Direct Construction of 1,4-Dihydropyridazines and Pyrazoles via Annulation of Alkyl 2-Aroyl-1-chlorocyclopropanecarboxylates.

An efficient and chemodivergent synthesis of highly functionalized 1,4-dihydropyridazines and pyrazoles has been accomplished via base-promoted annulation between hydrazones and alkyl 2-aroyl-1-chlorocyclopropanecarboxylates, respectively. This transition-metal-free domino reaction proceeded rapidly under mild basic conditions, affording potentially bioactive 1,4-dihydropyridazine and pyrazole derivatives in moderate yields. The conversion of 1,4-dihydropyridazine to pyrazole was confirmed by adjusting the quantity of the base.

Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non-coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. AIMS: The purpose of this study is to construction a exosomes-related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. METHODS: Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes-related lncRNAs (ERLRs) from Top10 exosomes-related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs-based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high- and low-risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. RESULTS: A score consisting of 4ERLRs was identified, and patients with higher ERLRs-based score tended to have a worse prognosis than those with lower ERLRs-based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III-IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa-miR-31-5p/TLN2 axis. CONCLUSIONS: Based on machine learning, a novel ERLRs-based score was constructed for predicting the survival of ccRCC patients. The ERLRs-based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa-miR-31-5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

How entrepreneurship education affects college students' entrepreneurial intention: Samples from China.

Colleges and universities play a pivotal role in nurturing students' entrepreneurial aspirations, as evidenced by a significant increase in entrepreneurial education. Improving its quality and igniting students' motivation are crucial. This study, grounded in established theoretical frameworks, introduces variables such as entrepreneurial intention, attitude, and self-efficacy, forming a moderated mediation model. An analysis of 347 questionnaires using Mplus 8.0 reveals the following insights: (1) Collegiate-level entrepreneurship education is positively correlated with students' entrepreneurial intentions; (2) Entrepreneurial attitude and self-efficacy mediate the relationship between entrepreneurship education and students' entrepreneurial intentions; (3) Entrepreneurial social support moderates the link between entrepreneurship education and students' entrepreneurial intentions. These findings contribute to the body of knowledge in entrepreneurship education and provide valuable guidance for enhancing its effectiveness and fostering students' entrepreneurial aspirations.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

Magnetic MnFe2O4/ZIF-67 nanocomposites with high activation of peroxymonosulfate for the degradation of tetracycline hydrochloride in wastewater.

Advanced oxidation processes (AOPs) based on PMS have been used to degrade various refractory pollutants such as drugs, endocrine disruptors, dyes and perfluorinated compounds due to their wide application range, mild reaction conditions, fast reaction rate and simple operation. In this study, tetracycline hydrochloride (TCH) was degraded based on this method. Magnetic MnFe2O4/ZIF-67 nanocomposites were successfully prepared by a hydrothermal method, which combined the magnetic separation characteristics of MnFe2O4 with the high catalytic activity of ZIF-67 and were used to activate peroxymonosulfate (PMS) to efficiently degrade TCH. Satisfactory removal results were obtained with this simple and readily available material, with 82.6% of TCH removed in 15 min. The effect of different conditions on the degradation effect was investigated, and the optimal catalyst concentration and PMS concentration were determined to be 0.1 g L-1 and 0.2 g L-1, respectively, and all had good degradation effects at pH 5 to 10. XPS, impedance test and radical quenching experiments were used to investigate the degradation mechanism. The results showed that sulfate radical (SO4-˙) was the main active species in the degradation process. In addition, the catalyst has good cyclic stability, which provides a new idea for the removal of TCH in wastewater. It is worth mentioning that the catalyst also has good degradation property for other pollutants.

Preparation and characterization of furfural residue derived char-based catalysts for biomass tar cracking.

