Asymmetrically Coordinated Mn-S1 N3 Configuration Induces Localized Electric Field-Driven Peroxymonosulfate Activation for Remarkably Efficient Generation of 1 O2.

Singlet oxygen (1 O2 ) species generated in peroxymonosulfate (PMS)-based advanced oxidation processes offer opportunities to overcome the low efficiency and secondary pollution limitations of existing AOPs, but efficient production of 1 O2 via tuning the coordination environment of metal active sites remains challenging due to insufficient understanding of their catalytic mechanisms. Herein, an asymmetrical configuration characterized by a manganese single atom coordinated is established with one S atom and three N atoms (denoted as Mn-S1 N3 ), which offer a strong local electric field to promote the cleavage of O─H and S─O bonds, serving as the crucial driver of its high 1 O2 production. Strikingly, an enhanced the local electric field caused by the dynamic inter-transformation of the Mn coordination structure (Mn-S1 N3 ↔ Mn-N3 ) can further downshift the 1 O2 production energy barrier. Mn-S1 N3 demonstrates 100% selective product 1 O2 by activation of PMS at unprecedented utilization efficiency, and efficiently oxidize electron-rich pollutants. This work provides an atomic-level understanding of the catalytic selectivity and is expected to guide the design of smart 1 O2 -AOPs catalysts for more selective and efficient decontamination applications.

"Two-Stage Rocket-Propelled" Strategy Boosting Theranostic Efficacy with Mitochondria-Specific Type I-II Photosensitizers.

Imaging-guided photodynamic therapy (PDT) holds great potential for tumor therapy. However, achieving the synergistic enhancement of the reactive oxygen species (ROS) generation efficiency and fluorescence emission of photosensitizers (PSs) remains a challenge, resulting in suboptimal image guidance and theranostic efficacy. The hypoxic tumor microenvironment also hinders the efficacy of PDT. Herein, we propose a "two-stage rocket-propelled" photosensitive system for tumor cell ablation. This system utilizes MitoS, a mitochondria-targeted PS, to ablate tumor cells. Importantly, MitoS can react with HClO to generate a more efficient PS, MitoSO, with a significantly improved fluorescence quantum yield. Both MitoS and MitoSO exhibit less O2-dependent type I ROS generation capability, inducing apoptosis and ferroptosis. In vivo PDT results confirm that this mitochondrial-specific type I-II cascade phototherapeutic strategy is a potent intervention for tumor downstaging. This study not only sheds light on the correlation between the PS structure and the ROS generation pathway but also proposes a novel and effective strategy for tumor downstaging intervention.

Frontier of toxicology studies in zebrafish model.

Based on the 87 original publications only from quartiles 1 and 2 of Journal Citation Report (JCR) collected by the major academic databases (Science Direct, Web of Science, PubMed, and Wiley) in 2022, the frontier of toxicology studies in zebrafish model is summarized. Herewith, a total of six aspects is covered such as developmental, neurological, cardiovascular, hepatic, reproductive, and immunizing toxicities. The tested samples involve chemicals, drugs, new environmental pollutants, nanomaterials, and its derivatives, along with those related mechanisms. This report may provide a frontier focus benefit to researchers engaging in a zebrafish model for environment, medicine, food, and other fields.

Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial.

Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration-time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

Acute myocardial infarction due to coronary embolism caused by a metastatic mass from lung cancer.

BACKGROUND: Acute arterial embolism due to tumor embolus is a rare complication in cancer patients, even rarer is lung tumor embolization leading to acute myocardial infarction. We report a patient who had a diagnosis of acute myocardial infarction(AMI)which was brought on by a coronary artery embolism by a metastatic lung cancer tumor. Clinicians need to be aware that tumor embolism can result in AMI. CASE PRESENTATION: An 80-yeal-old male patient presented with persistent chest pain for 2 h and his electrocardiogram(ECG)showed anterior ST-segment elevation myocardial infarction. Instead of implanting a stent, thrombus aspiration was performed. Pathological examination of coronary artery thrombosis showed that a few sporadic atypical epithelial cells were scattered in the thrombus-like tissue. Combined with immune phenotype and clinical history, metastatic squamous cell carcinoma is more likely. CONCLUSIONS: We report a rare case of a patient who was diagnosed of AMI due to a coronary artery embolism by a metastatic mass from lung cancer. Since there is no evidence-based protocol available for the treatment of isolated coronary thrombosis, we used thrombus aspiration to treat thrombosis rather than implanting a stent.

Semi-supervised heterogeneous graph contrastive learning for drug-target interaction prediction.

