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Abstract Since their inception, frequency combs generated in microresonators, known as microcombs, have sparked significant scientific interests. Among the various applications leveraging microcombs, soliton microcombs are often preferred due to their inherent mode-locking capability. However, this choice introduces additional system complexity because an initialization process is required. Meanwhile, despite the theoretical understanding of the dynamics of other comb states, their practical potential, particularly in applications like sensing where simplicity is valued, remains largely untapped. Here, we demonstrate controllable generation of sub-combs that bypasses the need for accessing bistable regime. And in a graphene-sensitized microresonator, the sub-comb heterodynes produce stable, accurate microwave signals for high-precision gas detection. By exploring the formation dynamics of sub-combs, we achieved 2 MHz harmonic comb-to-comb beat notes with a signal-to-noise ratio (SNR) greater than 50 dB and phase noise as low as − 82 dBc/Hz at 1 MHz offset. The graphene sensitization on the intracavity probes results in exceptional frequency responsiveness to the adsorption of gas molecules on the graphene of microcavity surface, enabling detect limits down to the parts per billion (ppb) level. This synergy between graphene and sub-comb formation dynamics in a microcavity structure showcases the feasibility of utilizing microcombs in an incoherent state prior to soliton locking. It may mark a significant step toward the development of easy-to-operate, systemically simple, compact, and high-performance photonic sensors. Graphical Abstract

Background: Tinnitus treatment remains a global challenge, and current therapeutic approaches are still controversial. This study aims to elucidate the potential mechanisms of Xiao-Chai-Hu-Tang (XCHT) in treating tinnitus through the analysis of network pharmacology, mendelian randomization and molecular docking, and molecular dynamics simulation analysis. We hope to contribute to the research on the target of action of traditional Chinese medicine and exploration of the mechanism of tinnitus. Methods: We utilized network pharmacology to screen potential targets of action of XCHT on tinnitus. Mendelian randomization was employed to determine the causal relationship between potential targets of action and tinnitus. Finally, molecular docking and molecular dynamics simulation with clear targets and the combination of the active ingredient in effectiveness. Results: Through network pharmacology, we identified 38 potential targets of action. Mendelian randomization analysis revealed that HIF1A (OR [95 % CI] = 0.78 [0.65, 0.94], P = 0.008) and CCND1 (OR [95 % CI] = 1.22 [1.00, 1.49], P = 0.04) exhibited significant results with tinnitus. Molecular docking and molecular dynamics simulation of HIF1A and active ingredients demonstrated good binding efficacy. Conclusion: HIF1A may play a key role in the treatment of tinnitus by XCHT, which may play a certain protective role in tinnitus patients and may inhibit the occurrence and development of tinnitus. However, the specific mechanism and effect need to be further studied and verified.

Objective: To establish a method for simultaneous determination of cytosine, uracil, cytidine, hypoxanthine, uridine, thymidine, adenine, guanosine, thymidine and adenosine in different selenium-rich bamboo shoots. Methods: The determination was performed on Inertsil ODS-3 C18 column with mobile phase consisting of acetonitrile-water (gradient elution). The detection wavelength was set at 260 nm and the flow rate was 0.8 mL·min−1. The column temperature was 30 ℃, and the sample size was 20 μL. Fingerprints of 21 selenium-rich bamboo shoots were drawn for similarity evaluation of common peaks. The nucleosides of 21 selenium-rich bamboo shoots were analysised by principal component analysis, correlation analysis and cluster analysis. Results: 10 nucleosides were separated within 30 min, and the linear relationship was good (R2≥0.9990). RSDS of precision, stability, repeatability and accuracy tests were all less than 2%. Significant differences in the contents and structure ratio of 10 nucleosides were found in different selenium-rich bamboo shoots, and there were different degrees of correlation between nucleoside components. Four principal components were selected by principal component analysis. Thymidine, thymine, adenosine and guanosine were identified as four core indexes, which could be used to evaluate the quality of different selenium-rich bamboo shoots. The correlation between uracil and cytidine, guanosine and thymidine, thymidine and adenosine was high, and the contents of these indexes would influence each other. After cluster analysis, it was concluded that the new selenium-rich bamboo shoots were mainly concentrated in one category, and the common selenium-rich bamboo shoots in the market are mainly divided into two categories. Conclusion: The method was rapid, simple and reproducible, and could be used for the determination of 10 nucleosides in 21 selenium-rich bamboo shoots. At the same time, the results would provide a theoretical basis for the efficient development and utilization of bamboo shoots in the later period.

