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The excellent photophysical and electrochemical properties of porphyrins have inspired widespread interest in the realm of electrochemiluminescence (ECL). The aggregation-caused deficiency of ECL emission in aqueous solution, however, still severely impedes further applications. Herein, a molecule with a donor-acceptor (D-A) configuration, ATPP-Cou, consisting of monoaminoporphyrin as an electron donor and coumarin as an electron acceptor, was designed as an ECL luminophore to address the susceptibility of the porphyrin to aggregation-caused quenching (ACQ) in aqueous solution. ATPP-Cou demonstrated a three-fold enhanced ECL signal compared to pristine ATPP. Despite the acknowledged significance of intramolecular charge transfer (ICT) in generating excited states in ECL, there is a lack of quantitative descriptions. Herein, intensity-modulated photocurrent spectroscopy (IMPS) and scanning photoelectrochemical microscopy (SPECM) were utilized to validate the influence of ICT on the enhancement performance of D-A type ECL molecules. Additionally, ATPP-Cou was also developed as a probe for the successful detection of Cu2+ in aqueous solution. The present study not only enriches the repertoire of efficient porphyrin-based ECL luminophores applicable in aqueous environments but also exemplifies the successful integration of novel measurement techniques to provide more comprehensive insights into the underlying mechanisms responsible for improved ECL performance.

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The development of dual linkage covalent organic frameworks (DL-COFs) is fundamentally important for creating diversified structures and functions. Herein, imine-hydrazone DL-COFs were synthesized for the first time. Three novel imine-hydrazone DL-COFs have been constructed with bifunctional molecule 4-amino-2-methoxybenzohydrazide as the key building block via imine and hydrazone condensations simultaneously.

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Cytochromes P450 (P450s or CYPs) are the most important phase I metabolic enzymes in the human body and are responsible for metabolizing ∼75% of the clinically used drugs. P450-mediated metabolism is also closely associated with the formation of toxic metabolites and drug-drug interactions. Therefore, it is of high importance to predict if a compound is the substrate of a given P450 in the early stage of drug development. In this study, we built the multitask learning models to simultaneously predict the substrates of five major drug-metabolizing P450 enzymes, namely, CYP3A4, 2C9, 2C19, 2D6, and 1A2, based on the collected substrate data sets. Compared to the single-task model and conventional machine learning models, the multitask fingerprints and graph neural networks model achieved superior performance with the average AUC values of 90.8% on the test set. Notably, the multitask model demonstrated its good performance on the small amount of substrate data sets such as CYP1A2, 2C9, and 2C19. In addition, the Shapley additive explanation and the attention mechanism were used to reveal specific substructures associated with P450 substrates, which were further confirmed and complemented by the substructure mining tool and the literature.

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This article reports a case of mediastinal lymph node tuberculosis with no obvious symptoms and a concealed focus. This patient, a 33-year-old male, suffered from pain behind the sternum after eating. He underwent three gastroscopic examinations and two fine needle punctures guided by ultrasound gastroscopy but was not diagnosed. Chest-enhanced CT revealed a mediastinal mass compressing the adjacent esophagus, suggesting the possibility of enlarged lymph nodes. Furthermore, T cells from patients infected with tuberculosis tested positive. Ultrasound bronchoscopy revealed enlarged lymph nodes in area 7, and then EBUS-TBNA was performed in that region. Only a few scattered lymphocytes and necrotic tissue were found under the biopsy microscope. The EBUS-TBNA biopsy Xpert MTB/RIF showed low positive results, and the EBUS-TBNA puncture fluid Xpert MTB/RIF was positive. Therefore, he was diagnosed with mediastinal lymph node tuberculosis. After antituberculosis treatment with the 2HREZ/10HRE regimen, the patient's pain behind the sternum gradually alleviated, and the enlarged mediastinal lymph nodes gradually narrowed.

