NH2 ). Computational studies verify that the low-polarity surface of this MOFs-based platform provides a delicate environment for C2 H6 recognition, and the specific binding sites (FDCA and IPA-NH2 ) exhibit favorable trapping of C2 H2 and CO2 via CHδ+ ···Oδ- and Cδ+ ···Nδ- electrostatic interactions, respectively. The proposed Lego-brick strategy to customize binding sites within the MOFs structure provides new ideas for the design of adsorbents for compounded separation tasks.

Sequential Separation of Linear, Mono-, and Di-Branched Hexane Isomers on a Robust Coordination Polymer with Nonbonding Flexibility.

Efficient separation of hexane isomers is a crucial process for upgrading gasoline. Herein, the sequential separation of linear, mono-, and di-branched hexane isomers by a robust stacked 1D coordination polymer termed as Mn-dhbq ([Mn(dhbq)(H2 O)2 ], H2 dhbq = 2,5-dihydroxy-1,4-benzoquinone) is reported. The interchain space of the activated polymer is of optimal aperture size (5.58 Å) that could exclude 2,3-dimethylbutane, while the chain structure can discriminate n-hexane with high capacity (1.53 mmol g-1 at 393 K, 6.67 kPa) by high-density open metal sites (5.18 mmol g-1 ). With the temperature- and adsorbate-dependent swelling of interchain spaces, the affinity between 3-methylpentane and Mn-dhbq can be deliberately controlled from sorption to exclusion, and thus a complete separation of ternary mixture can be achieved. Column breakthrough experiments confirm the excellent separation performance of Mn-dhbq. The ultrahigh stability and easy scalability further highlight the application prospect of Mn-dhbq for separation of hexane isomers.

Glycolysis-related biomarker TCIRG1 participates in regulation of renal cell carcinoma progression and tumor immune microenvironment by affecting aerobic glycolysis and AKT/mTOR signaling pathway.

BACKGROUND: Renal cell carcinoma (RCC) is a hypermetabolic disease. Abnormal up-regulation of glycolytic signaling promotes tumor growth, and glycolytic metabolism is closely related to immunotherapy of renal cancer. The aim of the present study was to determine whether and how the glycolysis-related biomarker TCIRG1 affects aerobic glycolysis, the tumor microenvironment (TME) and malignant progression of clear cell renal cell carcinoma (ccRCC). METHODS: Based on The Cancer Genome Atlas (TCGA, n = 533) and the glycolysis-related gene set from MSigDB, we identified the glycolysis-related gene TCIRG1 by bioinformatics analysis, analyzed its immunological properties in ccRCC and observed how it affected the biological function and glycolytic metabolism using online databases such as TIMER 2.0, UALCAN, LinkedOmics and in vitro experiments. RESULTS: It was found that the expression of TCIRG1, was significantly increased in ccRCC tissue, and that high TCIRG1 expression was associated with poor overall survival (OS) and short progression-free interval (PFI). In addition, TCIRG1 expression was highly correlated with the infiltration immune cells, especially CD4+T cell Th1, CD8+T cell, NK cell, and M1 macrophage, and positively correlated with PDCD1, CTLA4 and other immunoinhibitors, CCL5, CXCR3 and other chemokines and chemokine receptors. More importantly, TCIRG1 may regulate aerobic glycolysis in ccRCC via the AKT/mTOR signaling pathway, thereby affecting the malignant progression of ccRCC cell lines. CONCLUSIONS: Our results demonstrate that the glycolysis-related biomarker TCIRG1 is a tumor-promoting factor by affecting aerobic glycolysis and tumor immune microenvironment in ccRCC, and this finding may provide a new idea for the treatment of ccRCC by combination of metabolic intervention and immunotherapy.

Hybrid Hydrogen-Bonded Organic Frameworks: Structures and Functional Applications.

As a new class of porous crystalline materials, hydrogen-bonded organic frameworks (HOFs) assembled from building blocks by hydrogen bonds have gained increasing attention. HOFs benefit from advantages including mild synthesis, easy purification, and good recyclability. However, some HOFs transform into unstable frameworks after desolvation, which hinders their further applications. Nowadays, the main challenges of developing HOFs lie in stability improvement, porosity establishment, and functionalization. Recently, more and more stable and permanently porous HOFs have been reported. Of all these design strategies, stronger charge-assisted hydrogen bonds and coordination bonds have been proven to be effective for developing stable, porous, and functional solids called hybrid HOFs, including ionic and metallized HOFs. This Review discusses the rational design synthesis principles of hybrid HOFs and their cutting-edge applications in selective inclusion, proton conduction, gas separation, catalysis and so forth.

The Functional Role and Regulatory Mechanism of FTO m6A RNA Demethylase in Human Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m6A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer.

Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.

Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.

Epigenetic Modulation of Inflammatory Pathways in Myometrial Stem Cells and Risk of Uterine Fibroids.

The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a "hyper-inflammatory phenotype" and an increased hormone-dependent risk of UFs later in life.