The entropy TOPSIS model was used to compare the effects of Sevage method， acetonitrile method and trichloroacetic acid (TCA) method for removaling crude Bletilla striata polysaccharide (BSP) protein, and to explore the rationality of entropy TOPSIS for BSP deproteinization system evaluation. Based on the comprehensive score of BSP retention rate and protein removal rate, the optimal treatment conditions were screened out. Nine evaluation indicators including monosaccharide components, oxidative radical scavenging ability (ORAC), and half scavenging concentration of DPPH radicals (IC50) were constructed. Supplemented by UV and FTIR, the entropy TOPSIS was used to evaluate the results of three BSP deproteinization programs. After comprehensive score, the best extraction times of sevage method was 1 time. At same time, the protein removal rate was 22.9%, and the polysaccharide retention rate was 99.11%. The optimal mass concentration of the TCA method was 10%, when the protein removal rate was 70.64%, and the polysaccharide retention rate was 70.03%. Compared with the ORAC values and IC50 of the three polysaccharide, it was found that the value of polysaccharide ORAC treated by the acetonitrile method was higher than that of the positive control group (P

This research introduces a new adaptive control approach tailored for networked control systems, aimed at addressing the challenges of Denial of Service (DoS) attacks and round-trip time delays. Initially, a compensation mechanism based on estimated values is introduced to counter DoS attacks; subsequently, for round-trip time delay issues, a predictive delay compensation control strategy is designed. The proposed control strategy does not rely on the specific structure or a particular model of the system, but instead solely updates the controller using the system's input and output values. Moreover, we successfully demonstrate the bounded stability of the system using the direct Lyapunov method. Ultimately, the effectiveness and practicality of this method are confirmed through simulation results.

BackgroundThe association between benign paroxysmal positional vertigo (BPPV) and various mental disorders is still controversial. This study used the Mendelian randomization (MR) method to clarify the correlation between BPPV and seven mental disorders (bipolar disorder, depression, anxiety disorder, schizophrenia, suicidality, neuroticism, and mood swings) to aid in the exploration of BPPV complications and prevention and early treatment of mental disorders.MethodsThe datasets for BPPV and seven mental disorders were obtained from genome-wide association studies (GWASs). Two-sample MR was used to analyze the correlation between exposure (BPPV) and various outcomes (bipolar disorder, depression, anxiety disorder, schizophrenia, suicidality, neuroticism, and mood swings). A reverse MR study was also performed. The inverse variance weighting (IVW) method, the MR–Egger method, the simple mode method, the weighted mode method, and the weighted median method were selected.ResultsThe MR analysis and the reverse MR analysis results did not reveal significant associations between BPPV and bipolar disorder, depression, anxiety disorder, schizophrenia, suicidal tendencies, neuroticism, and mood swings. Interestingly, neuroticism (IVW: OR = 1.142, 95% CI: 1.059–1.231, P = 0.001; P-MR-PRESSO adjustment = 0.0002) and mood swings (IVW: OR = 3.119, 95% CI: 1.652–5.884, P = 0.0004) may have a significant association with BPPV. After MR-PRESSO adjustment, there was no horizontal pleiotropy or heterogeneity, and a significant association between neuroticism, mood swings, and BPPV has still been suggested.ConclusionWe conducted MR analysis on genetic data from European populations and discovered a causal relationship between BPPV and the seven mental disorders. Our research findings suggest that BPPV may not have a significant causal relationship with bipolar disorder, depression, anxiety disorder, schizophrenia, or suicidal tendencies. However, neuroticism and mood swings may be risk factors for BPPV.