Identification of drug-target interactions (DTIs) is an important step in drug discovery and drug repositioning. In recent years, graph-based methods have attracted great attention and show advantages on predicting potential DTIs. However, these methods face the problem that the known DTIs are very limited and expensive to obtain, which decreases the generalization ability of the methods. Self-supervised contrastive learning is independent of labeled DTIs, which can mitigate the impact of the problem. Therefore, we propose a framework SHGCL-DTI for predicting DTIs, which supplements the classical semi-supervised DTI prediction task with an auxiliary graph contrastive learning module. Specifically, we generate representations for the nodes through the neighbor view and meta-path view, and define positive and negative pairs to maximize the similarity between positive pairs from different views. Subsequently, SHGCL-DTI reconstructs the original heterogeneous network to predict the potential DTIs. The experiments on the public dataset show that SHGCL-DTI has significant improvement in different scenarios, compared with existing state-of-the-art methods. We also demonstrate that the contrastive learning module improves the prediction performance and generalization ability of SHGCL-DTI through ablation study. In addition, we have found several novel predicted DTIs supported by the biological literature. The data and source code are available at: https://github.com/TOJSSE-iData/SHGCL-DTI.

OAT3 mediates methotrexate resistance in the treatment of rheumatoid arthritis.

OBJECTIVE: To study whether organic anion transporter 3 (OAT3) is involved in the development of methotrexate (MTX) resistance in the treatment of rheumatoid arthritis. METHODS: The experimental components of the animals were the normal group, collagen-induced arthritis (CIA) model group, and MTX treatment group. MTX-treated rats were divided into the MTX effective group (MTX-E) and the MTX ineffective group (MTX-N). MTX-N receives additional treatment with OAT3 lentivirus injected into the joint cavity. Transient transfection was used to alter the expression of OAT3 in rat fibroblast-like synovial (rat-FLS). RESULTS: The rate of effectiveness of MTX in treating CIA rats was 48.98%. Compared with CIA rats, MTX-E can greatly improve ankle joint synovial hyperplasia and joint damage, but MTX-N has no significant changes. The expression of OAT3 in the synovium of MTX-E was significantly higher than that of MTX-N. The MTX content in the MTX-E synovium was also higher than that in the MTX-N synovium. After injection of OAT3 overexpression lentivirus into the joint cavity of MTX-N, the effective rate of MTX reached 80%. The ankle synovial hyperplasia and joint damage were significantly improved in the overexpression group, and the MTX content was also significantly increased in the synovium. After rat FLS overexpressed OAT3, the inhibitory effect of MTX on rat FLS proliferation activity was significantly enhanced, and the absorption of MTX was also significantly increased, while silencing the expression of rat FLS OAT3 reversed the outcomes. CONCLUSION: OAT3 mediates the formation of MTX resistance and is a potential target for improving MTX resistance.

Sulfur atom modification on thymine improves the specificity and sensitivity of DNA polymerization and detection.

Although accurate base-pairing ensures specificity of molecular recognition, DNA polymerization and DNA amplification, there are many non-specific pairings that arise from mismatched pairs, such as the T/G wobble pair. We have found that by using 2-S-TTP (STTP), we can minimize T/G mismatch, improve the DNA polymerization specificity and enhance the detection sensitivity (up to 20 fold), without significantly compromising the polymerization efficiency (the extension rate ratio of TTP vs.STTP is 1.08). With the STTP strategy, DNA polymerization is more specific and allows the detection of pathogens (such as COVID-19) in single digits (up to 5 copies), which is not possible with conventional RT-PCR. We have discovered that STTP can generally promote much higher specificity and sensitivity in DNA polymerization and nucleic acid detection than canonical TTP.

Paeoniflorin-6'-o-benzene sulfonate ameliorates the progression of adjuvant-induced arthritis by inhibiting the interaction between Ahr and GRK2 of fibroblast-like synoviocytes.

Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses, which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). The results of our group in recent years have shown that Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin, has a good effect on improving RA animal models. However, whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear. Here, we showed that CP-25 treatment ameliorated adjuvant-induced arthritis (AA), a rat model of RA, by inhibiting Ahr-related activities in fibroblasts like synoviocytes (FLS). AA rats were treated with CP-25 or paroxetine from days 17 to 33 after immunization. We showed that CP-25 alleviated arthritis symptoms and the pathological changes. Treatment with CP-25 decreased the expression of Ahr in the synovium of AA rats. CP-25 inhibited the expression of Ahr and the G protein-coupled receptor kinase 2 (GRK2) as well as the co-expression of GRK2 with Ahr in FLS of AA rats. Furthermore, CP-25 down-regulated the production of Kyn in FLS of AA rats. These results suggested that CP-25 may inhibit the expression and activation of Ahr. Besides, treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation. In addition, we also demonstrated that CP-25 down-regulated the total and nuclear expression of Ahr and the expression of GRK2 in Kyn-treated MH7A. Moreover, the co-expression and co-localization of Ahr and GRK2in Kyn-treated MH7A were also repressed by CP-25. The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA, which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.

