CircPKN2 promotes ferroptosis in bladder cancer by promoting the ubiquitination of Stearoyl-CoA Desaturase 1.

Bladder cancer (BC) is one of the most common malignancies in the male urinary system and currently lacks an optimal treatment strategy. To elucidate the pathogenic mechanisms of BC from the perspective of circular RNAs, we conducted this study. Building upon our previous research, a novel circRNA, circPKN2, captured our interest due to its significant downregulation in BC, and its close association with the prognosis of BC patients. Our research findings indicate that circPKN2 can inhibit the proliferation and migration of BC cells in vitro. Furthermore, we discovered that circPKN2 exerts its anti-cancer effects in BC by promoting ferroptosis. Mechanistic studies revealed that circPKN2 recruits STUB1 to facilitate the ubiquitination of SCD1, thereby suppressing the WNT pathway and promoting ferroptosis in BC. Additionally, our research unveiled the regulatory role of the splicing factor QKI in the biogenesis of circPKN2. Animal studies demonstrated that circPKN2 enhances ferroptosis in BC cells in vivo, inhibiting tumor growth and metastasis. The discovery of the anti-cancer factor circPKN2 holds promise for providing new therapeutic targets in the prevention and treatment of BC.

Nanoparticles targeting OPN loaded with BY1 inhibits vascular restenosis by inducing FTH1-dependent ferroptosis in vascular smooth muscle cells.

Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis.

Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.

The complete mitochondrial genome of Tauraco livingstonii (Musophagidae: Tauraco).

Livingstone's turaco, Tauraco livingstonii, belongs to the family Musophagidae. In this study, we obtained the complete mitochondrial genome sequence of Livingstone's turaco by high-throughput sequencing technology and constructed a phylogenetic tree. It was found that the mitochondria of this species are 19,015 bp in length and contain a total of 37 genes, comprising 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The base composition of the mitochondrial genome is 31.61% A, 24.22% T, 30.64% C, and 13.52% G, with a GC content of 44%. Notably, an intriguing phenomenon of mitochondrial genome rearrangements was observed, characterized by the duplication of the tRNA Glu-L-CR gene order. In addition, the results of the phylogenetic tree analysis shed light on the taxonomic position of Livingstone's turaco and supported the taxonomy of Otidimorphae. The study provides a basis for future phylogenetic and taxonomic investigations of Musophagiformes.

Recent Progress in Droplet Structure Machining for Advanced Optics.

The development of optical and photonic applications using soft-matter droplets holds great scientific and application importance. The machining of droplet structures is expected to drive breakthroughs in advancing frontier applications. This review highlights recent advancements in micro-nanofabrication techniques for soft-matter droplets, encompassing microfluidics, laser injection, and microfluidic 3D printing. The principles, advantages, and weaknesses of these technologies are thoroughly discussed. The review introduces the utilization of a phase separation strategy in microfluidics to assemble complex emulsion droplets and control droplet geometries by adjusting interfacial tension. Additionally, laser injection can take full advantage of the self-assembly properties of soft matter to control the spontaneous organization of internal substructures within droplets, thus providing the possibility of high-precision customized assembly of droplets. Microfluidic 3D printing demonstrates a 3D printing-based method for machining droplet structures. Its programmable nature holds promise for developing device-level applications utilizing droplet arrays. Finally, the review presents novel applications of soft-matter droplets in optics and photonics. The integration of processing concepts from microfluidics, laser micro-nano-machining, and 3D printing into droplet processing, combined with the self-assembly properties of soft materials, may offer novel opportunities for processing and application development.

ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates.

ABSTRACT: Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus.

A visible-light-catalyzed sulfonylation reaction of an aryl selenonium salt via an electron donor-acceptor complex.