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A novel slightly halophilic, aerobic, and Gram-stain-negative strain, designated as CH-27T, was isolated during a bacterial resource investigation of intertidal sediment collected from Xiaoshi Island in Weihai, PR China. Cells of strain CH-27T were rod-shaped with widths of 0.3-0.6 µm and lengths of 2.0-11.0 µm. Strain CH-27T grew optimally at 37 °C, pH 7.0 and with 2.0 % (w/v) NaCl. Catalase activity was weakly positive and oxidase activity was positive. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CH-27T was most related to Marinihelvus fidelis KCTC 92639T (93.6 %), followed by Wenzhouxiangella marina MCCC 1K00261T (92.0 %). Based on genome comparisons between strain CH-27T and M. fidelis KCTC 92639T, the average amino acid identity was 63.6 % and the percentage of conserved proteins was 48.3 %. The major cellular fatty acid of strain CH-27T (≥10 %) was iso-C15 : 0 and the sole respiratory quinone was quinone-8. The polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, and aminophospholipid. The DNA G+C content was 62.7 mol%. Based on comprehensive analysis of its phylogenetic, physiological, biochemical, and chemotaxonomic characteristics, strain CH-27T represents a novel species in a novel genus, for which the name Elongatibacter sediminis gen. nov., sp.nov. is proposed. The type strain is CH-27T (=MCCC 1H00480T=KCTC 8011T).

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Artificial enzymes with high stability, adjustable catalytic activity, controllable preparation, and good reproducibility have been widely studied. Noble metal nanozymes, particularly gold nanoparticles (Au NPs), exhibit good catalytic activity, but their stability is poor. In this study, zeolitic imidazolate framework-8 (ZIF-8) was used as a carrier for Au NPs, thus improving the utilization efficiency and conservation stability of the nanozymes. A ZIF-8/Au nanocomposite with peroxidase activity and a raspberry-shaped structure was synthesized. In the assay, ZIF-8/Au catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to a blue product oxidized TMB (oxTMB). Glutathione (GSH) selectively inhibited this reaction, with a detection limit of 0.28 µM and linear range of 0.5-60 µM. Using the photo and chromaticity analysis functions, we developed a portable analysis method using a smartphone equipped with a camera module as a detection terminal for a wide range of rapid screening techniques for GSH. Preparation of raspberry-shaped ZIF-8/Au improved the catalytic activity of Au NPs and good results were demonstrated in serum, which suggests their promising application under physiological conditions.

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Exploring novel electrochemiluminescence (ECL) molecules with high efficiency and good stability in aqueous solutions is crucial for achieving highly sensitive detection of analytes. However, developing chiral luminophores with efficient ECL performance is still a challenge. Herein, we first uncover that artemisinin (ART), a well-known chiral antimalarial drug, features a strong ECL emission at 726 nm with the assistance of a co-reactant potassium persulfate (K2S2O8), and an ECL efficiency of 195.3%, compared to that of standard Ru(bpy)3Cl2/K2S2O8. Mechanistic studies indicate that the strong ECL signal of ART is generated when the excited state formed by the reduction of ART peroxide bonds and combination with persulfate returns to the ground state. Significantly, we found that the ECL sensor based on chiral ART could efficiently identify and detect chiral cysteine (Cys) through ECL signals, with a lower limit of detection of 3.7 nM for l-Cys. Density functional theory calculations and scanning electrochemical microscopy technology further confirm that the disparity in the ECL signals is attributed to the different affinity between chiral ART and d/l-Cys, resulting in distinct electron transfer rates. The study demonstrates a new role of ART in ECL investigation and for the first time, achieves the development of ART for the enantioselective recognition and sensitive detection of chiral substances. This will be of vital significance for ECL and chirality research.

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Cytochrome P450 3A4 (CYP3A4) is one of the most important drug-metabolizing enzymes in the human body and is well known for its complicated, atypical kinetic characteristics. The existence of multiple ligand-binding sites in CYP3A4 has been widely recognized as being capable of interfering with the active pocket through allosteric effects. The identification of ligand-binding sites other than the canonical active site above the heme is especially important for understanding the atypical kinetic characteristics of CYP3A4 and the intriguing association between the ligand and the receptor. In this study, we first employed mixed-solvent molecular dynamics (MixMD) simulations coupled with the online computational predictive tools to explore potential ligand-binding sites in CYP3A4. The MixMD approach demonstrates better performance in dealing with the receptor flexibility compared with other computational tools. From the sites identified by MixMD, we then picked out multiple sites for further exploration using ensemble docking and conventional molecular dynamics (cMD) simulations. Our results indicate that three extra sites are suitable for ligand binding in CYP3A4, including one experimentally confirmed site and two novel sites.