Monocomponent Nanodots with Dichromatic Output Regulated by Synergistic Dual-Stimuli for Cervical Cancer Tissue Imaging and Photodynamic Tumor Therapy.

Inflammation exists in the microenvironment of most, if not virtually all, tumors, which greatly exacerbates the difficulty of cancer treatment. Considering the superiority of activatable photosensitizers (PSs), a novel strategy of 'making friends with the enemy' for tumor treatment was proposed. In this strategy, the "enemy" refers to inflammatory cytokines and the tumor site is targeted by detecting the enemy. Upon detection, a dichromatic fluorescence signal is released and the PS is activated specifically by the inflammatory cytokines. In this study, a multifunctional PS (TPE-PTZ-Py) was rationally designed, which can be activated specifically under the synergistic action of hypochlorous acid (HClO) (one kind of inflammatory cytokines) and acid (one typical marker of tumor), and output a ratiometric fluorescence signal simultaneously. The sulfoxide analogue (TPE-PTZO-PyH) as the response product effectively produced 1O2 (1.8-fold higher than that obtained with Rose Bengal) and showed high phototoxicity (IC50 < 7.6 µM). More importantly, imaging analyses confirmed that TPE-PTZ-Py could be activated in human cervical cancer tissue. To date, several phenothiazine (PTZ)-based fluorescent probes have been developed for the selective sensing and imaging of HClO in subcellular organelles; however, this is the first phenothiazine-based nanodrug designed for the treatment of inflammation-associated tumors with a few side effects.

Ordered Porous TiO2@C Layer as an Electrocatalyst Support for Improved Stability in PEMFCs.

Proton exchange membrane fuel cells (PEMFCs) are the most promising clean energy source in the 21st century. In order to achieve a high power density, electrocatalytic performance, and electrochemical stability, an ordered array structure membrane electrode is highly desired. In this paper, a new porous Pt-TiO2@C ordered integrated electrode was prepared and applied to the cathode of a PEMFC. The utilization of the TiO2@C support can significantly decrease the loss of catalyst caused by the oxidation of the carbon from the conventional carbon layer due to the strong interaction of TiO2 and C. Furthermore, the thin carbon layer coated on TiO2 provides the rich active sites for the Pt growth, and the ordered support and catalyst structure reduces the mass transport resistance and improves the stability of the electrode. Due to its unique structural characteristics, the ordered porous Pt-TiO2@C array structure shows an excellent catalytic activity and improved Pt utilization. In addition, the as-developed porous ordered structure exhibits superior stability after 3000 cycles of accelerated durability test, which reveals an electrochemical surface area decay of less than 30%, considerably lower than that (i.e., 80%) observed for the commercial Pt/C.

Selenium-atom-modified thymidine enhances the specificity and sensitivity of DNA polymerization and detection.

Nucleobase mismatches can jeopardize DNA polymerization specificity, causing mutations and errors in DNA replication and detection. Herein we report the first synthesis of novel 2-Se-thymidine triphosphate (SeTTP), describe the single-selenium atom-specific modification strategy (SAM) against T/G mismatches, and demonstrate SAM-assisted polymerization and detection with much higher specificity and sensitivity. SAM can effectively suppress the formation of non-specific products in DNA polymerization and detection. Thus, SAM enhances the specificity of DNA synthesis by approximately 10 000 fold, and in turn, it allows the detection of clinical COVID-19 viral RNA in low copy numbers (single-digit copies), while the conventional RT-qPCR does not.

Optimized Biocatalytic Synthesis of 2-Selenopyrimidine Nucleosides by Transglycosylation*.

Selenium-modified nucleosides are powerful tools to study the structure and function of nucleic acids and their protein interactions. The widespread application of 2-selenopyrimidine nucleosides is currently limited by low yields in established synthetic routes. Herein, we describe the optimization of the synthesis of 2-Se-uridine and 2-Se-thymidine derivatives by thermostable nucleoside phosphorylases in transglycosylation reactions using natural uridine or thymidine as sugar donors. Reactions were performed at 60 or 80 °C and at pH 9 under hypoxic conditions to improve the solubility and stability of the 2-Se-nucleobases in aqueous media. To optimize the conversion, the reaction equilibria in analytical transglycosylation reactions were studied. The equilibrium constants of phosphorolysis of the 2-Se-pyrimidines were between 5 and 10, and therefore differ by an order of magnitude from the equilibrium constants of any other known case. Hence, the thermodynamic properties of the target nucleosides are inherently unfavorable, and this complicates their synthesis significantly. A tenfold excess of sugar donor was needed to achieve 40-48 % conversion to the target nucleoside. Scale-up of the optimized conditions provided four Se-containing nucleosides in 6-40 % isolated yield, which compares favorably to established chemical routes.

