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关键词： Density functional theory   Heavy oil processing   Hydrothermal cracking   N-cyclohexylnaphthalen-1-amine   Reaction mechanism  

摘要： Hydrothermal cracking is recognized as a promising technology for heavy oil upgrading, where a molecular-level understanding of the role of water and its ionic products is considered essential for its optimization and advancement. In this work, the multifaceted role of water in the degradation of a representative model compound, N-cyclohexylnaphthalen-1-amine (CNA), was investigated using density functional theory (DFT). It was demonstrated that water functions as an in-situ source of acid-base catalysts, in which the cleavage of aliphatic C–N bonds is dramatically promoted by hydronium ions, while the dissociation products are stabilized by water molecules and hydroxide ions. Notably, the aromatic C–N bonds were identified to exhibit superior reactivity in nucleophilic substitution compared to their aliphatic counterparts; nucleophilic substitution occurs more readily at the α-carbon site of the naphthalene ring than at that of a benzene ring. By constructing the hydrothermal cracking reaction network of the model compound, it is clarified that water and its ionic products in the hydrothermal system function as in-situ acid/base species that can catalyze, regulate, or directly participate in the hydrothermal cracking process. Furthermore, the preferential dependence of different reaction routes on the local acid-base environment is revealed. This study provides a theoretical basis for mechanistic investigations of heavy oil upgrading under acid-base regulated conditions and for the optimization of process conditions.

关键词： Toripalimab-tpzi   Head and neck cancer   Immunotherapy   PD-1 inhibitor   Precision medicine  

摘要： The recent humanized anti-programmed death-1 (PD-1) monoclonal antibody, toripalimab-tpzi, has now become a promising immunotherapeutic agent in the control of head and neck cancer (HNC), especially head and neck squamous cell carcinoma (HNSCC), the most common form of the disease, constituting approximately 90 % of all cases. In this conceptual review, the authors critically examine the molecular processes, clinical activity, safety, biomarker-guided precision of their approach, resistance biology, and combination regimens of toripalimab-tpzi in HNSCC. Toripalimab-tpzi offers antitumor effects due to selective inhibition restricting the PD-1/programmed death-ligand 1 (PD-L1) axis, which restores cytotoxic T-cell activity and intensifies the antitumor immune responses. In the Phase I-III clinical trials on recurrent or metastatic HNSCC, the objective response rates of toripalimab-tpzi were around 20-36, the median progression-free survival (PFS) was 2.8–4.5 months, and the median overall survival was 10–15 months, especially with PD-L1-enriched populations. The safety profile is comparable to the PD-1 class effects, and the majority of the immune-related adverse events (irAEs) were grade 1-2 and grade 3-4 toxicities that were rare in less than 20 percent of the patients. The new evidence is pointing to the significance of patient selection according to biomarker to maximize therapeutic response. The single predictive utility of such markers as PD-L1 expression, tumor mutational burden, microsatellite instability, tumor-infiltrating lymphocytes, or immune gene signatures is variable, with the deficiency of single-biomarker systems. Integration therapy involving toripalimab-tpzi and platinum-based chemotherapy, radiotherapy, targeted therapies, or other immunomodulators has been shown to result in better response rates (up to 4060 % in select studies) and may result in resistance being overcome by intrinsic or acquired immunomodulatory mechanisms. Unlike previous gene

关键词： Cassini-like identity   Clifford algebras   Conics   Fibonacci numbers   Generalized Fibonacci sequence   Horadam numbers  

摘要： The goal of this article is to introduce a geometric interpretation of the Cassini-like identity, which is an identity between the terms of the Horadam numbers. The geometric interpretation is obtained from the Cassini-like identity and the recurrence relation of the Horadam sequence. The scalar products obtained from the Cassini-like identity are used to define angle, norm, skew-symmetric matrix and rotation maps. Two different scalar products are defined on ${\mathbb{R}}^2$ from the Cassini-like identity. In this way, the terms of the Horadam sequence are obtained without using the recurrence relation but with the help of the obtained rotation matrix. In order to give a geometric interpretation in ${\mathbb{R}}^3$, the scalar product and the set of Cassini numbers are defined. Using the properties of Cassini numbers, rotation matrices are obtained between the terms of the Horadam numbers with characteristic equation $x^2-qx\pm 1=0$.

关键词： Chemisorption   Freundlich isotherms   Magnetic adsorbents   Statistical analysis   X-ray diffraction  

摘要： Human or naturally-polluted water resources with fluoride concentrations above WHO standards (1.5 mg/L) cause health hazards including skeletal and dental fluorosis.