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Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC)  of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition.

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Nuclear Dbf2-related kinase 1 (NDR1) is a nuclear Dbf2-related (NDR) protein kinase family member, which regulates cell functions and participates in cell proliferation and differentiation through kinase activity. NDR1 regulates physiological functions by interacting with different proteins. Protein-protein interactions (PPIs) are crucial for regulating biological processes and controlling cell fate, and as a result, it is beneficial to study the actions of PPIs to elucidate the pathological mechanism of diseases. The previous studies also show that the expression of NDR1 is deregulated in numerous human cancer samples and it needs the context-specific targeting strategies for NDR1. Thus, a comprehensive understanding of the direct interaction between NDR1 and varieties of proteins may provide new insights into cancer therapies. In this review, we summarize recent studies of NDR1 in solid tumors, such as prostate cancer and breast cancer, and explore the mechanism of action of PPIs of NDR1 in tumors.

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BACKGROUND: To assist doctors in making better treatment decisions and improve patient prognosis, it is important to determine which therapy modalities are suitable for various forms of idiopathic hypertrophic cranial pachymeningitis (IHCP). METHODS: All cases were received from the hospital medical record system, and some follow-up information was gathered through telephone follow-up. RESULTS: A total of 26 patients, 14 men and 12 women, with ages ranging from 20 to 73 years and a mean of 47.42 years, were included in the research. Regular types were less likely to recur than irregular and nodular types, focal types were less likely to recur than diffuse types, and corticosteroid-refractory types were more likely to recur than corticosteroid-sensitive types. CONCLUSIONS: The extent and shape of the lesion and susceptibility to corticosteroids are potential factors that could influence recurrence. Futhermore, this paper also proposes the fibroblasts as a new therapeutic target which may improve the quality of prognostic survival of patients.

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The precisely modulated synthesis of programmable light-emitting materials remains a challenge. To address this challenge, we construct four tetraphenylethylene-based supramolecular architectures (SA, SB, SC, and SD), revealing that they exhibit higher electrochemiluminescence (ECL) intensities and efficiencies than the tetraphenylethylene monomer and can be classified as highly efficient and precisely modulated intramolecular aggregation-induced electrochemiluminescence (PI-AIECL) systems. The best-performing system (SD) shows a high ECL cathodic efficiency exceeding that of the benchmark tris(2,2'-bipyridyl)ruthenium(II) chloride in aqueous solution by nearly six-fold. The electrochemical characterization of these architectures in an organic solvent provides deeper mechanistic insights, revealing that SD features the lowest electrochemical band gap. Density functional theory calculations indicate that the band gap of the guest ligand in the SD structure is the smallest and most closely matched to that of the host scaffold. Finally, the SD system is used to realize ECL-based cysteine detection (detection limit=14.4 nM) in real samples. Thus, this study not only provides a precisely modulated supramolecular strategy allowing chromophores to be controllably regulated on a molecular scale, but also inspires the programmable synthesis of high-performance aggregation-induced electrochemiluminescence emitters.

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Confinement effects in highly porous nanostructures can effectively adjust the selectivity and kinetics of electrochemical reactions, which can boost the methanol oxidation reaction (MOR). In this work, carbonized ZIF-8-confined hollow PtCo nanospheres (PtCo@carbonized ZIF-8) were fabricated using a facile strategy. A monodisperse confined region was successfully prepared, and the dispersion of the PtCo nanoparticles (NPs) could be precisely regulated, allowing for the effective tuning of the confined region. Thus, the precise regulation of the catalytic reaction was achieved. Importantly, hollow PtCo NPs were prepared using a method based on the Kirkendall effect, and their forming mechanism was systematically investigated. Because of the confinement effects of carbonized zeolitic imidazolate framework-8 (ZIF-8), the crystal and electronic structures of the PtCo NPs were able to be effectively tuned. Our electrochemical results show that PtCo@carbonized ZIF-8 composites manifest a higher mass activity (1.4 A mgPt-1) and better stability compared to commercial Pt/C.