An efficient synthesis of sulfone structures through selenonium salts and sodium sulfinates was developed. Under the irradiation of a blue LED lamp, the two substrates generate aryl and sulfonyl radicals through the activation of the intermediate electron donor acceptor (EDA) complex, thereby synthesizing aromatic, heteroaromatic and aliphatic sulfones in medium to good yields. The advantages of this strategy are metal-free, mild conditions and the leaving group is recycled to construct new selenonium salts.

Aromatic and magnetic properties in a series of heavy rare earth-doped Ge6 cluster anions.

A series of pentagonal bipyramidal anionic germanium clusters doped with heavy rare earth elements, REGe 6 - (RE = Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), have been identified at the PBE0/def2-TZVP level using density functional theory (DFT). Our findings reveal that the centrally doped pentagonal ring structure demonstrates enhanced stability and heightened aromaticity due to its uniform bonding characteristics and a larger charge transfer region. Through natural population analysis and spin density diagrams, we observed a monotonic decrease in the magnetic moment from Gd to Yb. This is attributed to the decreasing number of unpaired electrons in the 4f orbitals of the heavy rare earth atoms. Interestingly, the system doped with Er atoms showed lower stability and anti-aromaticity, likely due to the involvement of the 4f orbitals in bonding. Conversely, the systems doped with Gd and Tb atoms stood out for their high magnetism and stability, making them potential building blocks for rare earth-doped semiconductor materials.

Exploring the stability and aromaticity of rare earth doped tin cluster MSn16- (M = Sc, Y, La).

Rare earth elements have high chemical reactivity, and doping them into semiconductor clusters can induce novel physicochemical properties. The study of the physicochemical mechanisms of interactions between rare earth and tin atoms will enhance our understanding of rare earth functional materials from a microscopic perspective. Hence, the structure, electronic characteristics, stability, and aromaticity of endohedral cages MSn16- (M = Sc, Y, La) have been investigated using a combination of the hybrid PBE0 functional, stochastic kicking, and artificial bee colony global search technology. By comparing the simulated results with experimental photoelectron spectra, it is determined that the most stable structure of these clusters is the Frank-Kasper polyhedron. The doping of atoms has a minimal influence on density of states of the pure tin system, except for causing a widening of the energy gap. Various methods such as ab initio molecular dynamics simulations, the spherical jellium model, adaptive natural density partitioning, localized orbital locator, and electron density difference are employed to analyze the stability of these clusters. The aromaticity of the clusters is examined using iso-chemical shielding surfaces and the gauge-including magnetically induced currents. This study demonstrates that the stability and aromaticity of a tin cage can be systematically adjusted through doping.

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer.

BACKGROUND: Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a micro-barrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells. METHODS: The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin ß8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. RESULTS: Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts. CONCLUSIONS: The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Diagnostic performance of a new two-dimensional shear wave elastography expression using siemens ultrasound system combined with ACR TI-RADS for classification of benign and malignant thyroid nodules: A prospective multi-center study.