关键词： Bis-triazole Schiff bases   Corrosion inhibitors   Q235 steel   Quantum chemical calculations  

摘要： Q235 steel is susceptible to severe corrosion during the pickling process, especially in hydrochloric acid media, which not only shortens the service life of the equipment, but also may cause safety hazards and environmental pollution.

关键词： Pterocarpus soyauxii   Pterocarpus mildbraedii   HIV-1   SARS-CoV-2   molecular docking   network pharmacology  

摘要： This research explored the therapeutic efficacy of bioactive substances derived from Pterocarpus soyauxii and Pterocarpus mildbraedii against HIV-1 and SARS-CoV-2 co-infection. Pharmacokinetic characteristics were evaluated with ADMETlab 3.0. Network pharmacology analyses were conducted using Swiss Target Prediction, GeneCards, STRING, Cytoscape and Metascape, along with pathway mapping in Srplot. The protein structures of EGFR, MMP9 and SARS-CoV-2 polyprotein 1ab were assessed through the SwissModel and ProSA-web databases. Molecular docking and binding sites determination were performed through 1-Click Docking and BC-Dock2 web servers. Inhibitory activity of the compounds on the CDK2 and HIV-1 proteins was carried out in the kinCSM way2drug databases. Results show that Khrinone A and E exhibited positive absorption and distribution profiles. Network pharmacology revealed essential molecular targets and enriched KEGG pathways associated with viral replication. MolProbity scores ranged from 0.77 to 2.28, with over 92% of residues located in Ramachandran preferred regions. Molecular docking revealed significant binding affinities, especially Pterocarpin (-9.9 kcal/mol) with MMP9 and Khrinone A (-8.9 kcal/mol) with NOS2, surpassing reference inhibitors. In comparison to EGFR, the affinities of natural ligands (-7.7 kcal/mol to -7.0 kcal/mol) were similar to Gefitinib, whereas Claussequinone and Khrinone E demonstrated compelling interactions with HIV-1 reverse transcriptase (-7.4 kcal/mol to -7.2 kcal/mol), resembling those of Lawsone (-8.3 kcal/mol). Additionally, Khrinone A and E can serve as potent CDK2 inhibitors (IC50 < 10 mu M), exhibiting pKi values (5.902-5.929) comparable to those of Palbociclib (6.029). These results indicate that compounds derived from Pterocarpus have multitarget antiviral and host-modulating abilities, reinforcing their potential as valuable candidates for therapeutic intervention in HIV/SARS-CoV-2 co-infection.

关键词： metabolic myopathy   mouse model   purine metabolism   adenylosuccinate synthetase   ADSS1  

摘要： ADSS1 myopathy is an ultrarare congenital myopathy characterized by progressive cardiac and skeletal muscle degeneration with childhood to adolescent onset. This autosomal recessive disease is caused by mutations in the ADSS1 gene, encoding the enzyme adenylosuccinate synthetase (AdSS1). AdSS1 plays a critical role in the adenine nucleotide cycle, which is important for energy metabolism in muscle cells. Enzymatic defects, engendered by loss-of-function mutations in ADSS1, lead to a bottleneck in the adenine nucleotide cycle, causing metabolic dysfunction that ultimately results in progressive muscle weakness, mobility impairment, and respiratory and cardiac dysfunction, often requiring the use of a ventilator. Despite its debilitating nature, there are currently no cures or targeted treatments available, and little research into possible therapeutic strategies has been done. With a limited patient profile encompassing fewer than 200 known patients worldwide, establishing a mouse model for ADSS1 myopathy is critical to understanding its pathogenesis and for developing future therapies. Here, we present and characterize the first mouse model of ADSS1 myopathy-a constitutive Adss1 knockout model-by (1) defining its natural history, (2) exploring its metabolic pathomechanisms, and (3) characterizing its histopathological features. We find that Adss1KO/KO mice have subtle motor deficits and present with histopathological features consistent with patient phenotypes. Overall, we show that despite a relatively mild phenotype, this novel mouse model has quantifiable pathological features that can be used to develop therapies for, and further probe pathophysiology of, ADSS1 myopathy.