This study proposed an innovative strategy of catalytic cracking of tar during biomass pyrolysis/gasification using furfural residue derived biochar-based catalysts. Fe, Co, and Ni modified furfural residue char (FRC-Fe, FRC-Co, and FRC-Ni) were prepared by one-step impregnation method. The influences of cracking temperature and metal species on the tar cracking characteristics were investigated. The results showed that the tar conversion efficiency for all catalysts were improved with the cracking temperature increasing, the higher tar conversion efficiency achieved at 800 °C were 66.72 %, 89.58 %, 84.58 %, and 94.70 % for FRC, FRC-Fe, FRC-Co, and FRC-Ni respectively. FRC-Ni achieved the higher gas (H2, CO, CH4, CO2) yield 681.81 mL/g. At 800 °C, the catalyst (FRC-Ni) still reached a high tar conversion efficiency over 85.90 % after 5 cycles. SEM-EDS results showed that the distribution of Ni particles on the biochar support was uniform. TGA results demonstrated that FRC-Ni exhibited better thermal stability. XRD results indicated that there was no significant change in the grain size of Ni before and after the reaction. The FRC-Ni catalyst was reasonably stable due to its better anti-sintering and coke-resistant capabilities.

Output information-based intermittent optimal control for continuous-time nonlinear systems with unmatched uncertainties via adaptive dynamic programming.

Intermittent control stands as a valuable strategy for resource conservation and cost reduction across diverse systems. Nonetheless, prevailing research is intractable to address the challenges posed by robust optimal intermittent control of nonlinear input-affine systems with unmatched uncertainties. This paper aims to fill this gap. Initially, we introduce an enhanced finite-time intermittent control approach to ensure stability within nonlinear dynamic systems harboring bounded errors. A neural networks (NNs) state observer is constructed to estimate system information. Subsequently, an optimal intermittent controller that operates within a finite time span, guaranteeing system stability by employing the Hamilton-Jacobi-Bellman (HJB) methodology. Furthermore, we devise an output information-based event-triggered intermittent (ETI) approach rooted in the robust adaptive dynamic programming (ADP) algorithm, furnishing an optimal intermittent control law. In this process, a critic NNs is introduced to estimate the cost function and optimal intermittent controller. Simulation results show that our proposed method is superior to existing intermittent control strategies.

Survival analysis of laparoscopic surgery and open surgery for hilar cholangiocarcinoma: a retrospective cohort study.

BACKGROUND/PURPOSE: This study compared the clinical efficacy and safety of laparoscopic versus open resection for hilar cholangiocarcinoma (HCCA) and analyzed potential prognostic factors. METHODS: The study included patients who underwent HCCA resection at our center from March 2012 to February 2022. Perioperative complications and postoperative prognosis were compared between the laparoscopic surgery (LS) and open surgery (OS) groups. RESULTS: After screening 313 HCCA patients, 68 patients were eligible for the study in the LS group (n = 40) and OS group (n = 28). Kaplan-Meier survival curve analysis revealed that overall survival > 2 years and 3-year disease-free survival (DFS) were more common in the LS than OS group, but the rate of 2-year DFS was lower in the LS group than OS group. Cox multivariate regression analysis revealed age (< 65 years), radical resection, and postoperative adjuvant therapy were associated with reduced risk of death (hazard ratio [HR] = 0.380, 95% confidence interval [CI] = 0.150-0.940, P = 0.036; HR = 0.080, 95% CI = 0.010-0.710, P = 0.024 and HR = 0.380, 95% CI = 0.150-0.960, P = 0.040), whereas preoperative biliary drainage was an independent factor associated with increased risk of death (HR = 2.810, 95% CI = 1.130-6.950, P = 0.026). Perineuronal invasion was identified as an independent risk factor affecting DFS (HR = 5.180, 95% CI = 1.170-22.960, P = 0.030). CONCLUSIONS: Compared with OS, laparoscopic HCCA resection does not significantly differ in terms of clinical efficacy. Age (<65 years), radical resection, and postoperative adjuvant therapy reduce the risk of death, and preoperative biliary drainage increases the risk of death.

Visible-Light-Driven Iron-Catalyzed Intermolecular Benzylic C(sp3)-H Amination with 1,2,3,4-Tetrazoles.