The protease Mpro (referred to as 3CLpro or 3CL protease) is a cysteine protease that is highly conserved in coronavirus and is indispensable for viral replication. Because there is no homologous protein for MPro in the human body, SARS-CoV-2 3CL protease is an ideal target against coronavirus. Bletilla striata (Reich. Bf.) is a well-known form of Traditional Chinese Medicine and can exert many pharmacological effects, including hemostasis, anti-microbial and anti-virus activities. Our preliminary screening showed that the n-butanol component of a methanol extract of B. striata exhibited potent inhibitory activity against SARS-CoV-2 3CL protease (58.82% at 200 μg/mL). In this study, we biologically evaluated ten isolated chemical compounds from B. striata and investigated the inhibitory activities of its constituents on SARS-CoV-2 3CL protease. Following bioactivity-guided fractionation, four bibenzyls (1, 4, 6 and 7), three phenols (5, 8 and 9), two anthraquinones (2 and 3) and one glucosyloxybenzyl 2-isobutylmalate (10) were isolated and evaluated for their ability to inhibit SARS-CoV-2 3CL protease by fluorescence resonance energy transfer (FRET) analysis. The binding mode between compounds and enzymes was investigated by molecular docking and Saturation Transfer Differences - nuclear magnetic resonance (STD-NMR). Moreover, Pleiobibenzynin B (7), Blestritin B, Gymconopin D (4), Physcion, 3′-O-methyl dioscin III (6), Gastrodin (8) and caffeic acid (5) all exhibited inhibitory activity against 3CL protease in vitro. The four bibenzyls (1, 4, 6 and 7) exhibited good inhibitory activity against SARS-CoV-2 3CL protease (7.37–39.86 μM). These findings identify potential new inhibitors against SARS-CoV-2 3CL protease, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs.

BackgroundPatients with schizophrenia are at a higher risk of developing cancer. However, the causal relationship between schizophrenia and different tumor types remains unclear.MethodsUsing a two-sample, two-way Mendelian randomization method, we used publicly available genome-wide association analysis (GWAS) aggregate data to study the causal relationship between schizophrenia and different cancer risk factors. These tumors included lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, gastric cancer, alcohol-related hepatocellular cancer, tumors involving the lungs, breast, thyroid gland, pancreas, prostate, ovaries and cervix, endometrium, colon and colorectum, and bladder. We used the inverse variance weighting (IVW) method to determine the causal relationship between schizophrenia and different tumor risk factors. In addition, we conducted a sensitivity test to evaluate the effectiveness of the causality.ResultsAfter adjusting for heterogeneity, evidence of a causal relationship between schizophrenia and lung cancer risk was observed (odds ratio [OR]=1.001, 95% confidence interval [CI], 1.000–1.001; P=0.0155). In the sensitivity analysis, the causal effect of schizophrenia on the risk of lung cancer was consistent in both direction and degree. However, no evidence of causality or reverse causality between schizophrenia and other tumors was found.ConclusionThis study elucidated a causal relationship between the genetic predictors of schizophrenia and the risk of lung cancer, thereby providing a basis for the prevention, pathogenesis, and treatment of schizophrenia in patients with lung cancer.

In this paper, we collect the basic information data of online rumors and highly topical public opinions. In the research of the propagation model of online public opinion rumors, we use the improved SCIR model to analyze the characteristics of online rumor propagation under the suspicion mechanism at different propagation stages, based on considering the flow of rumor propagation. We analyze the stability of the evolution of rumor propagation by using the time-delay differential equation under the punishment mechanism. In this paper, the evolution of heterogeneous views with different acceptance and exchange thresholds is studied, using the standard Deffuant model and the improved model under the influence of the media, to analyze the evolution process and characteristics of rumor opinions. Based on the above results, it is found that improving the recovery rate is better than reducing the deception rate, and increasing the eviction rate is better than improving the detection rate. When the time lag τ < 110, it indicates that the spread of rumors tends to be asymptotic and stable, and the punishment mechanism can reduce the propagation time and the maximum proportion of deceived people. The proportion of deceived people increases with the decrease in the exchange threshold, and the range of opinion clusters increases with the decline in acceptance.

