The Value of Chemokine and Chemokine Receptors in Diagnosis, Prognosis, and Immunotherapy of Hepatocellular Carcinoma.

Background: Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy. Methods: CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC. Results: We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib. Conclusion: The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.

Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

A Superior Catalytic Air Electrode with Temperature-Induced Exsolution toward Protonic Ceramic Cells.

Protonic ceramic cells merit extensive exploration, attributed to their innate capabilities for potent and environmentally benign energy conversion. In this work, a temperature-induced exsolution methodology to synthesize SrCo0.5Nb0.5O3-δ (SCN) nanoparticles (NPs) with notably elevated activity on the surface of PrSrCo1.8Nb0.2O6-δ (PSCN) is proposed, directly addressing the extant challenge of restrained catalytic activity prevalent in air electrode materials. In situ assessments reveal that SCN NPs commence exsolution from the matrix at temperatures surpassing 900 °C during straightforward calcination processes and maintain stability throughout annealing. Notably, the resultant SCN-PSCN interface facilitates vapor adsorption and protonation processes, which are poised to enhance surface reaction kinetics pertaining to the proton-involved oxygen reduction and evolution reaction (P-ORR and P-OER). A fuel-electrode-supported protonic ceramic cell leveraging SCN-PSCN as the air electrode manifests compelling performance, attaining a peak power density of 1.30 W·cm-2 in the fuel cell modality and a current density of 1.91 A·cm-2 at 1.3 V in the electrolysis mode, recorded at 650 °C. Furthermore, density functional theory calculations validate that the introduction of SCN NPs onto the PSCN surface conspicuously accelerates electrode reaction rates correlated with P-ORR and P-OER, by significantly mitigating energy barriers associated with surface oxygen and vapor dissociation.

Global fixed-time trajectory tracking control of underactuated USV based on fixed-time extended state observer.

This paper studies the trajectory tracking problem of unmanned surface vehicle subject to unmeasurable velocities and unknown disturbances. By combining a fixed-time extended state observer (FESO) and a fixed-time differentiator, a fixed-time sliding mode control (FTSMC) law is proposed, in which a saturation function is adopted to make the terminal sliding mode surface leave the singularity area. The value of this paper can be described: first, this paper designs a novel guidance law that can converge in a fixed time to reduce the convergence time of the error. Then, unmeasurable velocities and lumped disturbances are estimated by applying a FESO. Meanwhile, a fixed-time differentiator is used to obtain real-time differential signals, thus reducing the difficulty of controller design. Subsequently, a novel auxiliary dynamic system is designed to address actuator saturation. According to Lyapunov's theory, the entire closed-loop control system has uniformly global fixed-time stability (UGFTS). The superiority of the designed controller is demonstrated through numerical simulations.

Effect of Ammonia on Laminar Combustion Characteristics of Methane-Air Flames at Elevated Pressures.

In this paper, laminar combustion characteristics of methane/ammonia/air flames are numerically investigated using the Chemkin/Premix code. The initial temperature is set as 298 K; the initial pressures are set as 1, 2, 5, 10, and 20 atm; and the equivalence ratios are set as 0.8-1.6. Laminar burning velocity (LBV); adiabatic flame temperature (AFT); net heat release rate (NHRR); and the mole fractions of H, NH2, NO, NO2, and HCN at stoichiometric ratio are studied with ammonia (NH3) addition. Meanwhile, temperature sensitivity and rate of production (ROP) are analyzed. The results show that with the increase of the initial pressures, LBV decreases and AFT and NHRR increase. With the increase of ammonia doping ratios, LBV, AFT, and NHRR decrease. From temperature sensitivity analyses, the main reactions that promote temperature rise are R39 (H + O2 < = > O + OH), R100 (OH + CH3 < = > CH2(S) + H2O), R102 (OH + CO < = > H + CO2), and R122 (HO2 + CH3 < = > OH + CH3O). The main reactions that inhibit temperature rise are R53 (H + CH3(+M) < = > CH4(+M)), R36 (H + O2 + H2O < = > HO2 + H2O), and R46 (H + HO2 < = > O2 + H2). For the rate of production of the free radical pool, the trends of H and NO are consuming first and then producing, and the trends of NH2, NO2, and HCN are the opposite. The pathway from methane to carbon dioxide is CH4 → CH3 → CH3O → CH2O → HCO → CO → CO2, and the pathway from ammonia to nitrogen is NH3 → NH2 → NH/HNO → NO/NO2 → N2.

