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We present an efficient method based on an extension of metadynamics for exploring complex free energy landscapes (FELs). The method employs two-step metadynamics simulations. In the first step, rapid metadynamics simulations using broad and tall Gaussians are performed to identify a free energy pathway (FEP) connecting the two states of interest. The FEP is then divided into a series of independent subphase spaces that comprise selected discrete images of the system. Using appropriate collective variables (CVs) chosen according to the FEP, the accurate FEL of each subphase space is separately calculated in subsequent divide-and-conquer metadynamics simulations with narrow and low Gaussians. Finally, all FELs calculated in each subphase space are merged to obtain the full FEL. We show that the method greatly improves the performance of the metadynamics approach. In particular, we are able to efficiently model chemical systems with complex FELs, such as chemical reactions at the air/water interface. We demonstrate the performance of this method on two model reactions: the hydrolysis of formaldehyde in the gas phase and at the air/water interface. [ABSTRACT FROM AUTHOR]

Reactive uptake of dinitrogen pentaoxide (N2O5) into aqueous aerosols is a major loss channel for NOx in the troposphere; however, a quantitative understanding of the uptake mechanism is lacking. Herein, a computational chemistry strategy is developed employing high-level quantum chemical methods; the method offers detailed molecular insight into the hydrolysis and ammonolysis mechanisms of N2O5 in microdroplets. Specifically, our calculations estimate the bulk and interfacial hydrolysis rates to be (2.3 ± 1.6) × 10−3 and (6.3 ± 4.2) × 10−7 ns−1, respectively, and ammonolysis competes with hydrolysis at NH3 concentrations above 1.9 × 10−4 mol L−1. The slow interfacial hydrolysis rate suggests that interfacial processes have negligible effect on the hydrolysis of N2O5 in liquid water. In contrast, N2O5 ammonolysis in liquid water is dominated by interfacial processes due to the high interfacial ammonolysis rate. Our findings and strategy are applicable to high-chemical complexity microdroplets.The authors report a computational strategy to simulate the hydrolysis and ammonolysis of N2O5 in aerosols using high-level quantum chemical methods. The computational results reveal a complete picture of the reactive uptake of N2O5 by atmospheric aerosols with or without NH3. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the diagnostic value of serum adenosine deaminase (ADA) in patients with myelodysplastic syndromes (MDS) and identify potential risk factors for MDS. Methods: Eighty patients with MDS and 80 healthy individuals were included. The serum ADA level was found to be significantly higher in patients with MDS compared with that of healthy controls (p = 0.014). Results: The receiver operator characteristic curve (ROC) for ADA had an area under curve (AUC) of 0.807 (p = 0.0018). Serum ADA level of 4.5 U/L had a sensitivity of 71.43% and specificity of 80% for MDS diagnosis. The multivariate analysis showed hemoglobin (Hb, OR = 1.322, 95% CI: 1.035 - 2.323, p = 0.039), prothrombin time (PT, OR = 1.524, 95% CI: 1.156 - 3.280, p = 0.042), fibrinogen (OR = 1.335, 95% CI: 1.022 - 2.775, p = 0.027), calculated international normalized ration (INR, OR = 2.212, 95% CI: 1.320 - 3.085, p = 0.038), D-dimer (OR = 2.043, 95% CI: 1.623 - 4.293, p = 0.038), fibrin degradation product (FDP, OR = 2.525, 95% CI: 1.129 - 3.340, p = 0.029), and serum ADA (OR = 2.057, 95% CI: 1.248 - 3.572, p = 0.033) were independently associated with MDS. Conclusions: Serum ADA might be a potential biomarker in the diagnosis of MDS. Serum ADA level, Hb level, PT, fibrinogen level, INR, D-dimer, and FDPs were independent risk factors of MDS. [ABSTRACT FROM AUTHOR]

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m²) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m² and was increased in 5 mg/m² increments until the MTD was determined or the maximum dose level of 75 mg/m² was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m², no DLT was reported. DLTs were observed in one patient who received 70 mg/m² docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m² docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion: Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m²), can be used safely at intraperitoneal doses of 75 mg/m² in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery. [ABSTRACT FROM AUTHOR]

Purpose: The role of developmental endothelial locus-1 (DEL-1) in Porphyromonas gingivalis (P. gingivalis)-induced periodontitis and the related molecular mechanisms are unclear. This study aimed to investigate the effect of DEL-1 on SH3 Domain Binding Protein 2 (SH3BP2) expression, and to explore the regulatory role of DEL-1 in periodontal inflammation. Materials and Methods: We constructed a P. gingivalis-induced rat experimental periodontitis model, and cultured P. gingivalis-stimulated THP-1 cells in vitro. THP-1 cell viability and cell cycle were examined by CCK-8 and flow cytometry. Rat gingival tissues were collected for hematoxylin-eosin staining. The expression of SH3BP2 and nicotinamide phosphoribosyltransferase (NAMPT) was examined using Western blot. Results: We found that the proliferation of P. gingivalis-infected THP-1 cells was increased by DEL-1. DEL-1 inhibited the expression of NAMPT and SH3BP2 in gingiva tissues of rats with periodontitis as well as in P. gingivalis-infected THP-1 cells. Conclusions: Overexpression of DEL-1 downregulated SH3BP2 expression and reduced gingival inflammation induced by P. gingivalis. DEL-1 presents some regulatory effects on gingival inflammation in a P. gingivalis-induced rat experimental periodontitis model, suggesting the therapeutic potential of DEL-1 in regulating periodontal inflammation. [ABSTRACT FROM AUTHOR]