Abstract Background Patients with malignancy are at a higher risk of developing nosocomial infections. However, limited studies investigated the clinical features and prognostic factors of nosocomial infections due to fungi in cancer patients. Herein, this study aims to investigate the clinical characteristics of in-hospital fungal infections and develop a nomogram to predict the risk of in-hospital death during fungal infection of hospitalized cancer patients. Methods This retrospective observational study enrolled cancer patients who experienced in-hospital fungal infections between September 2013 and September 2021. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of in-hospital mortality. Variables demonstrating significant statistical differences in the multivariate analysis were utilized to construct a nomogram for personalized prediction of in-hospital death risk associated with nosocomial fungal infections. The predictive performance of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. Results A total of 216 participants were included in the study, of which 57 experienced in-hospital death. C.albicans was identified as the most prevalent fungal species (68.0%). Respiratory infection accounted for the highest proportion of fungal infections (59.0%), followed by intra-abdominal infection (8.8%). The multivariate regression analysis revealed that Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 3–4 (odds ratio [OR] = 6.08, 95% confidence interval [CI]: 2.04–18.12), pulmonary metastases (OR = 2.76, 95%CI: 1.11–6.85), thrombocytopenia (OR = 2.58, 95%CI: 1.21–5.47), hypoalbuminemia (OR = 2.44, 95%CI: 1.22–4.90), and mechanical ventilation (OR = 2.64, 95%CI: 1.03–6.73) were independent risk factors of in-hospital death. A nomogram based on the identified risk factors was developed to predict the individual probability of in-hospital mortality. The nomogram demonstrated satisfactory performance in terms of classification ability (area under the curve [AUC]: 0.759), calibration ability, and net clinical benefit. Conclusions Fungi-related nosocomial infections are prevalent among cancer patients and are associated with poor prognosis. The constructed nomogram provides an invaluable tool for oncologists, enabling them to make timely and informed clinical decisions that offer substantial net clinical benefit to patients.

Abstract The catalytic asymmetric inverse-electron-demand oxa-Diels–Alder (IODA) reaction is a highly effective synthetic method for creating enantioenriched six-membered oxygen-containing heterocycles. Despite significant effort in this area, simple α,β-unsaturated aldehydes/ketones and nonpolarized alkenes are seldom utilized as substrates due to their low reactivity and difficulties in achieving enantiocontrol. This report describes an intermolecular asymmetric IODA reaction between α-bromoacroleins and neutral alkenes that is catalyzed by oxazaborolidinium cation 1f. The resulting dihydropyrans are produced in high yields and excellent enantioselectivities over a broad range of substrates. The use of acrolein in the IODA reaction produces 3,4-dihydropyran with an unoccupied C6 position in the ring structure. This unique feature is utilized in the efficient synthesis of (+)-Centrolobine, demonstrating the practical synthetic utility of this reaction. Additionally, the study found that 2,6-trans-tetrahydropyran can undergo efficient epimerization into 2,6-cis-tetrahydropyran under Lewis acidic conditions. This structural core is widespread in natural products.

To isolate gastrodin (GAS), 4-hydroxybenzyl alcohol (4-HBA), and phenolic compounds from Chinese medicine Gastrodia elata Blume, and to explore the binding mode of fatty acid binding protein 4 (FABP4/aP2) that is closely related to macrophage inflammation, we study their anti-inflammatory targets. After the ultrasonic extraction of the main active components with 70% ethanol, three resins and three eluents were selected, and eight phenolic monomers with similar structures, such as gastrodin and 4-hydroxybenzyl alcohol, were isolated from Gastrodia elata by AB-8 macroporous resin and silica gel column chromatography and eluted with the CHCl3-MeOH gradient. Their structures were identified by HPLC and nuclear magnetic resonance (NMR). The FABP4 protein was added to GAS and 4-HBA, and the NMR experiment was performed to observe ligand binding. Finally, according to the spectral information of STD-NMR and molecular docking technology, the interaction between ligands and protein was studied. The fluorescence competition experiment confirmed that both GAS and 4-HBA were in the binding cavity of FABP4. Moreover, 3-phenoxy-2-phenylbenzoic acid (PPA) is a possible inhibitor of FABP4, reducing macrophage-related inflammation and endoplasmic reticulum stress. This work provides a new basis for the anti-inflammatory mechanism of Gastrodia elata, paving the way for the research and development of FABP4 inhibitor drugs.