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Bismuth vanadate (BiVO4) has been considered a promising photoactive material in photoelectrochemical (PEC) water-splitting systems. However, the performance of BiVO4-based photoanodes is currently unsatisfactory, indicating the need for new architectural designs to improve their efficiency. In this paper, a porphyrin-phosphazene polymer (THPP-HCCP) was synthesized with a sizeable conjugated structure, and Ag particles were deposited on its surface as an organic-inorganic composite interface improvement layer. The deposition of the composite polymer film on BiVO4 resulted in a significant increase in photocurrent density, reaching up to 2.2 mA cm-2 (1.23 V vs. RHE), almost three times higher than pristine BiVO4, which benefits from the synergistic effect of Ag nanoparticles and porphyrin-phosphazene. Furthermore, photophysical and intensity-modulated photocurrent analysis demonstrated that the Ag-THPP-HCCP heterostructures could broaden the light-absorbing range and facilitate hole transfer to the semiconductor surface, resulting in an improved water oxidation process. The dynamic charge transport behavior of Ag-THPP-HCCP/BiVO4 was investigated using scanning photoelectrochemical microscopy, which showed that the rate constant (Keff) exhibits an almost 4-fold increase compared to pristine BiVO4, indicating a significant improvement in the transport of photogenerated holes. This experiment presents a novel strategy for designing high-efficiency polymer-based photoanodes.

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Porphyrins easily aggregate due to unfavorable π-π accumulation, causing luminescent quenching in the aqueous phase and subsequently reducing luminescent efficiency. It is a feasible way to immobilize porphyrin molecules through metal-organic framework materials (MOFs). In this study, 5,10,15,20-tetrakis (4-carboxyphenyl) porphyrin (TCPP) was introduced into the metal-organic skeleton (PCN-224) as a ligand. The result showed that the electrochemiluminescence (ECL) and photoluminescence (PL) efficiency of the MOF skeleton was 8.2 and 6.5 times higher than TCPP, respectively. Impressively, the periodic distribution of porphyrin molecules in the MOF framework can overcome the bottleneck of porphyrin aggregation, resulting in the organic ligand TCPP participating in the electron transfer reaction. Herein, based on the PCN-224, a sandwich-type ECL immunosensor was constructed for the determination of cardiac troponin I (cTnI). It provided sensitive detection of cTnI in the range of 1 fg/mL to 10 ng/mL with a detection limit of 0.34 fg/mL. This work not only innovatively exploited a disaggregation ECL (DIECL) strategy via the crystalline framework of MOF to enhance the PL and ECL efficiency of porphyrin but also provided a promising ECL platform for the ultrasensitive monitoring of cTnI.

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Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in the human body and is responsible for the metabolism of ∼50% of clinically used drugs. Therefore, the identification of the compound's sites of metabolism (SOMs) mediated by CYP3A4 is of utmost importance in the early stage of drug discovery and development. Herein, docking-based approaches incorporating geometric features were used for SOMs prediction of CYP3A4 substrates. The cross-docking poses of a relatively large data set containing 474 substrates were analyzed in depth, and a widely observed geometric pattern called the close proximity of SOMs was derived from the poses. On the basis of the close proximity, several structure-based models have been constructed, which demonstrated better performance than those structure-based models using the criterion of Fe-SOM distance. For further improving the prediction performance, the structure-based models were also combined with the well-known ligand-based model SMARTCyp. One combined model exhibited good performance on the SOMs prediction of an external substrate set containing kinase inhibitors, PROTACs, approved drugs, and some lead compounds.