Objective: The present study aimed to evaluate the efficacy of a new two-dimensional shear wave elastography (2D-SWE) method using a Siemens ultrasound system and its combination with the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for the differential diagnosis of benign and malignant thyroid nodules. Methods: Conventional ultrasound images and 2D-SWE (E-whole-mean and E-stiffest-mean) were prospectively analyzed in 593 thyroid nodules from 543 patients. Nodules were divided into diameter (D) ≤10 mm and D > 10 mm groups and graded using ACR TI-RADS. The receiver operating characteristic curve was plotted using pathological findings as the gold standard. Diagnostic performance was compared among 2D-SWE, ACR TI-RADS, and their combination. Results: The area under the curve (AUC) for E-whole-mean was higher than that for E-stiffest-mean (0.858 vs. 0.790, P < 0.001), which indicated that it was the better 2D-SWE parameter for differentiating malignant nodules from benign nodules with an optimal cut-off point of 11.36 kPa. In the all-sizes group, the AUC for E-whole-mean was higher than that for ACR TI-RADS (0.858 vs. 0.808, P < 0.001). The combination of E-whole-mean and ACR TI-RADS resulted in a higher AUC (0.929 vs. 0.858 vs. 0.808, P < 0.001), sensitivity (87.0% vs. 80.3% vs. 85.2%), specificity (85.1% vs. 74.0% vs. 73.6%), accuracy (86.3% vs. 78.1% vs. 81.1%), positive predictive value (91.5% vs. 85.1% vs. 85.6%), and negative predictive value (78.0% vs. 67.0% vs. 72.9%) compared to E-whole-mean or ACR TI-RADS alone. The AUC for the combination of 2D-SWE and ACR TI-RADS was superior to that for E-whole-mean or ACR TI-RADS alone in both D ≤ 10 mm and D > 10 mm groups (P < 0.001). Conclusion: As the better 2D-SWE parameter, E-whole-mean had a higher diagnostic power than ACR TI-RADS and enhanced the diagnostic performance of ACR TI-RADS when identifying benign and malignant thyroid nodules. The combination of E-whole-mean and ACR TI-RADS improved the diagnostic performance compared to using ACR TI-RADS alone, providing a new and reliable method for the clinical diagnosis of thyroid nodules.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.

An explainable machine-learning approach for revealing the complex synthesis path-property relationships of nanomaterials.

Machine learning (ML) models have recently shown important advantages in predicting nanomaterial properties, which avoids many trial-and-error explorations. However, complex variables that control the formation of nanomaterials exhibiting the desired properties still need to be better understood owing to the low interpretability of ML models and the lack of detailed mechanism information on nanomaterial properties. In this study, we developed a methodology for accurately predicting multiple synthesis parameter-property relationships of nanomaterials to improve the interpretability of the nanomaterial property mechanism. As a proof-of-concept, we designed glutathione-gold nanoclusters (GSH-AuNCs) exhibiting an appropriate fluorescence quantum yield (QY). First, we conducted 189 experiments and synthesized different GSH-AuNCs by varying the thiol-to-metal molar ratio and reaction temperature and time in reasonable ranges. The fluorescence QY of GSH-AuNCs could be systematically and independently programmed using different experimental parameters. We used limited GSH-AuNC synthesis parameter data to train an extreme gradient boosting regressor model. Moreover, we improved the interpretability of the ML model by combining individual conditional expectation, double-variable partial dependence, and feature interaction network analyses. The interpretability analyses established the relationship between multiple synthesis parameters and fluorescence QYs of GSH-AuNCs. The results represent an essential step towards revealing the complex fluorescence mechanism of thiolated AuNCs. Finally, we constructed a synthesis phase diagram exceeding 6.0 × 104 prediction variables for accurately predicting the fluorescence QY of GSH-AuNCs. A multidimensional synthesis phase diagram was obtained for the fluorescence QY of GSH-AuNCs by searching the synthesis parameter space in the trained ML model. Our methodology is a general and powerful complementary strategy for application in material informatics.

Production and Reconfiguration of Double Emulsions by Temperature Control.

Double emulsions are of great importance for both science and engineering. However, the production of multicore double-emulsion droplets is challenging and normally requires sophisticated microfluidic devices, which limits their availability to broader communities. Here, we propose a simple, precise, and scalable batch method for producing double emulsions with monodispersed multicores at milliliter per minute rates, using the most common means in laboratory, temperature. By rapidly cooling liquid crystal emulsions, the introduced temperature gradient around the emulsion droplets leads to the injection of monodispersed guest droplets to form double-emulsion droplets. The number of injected water droplets can be precisely controlled by adjusting the thermally induced mechanical force through the temperature difference and the cooling rate. In contrast to conventional microfluidic fabrication, this method processes all emulsion droplets simultaneously in a noncontact and in situ manner. Therefore, it has great flexibility, allows multiple processing of double emulsions of arbitrary shape, has good capacity for mass production, and offers excellent compatibility with technologies such as microfluidics. Finally, we demonstrate that temperature changes can also be used to release the inner droplets from the double emulsion. The proposed method offers a reversible tool for processing double emulsions with minimal cost and expertise and is applicable to droplet-based microsystems in materials science, photonics, sensors, pharmaceuticals, and biotechnology.