Anti-inflammatory drugs have become the second-largest class of common drugs after anti-infective drugs in animal clinical care worldwide and are often combined with other drugs to treat fever and viral diseases caused by various factors. In our previous study, a novel serine protease inhibitor-encoding gene (MDSPI16) with improved anti-inflammatory activity was selected from a constructed suppressive subducted hybridization library of housefly larvae. This protein could easily induce an immune response in animals and had a short half-life, which limited its wide application in the clinic. Thus, in this study, mPEG-succinimidyl propionate (mPEG-SPA, Mw = 5 kDa) was used to molecularly modify the MDSPI16 protein, and the modified product mPEG-SPA-MDSPI16, which strongly inhibited elastase production, was purified. It had good stability and safety, low immunogenicity, and a long half-life, and the IC50 for elastase was 86 nM. mPEG-SPA-MDSPI16 effectively inhibited the expression of neutrophil elastase and decreased ROS levels. Moreover, mPEG-SPA-MDSPI16 exerted anti-inflammatory effects by inhibiting activation of the NF-κB signaling pathway and the MAPK signaling pathway in neutrophils. It also exerted therapeutic effects on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. In summary, mPEG-SPA-MDSPI16 is a novel anti-inflammatory protein modified with PEG that has the advantages of safety, nontoxicity, improved stability, and strong anti-inflammatory activity in vivo and in vitro and is expected to become an effective anti-inflammatory drug.

Introduction Combined small cell lung cancer (C-SCLC) represents a rare subtype of all small cell lung cancer cases, with limited studies investigated its prognostic factors. The aim of this study was to construct a novel nomogram to predict the overall survival (OS) of patients with C-SCLC. Methods In this retrospective study, a total of 588 C-SCLC patients were selected from the Surveillance, Epidemiology, and End Results database. The univariate and multivariate Cox analyses were performed to identify optimal prognostic variables and construct the nomogram, with concordance index (C-index), receiver operating characteristic curves, and calibration curves being used to evaluate its discrimination and calibration abilities. Furthermore, decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) were also adopted to assess its clinical utility and predictive ability compared with the classic TNM staging system. Results Seven independent predictive factors were identified to construct the nomogram, including T stage, N stage, M stage, brain metastasis, liver metastasis, surgery, and chemotherapy. We observed a higher C-index in both the training (.751) and validation cohorts (.736). The nomogram has higher area under the curve in predicting 6-, 12-, 18-, 24-, and 36-month survival probability of patients with C-SCLC. Meanwhile, the calibration curves also revealed high consistencies between the actual and predicted OS. DCA revealed that the nomogram could provide greater clinical net benefits to these patients. We found that the NRI for 6- and 12-month OS were .196 and .225, and the IDI for 6- and 12-month OS were .217 and .156 in the training group, suggesting that the nomogram can predict a more accurate survival probability. Similar results were also observed in the validation cohort. Conclusion We developed and verified a novel nomogram that can help clinicians recognize high-risk patients with C-SCLC and predict their OS.