Trajectory linearization-based robust course keeping control of unmanned surface vehicle with disturbances and input saturation.

This article addresses the problem of course keeping for unmanned surface vehicle (USV) subject to rudder servo characteristics, disturbances, uncertainties and rudder saturation. A double loop robust compound control strategy is developed by incorporating finite-time uncertainty observer (FUO) and auxiliary dynamic system into trajectory linearization control (TLC). TLC is an effective robust control technique with simple design structure, which is used in the course control experiment of USV for the first time. In each loop, the FUO and auxiliary system are designed to compensate unknown lumped disturbances and input saturation, respectively. A nonlinear tracking differentiator (NTD) is concurrently introduced to realize differentiation and filtering for the reference command. Strict stability analysis indicates that the entire system is uniformly ultimately bounded (UUB). Results from simulations and experiments are presented to validate the developed strategy.

Hyperhomocysteinemia Accelerates Acute Kidney Injury to Chronic Kidney Disease Progression by Downregulating Heme Oxygenase-1 Expression.

AIMS: The risk factors promoting acute kidney injury (AKI) to chronic kidney disease (CKD) progression remain largely unknown. The aim of the present study was to investigate whether hyperhomocysteinemia (Hhcy) accelerates the development of renal fibrosis after AKI. RESULTS: Hhcy aggravated ischemia-reperfusion-induced AKI and the subsequent development of renal fibrotic lesions characterized by excessive extracellular matrix deposition. Mechanistically, the RNA binding protein human antigen R (HuR) bound to the 3'-untranslated region (3'-UTR) of heme oxygenase-1 (HO-1) messenger RNA (mRNA). Homocysteine (Hcy) downregulated HuR expression, reduced the binding of HuR to the 3'-UTR of HO-1, and thereafter decreased HO-1 expression. Administration of the HO-1 inducer cobalt protoporphyrin-IX significantly hindered Hhcy-augmented reactive oxygen species production and renal fibrotic lesions. Innovation and Conclusion: These data indicate that Hhcy might be a novel risk factor that promotes AKI to CKD progression. Lowering Hcy level or HO-1 induction might be a potential therapeutic strategy to improve the outcome of AKI.

Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients.

Background and Purpose- Trimethylamine N-oxide (TMAO)-a gut derived metabolite-has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods- We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results- After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02-1.46). Consistently, compared with participants in the lowest tertile (<1.79 µmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 µmol/L; odds ratio, 1.34; 95% CI, 1.00-1.81) or in TMAO tertile 3 (≥3.19 µmol/L; odds ratio, 1.43; 95% CI, 1.02-2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions- Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Modeling and Identification for Vector Propulsion of an Unmanned Surface Vehicle: Three Degrees of Freedom Model and Response Model.

This paper presents a complete scheme for research on the three degrees of freedom model and response model of the vector propulsion of an unmanned surface vehicle. The object of this paper is “Lanxin”, an unmanned surface vehicle (7.02 m × 2.6 m), which is equipped with a single vector propulsion device. First, the “Lanxin” unmanned surface vehicle and the related field experiments (turning test and zig-zag test) are introduced and experimental data are collected through various sensors. Then, the thrust of the vector thruster is estimated by the empirical formula method. Third, using the hypothesis and simplification, the three degrees of freedom model and the response model of USV are deduced and established, respectively. Fourth, the parameters of the models (three degrees of freedom model, response model and thruster servo model) are obtained by system identification, and we compare the simulated turning test and zig-zag test with the actual data to verify the accuracy of the identification results. Finally, the biggest advantage of this paper is that it combines theory with practice. Based on identified response model, simulation and practical course keeping experiments are carried out to further verify feasibility and correctness of modeling and identification.