[Effect of breastfeeding on the development of infection-related diseases during hospitalization in late preterm infants in 25 hospitals in Beijing, China].

OBJECTIVE: To investigate the incidence rate of infectious diseases during hospitalization in late preterm infants in Beijing, China, as well as the risk factors for infectious diseases and the effect of breastfeeding on the development of infectious diseases. METHODS: Related data were collected from the late preterm infants who were hospitalized in the neonatal wards of 25 hospitals in Beijing, China, from October 23, 2015 to October 30, 2017. According to the feeding pattern, they were divided into a breastfeeding group and a formula feeding group. The two groups were compared in terms of general status and incidence rate of infectious diseases. A multivariate logistic regression analysis was used to investigate the risk factors for infectious diseases. RESULTS: A total of 1 576 late preterm infants were enrolled, with 153 infants in the breastfeeding group and 1 423 in the formula feeding group. Of all infants, 484 (30.71%) experienced infectious diseases. The breastfeeding group had a significantly lower incidence rate of infectious diseases than the formula feeding group (22.88% vs 31.55%, P=0.033). The multivariate logistic regression analysis showed that breastfeeding was an independent protective factor against infectious diseases (OR=0.534, P=0.004), while male sex, premature rupture of membranes, gestational diabetes mellitus, and asphyxia were risk factors for infectious diseases (OR=1.328, 5.386, 1.535, and 2.353 respectively, P < 0.05). CONCLUSIONS: Breastfeeding can significantly reduce the incidence of infectious diseases and is a protective factor against infectious diseases in late preterm infants. Breastfeeding should therefore be actively promoted for late preterm infants during hospitalization.

Systematically Characterizing A-to-I RNA Editing Neoantigens in Cancer.

A-to-I RNA editing can contribute to the transcriptomic and proteomic diversity of many diseases including cancer. It has been reported that peptides generated from RNA editing could be naturally presented by human leukocyte antigen (HLA) molecules and elicit CD8+ T cell activation. However, a systematical characterization of A-to-I RNA editing neoantigens in cancer is still lacking. Here, an integrated RNA-editing based neoantigen identification pipeline PREP (Prioritizing of RNA Editing-based Peptides) was presented. A comprehensive RNA editing neoantigen profile analysis on 12 cancer types from The Cancer Genome Atlas (TCGA) cohorts was performed. PREP was also applied to 14 ovarian tumor samples and two clinical melanoma cohorts treated with immunotherapy. We finally proposed an RNA editing neoantigen immunogenicity score scheme, i.e. REscore, which takes RNA editing level and infiltrating immune cell population into consideration. We reported variant peptide from protein IFI30 in breast cancer which was confirmed expressed and presented in two samples with mass spectrometry data support. We showed that RNA editing neoantigen could be identified from RNA-seq data and could be validated with mass spectrometry data in ovarian tumor samples. Furthermore, we characterized the RNA editing neoantigen profile of clinical melanoma cohorts treated with immunotherapy. Finally, REscore showed significant associations with improved overall survival in melanoma cohorts treated with immunotherapy. These findings provided novel insights of cancer biomarker and enhance our understanding of neoantigen derived from A-to-I RNA editing as well as more types of candidates for personalized cancer vaccines design in the context of cancer immunotherapy.

Ordered SnO2@C Flake Array as Catalyst Support for Improved Electrocatalytic Activity and Cathode Durability in PEMFCs.

Pt-SnO2@C-ordered flake array was developed on carbon paper (CP) as an integrated cathode for proton exchange membrane fuel cell through a facile hydrothermal method. In the integrated cathode, Pt nanoparticles were deposited uniformly with a small particle size on the SnO2@C/CP support. Electrochemical impedance spectroscopy analysis revealed lower impedance in a potential range of 0.3-0.5 V for the ordered electrode structure. An electrochemically active surface area and oxygen reduction peak potential determined by cyclic voltammetry measurement verified the synergistic effect between Pt and SnO2, which enhanced the electrochemical catalytic activity. Besides, compared with the commercial carbon-supported Pt catalyst, the as-developed SnO2@C/CP-supported Pt catalyst demonstrated better stability, most likely due to the positive interaction between SnO2 and the carbon coating layer.