Open-cast coal mining in China has developed rapidly due to its obvious advantages over underground mining. However, it may have negative ecological effects, such as biodiversity loss, water shortage, and soil erosion. Identifying and protecting the key areas with high importance for ecological sustainability are great challenges. The construction of an ecological security pattern (ESP) can improve landscape connectivity and reduce the fragmentation of ecological patches. Thus, it can be seen as an effective measure to protect regional ecological sustainability. In this study, taking the Pingshuo open-cast mining area as a case study area, ecological sources are identified through ecosystem structure and function, and corridors are extracted by constructing an ecological resistance surface, thus forming a valid ecological network. The results show that in 2018, the ESP in the study area included 11 sources with an area of 147.74 km2 and 17 corridors with a length of 92.11 km. Specifically, the ecological sources are mainly distributed in Taocun Township, Jingping Township, and Xiangyangbao Township. Among these 11 sources, sources 7 and 8 are reclaimed waste dump land, meaning that the land reclamation work in Pingshuo greatly promotes connectivity. Furthermore, dump 1 can be restored in the future by constructing three new corridors, which will greatly improve the landscape connectivity of Yuling Township. Overall, this study not only provides an effective framework for constructing and optimizing ESPs in ecologically fragile coal mining areas, but it also adds new insights to the concept of land reclamation in these areas.

A tandem palladium-catalyzed Sonogashira coupling, propargyl-allenyl isomerization, and [2+2] cycloaddition sequence between electrondeficient haloarenes and 1,8-diynylic ethers is developed. The reaction shows good functional tolerance and proceeds under mild conditions to provide a new profile of benzooxepane-fused cyclobutene derivatives in moderate to high yields with high selectivity. The reaction mechanism is validated both by experimental studies and DFT calculations. [ABSTRACT FROM AUTHOR]

Background: The association between benign paroxysmal positional vertigo (BPPV) and various mental disorders is still controversial. This study used the Mendelian randomization (MR) method to clarify the correlation between BPPV and seven mental disorders (bipolar disorder, depression, anxiety disorder, schizophrenia, suicidality, neuroticism, and mood swings) to aid in the exploration of BPPV complications and prevention and early treatment of mental disorders. Methods: The datasets for BPPV and seven mental disorders were obtained from genome-wide association studies (GWASs). Two-sample MR was used to analyze the correlation between exposure (BPPV) and various outcomes (bipolar disorder, depression, anxiety disorder, schizophrenia, suicidality, neuroticism, and mood swings). A reverse MR study was also performed. The inverse variance weighting (IVW) method, the MR-Egger method, the simple mode method, the weighted mode method, and the weighted median method were selected. Results: The MR analysis and the reverse MR analysis results did not reveal significant associations between BPPV and bipolar disorder, depression, anxiety disorder, schizophrenia, suicidal tendencies, neuroticism, and mood swings. Interestingly, neuroticism (IVW: OR = 1.142, 95% CI: 1.059-1.231, P = 0.001; P-MR-PRESSO adjustment = 0.0002) and mood swings (IVW: OR = 3.119, 95% CI: 1.652-5.884, P = 0.0004) may have a significant association with BPPV. After MR-PRESSO adjustment, there was no horizontal pleiotropy or heterogeneity, and a significant association between neuroticism, mood swings, and BPPV has still been suggested. Conclusion: We conducted MR analysis on genetic data from European populations and discovered a causal relationship between BPPV and the seven mental disorders. Our research findings suggest that BPPV may not have a significant causal relationship with bipolar disorder, depression, anxiety disorder, schizophrenia, or suicidal tendencies. However, neuroticism and mood swings may be risk factors for BPPV. [ABSTRACT FROM AUTHOR]

This paper provides a novel safe reinforcement learning (RL) control algorithm to solve safe optimal problems for fully cooperative (FC) games of discrete-time multiplayer nonlinear systems with state and input constraints. The FC game is a special case of nonzero-sum (NZS) games, where all players cooperate to accomplish a common task. The algorithm is proposed based on the policy iteration (PI) framework utilizing only the measured data along the system trajectories in the environment. Different from most works about PI, an effective method of obtaining initial safe and stable control policies is given here. In addition, control barrier functions (CBFs) and an input constraint function are introduced to augment reward functions. And the monotonically nonincreasing property of the iterative value function in the PI algorithm maintains the safe set forward invariant. Then, the neural networks are employed to approximate the system dynamics, the iterative control policies, and the iterative value function, respectively. Furthermore, the proposed algorithm is supported by theoretical proofs that guarantee both safety and convergence. Finally, the effectiveness and safety of the algorithm are illustrated by the results of the simulation. [ABSTRACT FROM AUTHOR]