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ABSTRACT Objective: The recurrent laryngeal nerve (RLN) may be involved by papillary thyroid carcinoma ≤ 1 centimeter (PTC ≤ 1 cm). Current study investigated the predictive factors of RLN invasion in PTC ≤ 1 cm, the risk factors of disease recurrence in RLN invaded cases and the results of surgical management for RLN invasion. Materials and methods: Data of 374 PTC ≤ 1 cm patients were retrospectively collected. We performed univariate and multivariate analysis to identify predictive factors of RLN invasion and risk factors of disease recurrence. The abilities of factors in predicting RLN invasion were evaluated. Surgical outcomes and recurrence free survival (RFS) of patients were analyzed. Results: A total of 28 patients suffered RLN invasion, among which seven had disease recurrence. Preoperative vocal cord palsy (VCP), gross extrathyroidal extension, larger tumor size and tumor on the dorsal side of thyroid were verified as predictive factors of RLN invasion. RLN involved patients had poorer RFS, but better than those who also had upper-aerodigestive tract invasion. Upper-aerodigestive tract invasion, lateral neck lymph nodes metastasis (LNM) and BRAF V600E mutation were independent risk factors of disease recurrence in RLN invaded cases. Tumor shaving showed better RLN function preservation without increasing recurrent risk. Conclusions: Current study confirmed the rarity of RLN invasion in PTC ≤ 1 cm. Various aggressive features were verified as predictive factors of RLN invasion. Tumor shaving showed superiority in preserving nerve function without increasing recurrent risk. Special attentions should be paid for disease recurrence when RLN invasion accompanied by upper-aerodigestive tract invasion, lateral neck LNM or BRAF V600E mutation.

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Bladder cancer is the second most prevalent urological malignancy. It's a big contributor to cancer-related deaths throughout the globe. Researchers discovered that the hedgehog signaling (HhS) pathway contributed to the onset and spread of many different kinds of cancer. Nevertheless, the present understanding of the function of HhS in the bladder cancer molecular landscape is incomplete. Raw data were gotten from the IMvigor210, the Gene Expression Omnibus, and The Cancer Genome Atlas databases. Bioinformatics was used to examine the HhS score of each sample, and the enrichment of differentially expressed genes (DEGs), differentiation characteristics, immunological infiltration, and metabolic activity. The HhS prognostic signature was developed with significant assistance from the least absolute shrinkage and selection operator regression and Cox regression. An HhS-related nomogram was developed to assist in the prediction of patients' survival probability. We found that HhS was linked to poor prognosis in bladder cancer, and its activation was linked to the Basal subtype of bladder cancer. Bladder cancer with high HhS activity has higher glycolysis, nucleotide metabolism, amino acid metabolism, and other cancer-promoting metabolic activities. Furthermore, HhS mediates an immunosuppressive microenvironment in bladder cancer on the basis that HhS negatively correlates with the CD8 + T cells and correlates positively with immune checkpoints and T cell exhaustion scores. Finally, an HhS-related signature was developed for predicting the prognosis of patients with bladder cancer. Targeting HhS may be a potential therapy choice for bladder cancer.

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PURPOSE: To investigate the factors influencing the volume of the olfactory bulb (OB) in patients with post-viral olfactory dysfunction (PVOD). METHODS: We collected 92 olfactory bulb volumes from patients with PVOD who underwent a sinus computed tomographic and magnetic resonance imaging (MRI) scan of the head and collected clinical information including gender, age, disease course, minimal cross-sectional area, nasal airway resistance, and olfactory function. OB volume was measured in MRI and the scans were evaluated according to the Lund-Mackay (LM) scoring system. RESULTS: Male patients with PVOD had a larger OB volume (ß = 0.284, P < 0.05). OB volume was smaller in patients with a longer course of olfactory dysfunction (ß = - 0.254, P < 0.05). According to the LM scoring system, patients with a higher anterior ethmoidal sinus score had smaller OB volume (ß = - 0.476, P < 0.05). CONCLUSIONS: The study revealed that gender, disease course, and the score of anterior ethmoidal sinusitis can affect the OB volume in patients with PVOD.

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