A visible-light-driven iron-catalyzed C(sp3)-H amination of diphenylmethane derivatives with 1,2,3,4-tetrazoles under mild conditions has been developed. The reaction proceeds with photosensitizer-free conditions and features satisfactory to good yields. Mechanistic studies revealed that the reaction proceeded via an iron-nitrene intermediate, and H atom abstraction was the rate-determining step. Computational studies showed that the denitrogenation of 1,2,3,4-tetrazole depends on the conversion of the sextet ground state of 1,2,3,4-tetrazole-bounding iron species to the quartet spin state under visible-light irradiation.

Angle-Insensitive Ultrathin Broadband Visible Absorber Based on Dielectric-Semiconductor-Lossy Metal Film Stacks.

Ultrathin broadband absorbers with high efficiency, wide angular tolerance, and low fabrication cost are in demand for various applications. Here, we present an angle-insensitive ultrathin (<150 nm) broadband absorber with an average 96.88% (experiment) absorptivity in the whole visible range by utilizing a simple dielectric-semiconductor-lossy metal triple-layer film structure. The excellent broadband absorption performance of the device results from the combined action of the enhanced absorptions in the semiconductor and lossy metal layers exploiting strong interference effects and can be maintained over a wide viewing angle up to ±60°. Benefiting from the lossy metal providing additional absorption, our design reduces the requirement for the semiconductor's material dispersion and has great flexibility in the material selection of the metal layer. Additionally, the lithography-free nature of the proposed broadband visible absorber provides a high-throughput fabrication convenience, thus holding great potential for its large-area applications in various fields.

Modeling human ectopic pregnancies with trophoblast and vascular organoids.

Ruptured ectopic pregnancy (REP), a pregnancy complication caused by aberrant implantation, deep invasion, and overgrowth of embryos in fallopian tubes, could lead to rupture of fallopian tubes and accounts for 4%-10% of pregnancy-related deaths. The lack of ectopic pregnancy phenotypes in rodents hampers our understanding of its pathological mechanisms. Here, we employed cell culture and organoid models to investigate the crosstalk between human trophoblast development and intravillous vascularization in the REP condition. Compared with abortive ectopic pregnancy (AEP), the size of REP placental villi and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion in the REP condition. Our results reveal the important role of WNT-mediated angiogenesis and an organoid co-culture model for investigating intricate communications between trophoblasts and endothelial/endothelial progenitor cells.

Hydrogen-rich syngas production from biomass gasification using biochar-based nanocatalysts.

Nanocatalysts are beneficial for tar elimination and syngas production during biomass gasification. In this study, novel biochar-based nanocatalysts loaded with Ni/Ca/Fe nanoparticles was prepared by one-step impregnation method for catalytic steam gasification of biomass. Results showed that the metal particles were evenly distributed with the particle size of less than 20 nm. With the introduction of nanoparticles, H2 yield and tar conversion were obviously increased. Ni and Fe particles help to maintain the stability of the carrier microporous structure. Fe loaded biochar showed the best catalytic gasification performance, with 87% tar conversion and 42.46 mmol/g H2 production. The catalytic effect of Fe was also higher than that of Ni and Ca if deducting the influence of carrier consumption. It demonstrated that Fe-loaded biochar was a promising catalyst candidate for hydrogen-rich syngas production from biomass gasification.

Fixed/prescribed-time synchronization of BAM memristive neural networks with time-varying delays via convex analysis.

The synchronization problem of bidirectional associative memory memristive neural networks (BAMMNNs) with time-varying delays plays an essential role in the implementation and application of neural networks. Firstly, under the framework of the Filippov's solution, the discontinuous parameters of the state-dependent switching are transformed by convex analysis method, which is different from most previous approaches. Secondly, based on Lyapunov function and some inequality techniques, several conditions for the fixed-time synchronization (FXTS) of the drive-response systems are obtained by designing special control strategies. Moreover, the settling time (ST) is estimated by the improved fixed-time stability lemma. Thirdly, the driven-response BAMMNNs are investigated to be synchronized within a prescribed time by designing new controllers based on the FXTS results, where ST is irrelevant to the initial values of BAMMNNs and the parameters of controllers. Finally, a numerical simulation is exhibited to verify the correctness of the conclusions.

PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common diseases with the coexistence of reproductive malfunction and metabolic disorders. Previous studies have found increased branched chain amino acid (BCAA) levels in women with PCOS. However, it remains unclear whether BCAA metabolism is causally associated with the risk of PCOS. METHODS: The changes of BCAA levels in the plasma and follicular fluids of PCOS women were detected. Mendelian randomization (MR) approaches were used to explore the potential causal association between BCAA levels and the risk of PCOS. The function of the gene coding the protein phosphatase Mg2+/Mn2+-dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells. FINDINGS: BCAA levels were significantly elevated in both plasma and follicular fluids of PCOS women. Based on MR, a potential direct, causal role for BCAA metabolism was revealed in the pathogenesis of PCOS, and PPM1K was detected as a vital driver. Ppm1k-deficient female mice had increased BCAA levels and exhibited PCOS-like traits, including hyperandrogenemia and abnormal follicle development. A reduction in dietary BCAA intake significantly improved the endocrine and ovarian dysfunction of Ppm1k-/- female mice. Knockdown of PPM1K promoted the conversion of glycolysis to pentose phosphate pathway and inhibited mitochondrial oxidative phosphorylation in human granulosa cells. INTERPRETATION: Ppm1k deficiency-impaired BCAA catabolism causes the occurrence and development of PCOS. PPM1K suppression disturbed energy metabolism homeostasis in the follicular microenvironment, which provided an underlying mechanism of abnormal follicle development. FUNDING: This study was supported by the National Key Research and Development Program of China (2021YFC2700402, 2019YFA0802503), the National Natural Science Foundation of China (81871139, 82001503, 92057107), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001), Key Clinical Projects of Peking University Third Hospital (BYSY2022043), the China Postdoctoral Science Foundation (2021T140600), and the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01).

Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.

Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC-pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC-pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO-sGC) is impaired in ALI. Indeed, stimulating the NO-sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC-pericyte interactions. Collectively, our data demonstrate that impaired NO-sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.

Synthesis of bimetal MOFs for rapid removal of doxorubicin in water by advanced oxidation method.

Doxorubicin (DOX) has been an emerging environmental pollutant due to its significant genotoxicity to mankind. Advanced oxidation processes are a potential strategy to remove DOX in water solution. To develop a highly efficient catalytic agent to remove DOX, bimetal MOFs were synthesized, with Cu2+ and Co2+ as the central ions and adenine as the organic ligand. This study investigated the degradation of DOX by Co/Cu-MOFs combined with peroxymonosulfate (PMS). It was found that the degradation of DOX by Co/Cu-MOFs can reach 80% in only 10 seconds. This can be explained by the charge transfer from Co(iii) to Co(ii) being accelerated by Cu2+, resulting in the rapid generation of free radicals, which was proved by the EIS Nyquist diagram. Co/Cu-MOFs can be reused by simply washing with water without inactivation. Therefore, Co/Cu-MOFs can be used as an efficient catalytic agent to degrade DOX in environmental water.

Sound Source Localization Based on Multi-Channel Cross-Correlation Weighted Beamforming.

Beamforming and its applications in steered-response power (SRP) technology, such as steered-response power delay and sum (SRP-DAS) and steered-response power phase transform (SRP-PHAT), are widely used in sound source localization. However, their resolution and accuracy still need improvement. A novel beamforming method combining SRP and multi-channel cross-correlation coefficient (MCCC), SRP-MCCC, is proposed in this paper to improve the accuracy of direction of arrival (DOA). Directional weight (DW) is obtained by calculating the MCCC. Based on DW, suppressed the non-incoming wave direction and gained the incoming wave direction to improve the beamforming capabilities. Then, sound source localizations based on the dual linear array under different conditions were simulated. Compared with SRP-PHAT, SRP-MCCC has the advantages of high positioning accuracy, strong spatial directivity and robustness under the different signal-noise ratios (SNRs). When the SNR is -10 dB, the average positioning error of the single-frequency sound source at different coordinates decreases by 5.69%, and that of the mixed frequency sound sources at the same coordinate decreases by 5.77%. Finally, the experimental verification was carried out. The results show that the average error of SRP-MCCC has been reduced by 8.14% and the positioning accuracy has been significantly improved, which is consistent with the simulation results. This research provides a new idea for further engineering applications of sound source localization based on beamforming.