Exosomes-transferred LINC00668 Contributes to Thrombosis by Promoting NETs Formation in Inflammatory Bowel Disease.

Epidemiological studies show an association between inflammatory bowel disease (IBD) and increased risk of thrombosis. However, how IBD influences thrombosis remains unknown. The current study shows that formation of neutrophil extracellular traps (NETs) significantly increased in the dextran sulfate sodium (DSS)-induced IBD mice, which in turn, contributes to thrombus formation in a NETs-dependent fashion. Furthermore, the exosomes isolated from the plasma of the IBD mice induce arterial and venous thrombosis in vivo. Importantly, proinflammatory factors-exposed intestinal epithelial cells (inflamed IECs) promote neutrophils to release NETs through their secreted exosomes. RNA sequencing revealed that LINC00668 is highly enriched in the inflamed IECs-derived exosomes. Mechanistically, LINC00668 facilitates the translocation of neutrophil elastase (NE) from the cytoplasmic granules to the nucleus via its interaction with NE in a sequence-specific manner, thereby inducing NETs release and thrombus formation. Importantly, berberine (BBR) suppresses the nuclear translocation of NE and subsequent NETs formation by inhibiting the interaction of LINC00668 with NE, thus exerting its antithrombotic effects. This study provides a novel pathobiological mechanism linking IBD and thrombosis by exosome-mediated NETs formation. Targeting LINC00668 can serve as a novel molecular treatment strategy to treat IBD-related thrombosis.

Ancient DNA reveals genetic admixture in China during tiger evolution.

The tiger (Panthera tigris) is a charismatic megafauna species that originated and diversified in Asia and probably experienced population contraction and expansion during the Pleistocene, resulting in low genetic diversity of modern tigers. However, little is known about patterns of genomic diversity in ancient populations. Here we generated whole-genome sequences from ancient or historical (100-10,000 yr old) specimens collected across mainland Asia, including a 10,600-yr-old Russian Far East specimen (RUSA21, 8× coverage) plus six ancient mitogenomes, 14 South China tigers (0.1-12×) and three Caspian tigers (4-8×). Admixture analysis showed that RUSA21 clustered within modern Northeast Asian phylogroups and partially derived from an extinct Late Pleistocene lineage. While some of the 8,000-10,000-yr-old Russian Far East mitogenomes are basal to all tigers, one 2,000-yr-old specimen resembles present Amur tigers. Phylogenomic analyses suggested that the Caspian tiger probably dispersed from an ancestral Northeast Asian population and experienced gene flow from southern Bengal tigers. Lastly, genome-wide monophyly supported the South China tiger as a distinct subspecies, albeit with mitochondrial paraphyly, hence resolving its longstanding taxonomic controversy. The distribution of mitochondrial haplogroups corroborated by biogeographical modelling suggested that Southwest China was a Late Pleistocene refugium for a relic basal lineage. As suitable habitat returned, admixture between divergent lineages of South China tigers took place in Eastern China, promoting the evolution of other northern subspecies. Altogether, our analysis of ancient genomes sheds light on the evolutionary history of tigers and supports the existence of nine modern subspecies.

Visible-light-mediated α-amino alkylation of ketimines and aldimines for the synthesis of 1,2-diamines.

A visible-light-mediated protocol to prepare 1,2-diamines has been successfully explored based on the photoredox/Brønsted acid co-catalyzed α-amino alkylations of imines with tertiary amines. Both ketimines and aldimines are applicable to this transformation. Various 1,2-diamines with different functional groups were produced in moderate to excellent yields. Moreover, this approach could be performed on a gram scale, showing its practicality.