关键词： HIV integrase   LEDGF/p75   LEDGINs   natural products   molecular dynamics simulation   thermodynamics profile  

摘要： HIV integrase is an essential enzyme responsible for incorporating viral DNA into the host's genome, a vital phase in the HIV replication process. The host protein, Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75), connects with the HIV Integrase (IN) Catalytic Core Domain (CCD) via its Integrase Binding Domain (IBD) and anchors the pre-integration complex, aiding in the integration of HIV into regions of chromatin that are transcriptionally active. This interaction underscores the importance of the integrase-LEDGF/p75 complex as a target for therapeutic intervention. Interrupting this interaction with allosteric inhibitors of the LEDGF/p75-IN interaction, known as LEDGINs, has become a promising method to curb HIV replication. Although LEDGINs are still being studied for clinical application, they may be too costly for developing countries if approved, emphasizing the necessity for ongoing research into alternative methods. Natural substances like terpenes and flavonoids show antiviral properties. Consequently, utilizing natural compound libraries to target the HIV integrase-LEDGF/p75 interaction offers a new strategy for creating effective antiviral medications. This research assessed a collection of compounds derived from natural sources. To refine a library of over 76,000 compounds, Lipinski's rule of five was applied. Molecular docking and 300 ns Molecular Dynamics (MD) simulations were conducted to pinpoint compounds with strong binding affinity and stability to the CCD-IBD interface, using LEDGIN6 as a benchmark inhibitor. Through molecular docking studies, Guanipiperazine B, CHEBI:211233 and Okaramine T were identified as promising inhibitors of the HIV-1 integrase-LEDGF/p75 complex, showing stronger binding affinities compared to the reference drug LEDGIN6. Among these, Guanipiperazine B exhibited the most stable binding, as evidenced by the lowest Root Mean Square Deviation (RMSD) and RMSF values in MD simulations, indicating robust and stable interac

关键词： 2,3-dihydro-1,3,4-thiadiazole-benzenesulfonamide   triple inhibitors   EGFR   carbonic anhydrase   breast cancer  

摘要： A novel 2,3-dihydro-1,3,4-thiadiazole-benzenesulfonamide hybrid, N-(4-(( E )-1-((( Z )-5-acetyl-3-(4-sulfamoylphenyl)-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-chloro benzamide (N-ASTPC), was rationally designed as a triple inhibitor targeting carbonic anhydrase IX (CAIX), carbonic anhydrase XII (CAXII), and the epidermal growth factor receptor (EGFR) - key targets overexpressed in cancer. Molecular docking and 200-ns molecular dynamics (MD) simulations confirmed stable and high-affinity interactions of N-ASTPC with the active sites of all three targets. MM-GBSA binding free energy calculations and ProLIF interaction profiling further supported these findings, while principal component analysis (PCA) revealed limited conformational drift, indicating robust complex formation. Additionally, density functional theory (DFT) assessments affirmed N-ASTPC's electronic stability and favorable reactivity. Biological assays demonstrated potent inhibitory activity with IC50 values of 0.039 mu M, 0.04 mu M, and 0.05 mu M for CAIX, CAXII, and EGFR, respectively, comparable or superior to standard inhibitors (acetazolamide and erlotinib). Regarding in vitro cytotoxicity, N-ASTPC displayed selective toxicity toward cancer cells over normal fibroblasts, with notable effects in MDA-MB-231 and MCF-7 breast cancer lines compared to doxorubicin. Flow cytometry showed that N-ASTPC induces significant S-phase arrest and robust early apoptosis, confirmed by a similar to 5.7-fold increase in Bax, similar to 4.5-fold increase in caspase-3, and similar to 2-fold decrease in Bcl-2 expression - consistent with mitochondrial apoptotic pathway activation. Collectively, these findings establish N-ASTPC as a promising multifunctional anti-cancer lead compound capable of simultaneously disrupting tumor cell metabolism and signaling via CAIX, CAXII, and EGFR inhibition. Its multi-modal mechanism and selective apoptotic induction underscore its potential for further preclinical develop

关键词： after surgery   sepsis   sTREM1   diagnosis and prognosis  

摘要： Introduction Sepsis represents a critical response to infection;it is characterized by systemic inflammation, shock, and potential organ failure. Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) has been identified as a crucial marker in sepsis, connecting the activation of innate immunity to systemic inflammation. Methods This prospective nested case control study was carried out in the intensive care unit and surgery department from March 2018 to June 2019. Adults undergoing abdominal surgery, with and without sepsis, were included in the study, and sTREM-1 and cytokine levels were measured. Results A total of 120 patients were included in the study, comprising 31 noninfected individuals, 37 with sepsis, and 52 with septic shock. sTREM-1 levels were statistically significantly elevated in patients with sepsis and septic shock compared with noninfected individuals (P < .001). Receiver operating characteristic curve analysis revealed an area under the curve of 0.722 for sTREM-1 in the prediction of septic shock. Discussion Elevated sTREM-1 levels are associated with the severity of sepsis and may function as a prognostic biomarker. Additional research is required to confirm these findings and investigate therapeutic interventions aimed at the sTREM-1 pathway.