C3: Consensus Cancer Driver Gene Caller.

Next-generation sequencing has allowed identification of millions of somatic mutations in human cancer cells. A key challenge in interpreting cancer genomes is to distinguish drivers of cancer development among available genetic mutations. To address this issue, we present the first web-based application, consensus cancer driver gene caller (C3), to identify the consensus driver genes using six different complementary strategies, i.e., frequency-based, machine learning-based, functional bias-based, clustering-based, statistics model-based, and network-based strategies. This application allows users to specify customized operations when calling driver genes, and provides solid statistical evaluations and interpretable visualizations on the integration results. C3 is implemented in Python and is freely available for public use at http://drivergene.rwebox.com/c3.

Disruption of nucleobase stacking to restore reactivity.

Strong intermolecular interaction can prevent an organic molecule from dissolving in a reaction solution, thereby jeopardizing its reactivity and usefulness. Nucleobases and nucleosides (especially many purines and their derivatives) are notoriously difficult to dissolve in most organic solvents, generally attributed to their strong intermolecular interactions caused by the aromaticity, polarity and hydrogen-bonding. Guided by our computational study and prediction, to address this challenge, we have found that by doping the reaction solution with toluene (an inert aromatic compound), the added solvent molecules are capable of generating the stacking interaction with the solute molecules (e.g., purine derivatives) and disrupting the intermolecular stacking of the solute molecules. Thus, this inert doping can successfully address the insoluble challenge, dissolve the poorly soluble reactants (such as purine phosphoramidites), and restore the amidite reactivity for oligonucleotide synthesis. Our research has offered a simple strategy to efficiently synthesize labile oligonucleotides, via disrupting stacking interaction with inert aromatic molecules.

Flocculation-dewatering behavior of waste activated sludge particles under chemical conditioning with inorganic polymer flocculant: Effects of typical sludge properties.

The effects of typical sludge properties (solids concentration, soluble extracellular polymeric substances (SEPS) and alkalinity) on waste activated sludge flocculation-dewatering behavior and mechanisms under chemical conditioning with inorganic polymer flocculant-polyaluminum chloride (PACl) were systematically examined in this study. The results indicated that increasing the solids concentration was conductive to sludge dewatering and could greatly decrease the PACl demand in chemical conditioning. Solids concentration had important effects on properties of sludge floc flocculated with PACl, floc structure was more compact and of low EPS concentration at high solids concentrations. High levels of SEPS were adverse to sludge dewaterability after flocculation with PACl, since the SEPS could interact with hydroxy-aluminium through complexation and increase the demand of coagulants. In addition, advantageous speciations of hydroxy-aluminium were rapidly converted into amorphous hydroxides with low flocculation activity at high alkalinity, so the sludge conditioning efficiency was greatly declined. At the same time, the dominant mechanism of chemical conditioning was changed from charge neutralization to sweep coagulation. Finally, this study provides control strategies at complex sludge properties for improving the effectiveness of PACl as a chemical conditioner.

Enhanced mineralization of hypersaline wastewater with Fe2+/Cu2+ catalyzed UV-Fenton process: process optimization and catalytic mechanism.

The efficiency of Fenton oxidation was inhibited by the high content of salt in the industrial wastewater. However, enhanced mineralization of hypersaline industrial wastewater is necessary for advanced treatment and subsequent wastewater salt recovery process. Therefore, Fe2+ and Cu2+ catalyzed UV-Fenton oxidation were carried out to improve the total organic carbon (TOC) removal efficiency for a hypersaline wastewater from resin manufacturing. The performance of UV-Fe/Cu-Fenton oxidation was comparatively investigated and optimized using response surface methodology (RSM) to develop a practical high-efficient mineralization treatment technique for hypersaline wastewater. More than 90% of TOC was removed under optimal conditions of UV-Fe2+ and UV-Cu2+-Fenton oxidation, namely 9.6 mM Fe2+ and 176 mM H2O2, and 2.95 mM Cu2+ and 276 mM H2O2, respectively. The reactive oxygen radicals identified using electron spin resonance (ESR) spectroscopy revealed that hydroxyl radical was dominant oxidant in UV-Fe2+-Fenton process, while HO2·/O2·- played a more important role in the UV-Cu-Fenton system. The Cl- effect is also different for UV Fe and Cu Fenton. Moreover, no scaling and sludge problem makes UV-Cu-Fenton a promising alternative method for efficient mineralization of hypersaline industrial wastewater.