Conditional overexpression of neuritin in supporting cells (SCs) mitigates hair cell (HC) damage and induces HC regeneration in the adult mouse cochlea after drug-induced ototoxicity.

Hearing loss due to the loss of auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Using neurotrophic factors to induce the regeneration of hair cells (HCs) from adjacent nonsensory supporting cells (SCs) may be a promising strategy to treat hearing loss. Here, we demonstrate that overexpression of neuritin in SCs could mitigate drug-induced HC damage and directly induce HC regeneration from SCs by inhibiting the Notch signaling pathway. Using neuritin conditional knock-in mice, we found that upregulation of neuritin in SCs results in preserved HCs and partial recovery of hearing, inducing the regeneration of HCs from the transdifferentiation of SCs in ears damaged by kanamycin. Furthermore, neuritin overexpression in SCs downregulates the expression levels of Notch receptor Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) protein, two core components of the Notch signaling pathway. These observations confirmed in vitro that in cultured neonatal mouse cochleae, neuritin overexpression in SCs significantly inhibited gentamicin-induced HC damage and induced regeneration of HCs from the transdifferentiation of SCs, and that these effects were eliminated by adding the Notch ligand Jagged-1. These findings may provide a new avenue to stimulate HC regeneration after HC loss and highlight the therapeutic potential of neuritin for sensorineural hearing loss.

KANK4 Promotes Arteriogenesis by Potentiating VEGFR2 Signaling in a TALIN-1-Dependent Manner.

BACKGROUND: Arteriogenesis plays a critical role in maintaining adequate tissue blood supply and is related to a favorable prognosis in arterial occlusive diseases. Strategies aimed at promoting arteriogenesis have thus far not been successful because the factors involved in arteriogenesis remain incompletely understood. Previous studies suggest that evolutionarily conserved KANK4 (KN motif and ankyrin repeat domain-containing proteins 4) might involve in vertebrate vessel development. However, how the KANK4 regulates vessel function remains unknown. We aim to determine the role of endothelial cell-specifically expressed KANK4 in arteriogenesis. METHODS: The role of KANK4 in regulating arteriogenesis was evaluated using Kank4-/- and KANK4iECOE mice. Molecular mechanisms underlying KANK4-potentiated arteriogenesis were investigated by employing RNA transcriptomic profiling and mass spectrometry analysis. RESULTS: By analyzing Kank4-EGFP reporter mice, we showed that KANK4 was specifically expressed in endothelial cells. In particular, KANK4 displayed a dynamic expression pattern from being ubiquitously expressed in all endothelial cells of the developing vasculature to being explicitly expressed in the endothelial cells of arterioles and arteries in matured vessels. In vitro microfluidic chip-based vascular morphology analysis and in vivo hindlimb ischemia assays using Kank4-/- and KANK4iECOE mice demonstrated that deletion of KANK4 impaired collateral artery growth and the recovery of blood perfusion, whereas KANK4 overexpression leads to increased vessel caliber and blood perfusion. Bulk RNA sequencing and Co-immunoprecipitation/mass spectrometry (Co-IP/MS) analysis identified that KANK4 promoted EC proliferation and collateral artery remodeling through coupling VEGFR2 (vascular endothelial growth factor receptor 2) to TALIN-1, which augmented the activation of the VEGFR2 signaling cascade. CONCLUSIONS: This study reveals a novel role for KANK4 in arteriogenesis in response to ischemia. KANK4 links VEGFR2 to TALIN-1, resulting in enhanced VEGFR2 activation and increased EC proliferation, highlighting that KANK4 is a potential therapeutic target for promoting arteriogenesis for arterial occlusive diseases.