Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

Gut microbiota composition and changes in patients with sepsis: potential markers for predicting survival.

BACKGROUND: Sepsis can cause immune dysregulation and multiple organ failure in patients and eventually lead to death. The gut microbiota has demonstrated its precise therapeutic potential in the treatment of various diseases. This study aimed to discuss the structural changes of the gut microbiota in patients with sepsis and to analyze the differences in the gut microbiota of patients with different prognoses. METHODS: We conducted a multicenter study in which rectal swab specimens were collected on the first and third days of sepsis diagnosis. A total of 70 specimens were collected, and gut microbiota information was obtained by 16S rRNA analysis. RESULTS: The relative abundance of Enterococcus decreased in rectal swab specimens during the first three days of diagnosis in patients with sepsis, while the relative abundance of inflammation-associated Bacillus species such as Escherichia coli, Enterobacteriaceae, and Bacteroidetes increased. By comparing the differences in the flora of the survival group and the death group, we found that the abundance of Veillonella and Ruminococcus in the death group showed an increasing trend (p < 0.05), while the abundance of Prevotella_6 and Prevotella_sp_S4_BM14 was increased in surviving patients (p < 0.05). CONCLUSIONS: The Firmicutes/Bacteroidetes ratio, reflecting overall gut microbial composition, was significantly lower on day three of sepsis diagnosis. Changes in the abundance of specific gut microbiota may serve as prognostic markers in patients with sepsis.

Effectiveness of Global Leadership Initiative on Malnutrition and Subjective Global Assessment for diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers.

Malnutrition significantly hampers wound healing processes. This study aimed to compare the effectiveness of the Global Leadership Initiative on Malnutrition (GLIM) and Subjective Global Assessment (SGA) in diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers (DFU). GLIM criteria were evaluated for sensitivity (SE), specificity (SP), positive predictive value, negative predictive value and kappa (κ) against SGA as the reference. Modified Poisson regression model and the DeLong test investigated the association between malnutrition and non-healing ulcers over 6 months. This retrospective cohort study included 398 patients with DFU, with a mean age of 66·3 ± 11·9 years. According to SGA and GLIM criteria, malnutrition rates were 50·8 % and 42·7 %, respectively. GLIM criteria showed a SE of 67·3 % (95 % CI 60·4 %, 73·7 %) and SP of 82·7 % (95 % CI 76·6 %, 87·7 %) in identifying malnutrition, with a positive predictive value of 80·0 % and a negative predictive value of 71·1 % (κ = 0·50) compared with SGA. Multivariate analysis demonstrated that malnutrition, as assessed by SGA, was an independent risk factor for non-healing (relative risk (RR) 1·84, 95 % CI 1·45, 2·34), whereas GLIM criteria were associated with poorer ulcer healing in patients with estimated glomerular filtration rate ≥ 60 ml/min/1·73m2 (RR: 1·46, 95 % CI 1·10, 1·94). SGA demonstrated a superior area under the receiver's operating characteristic curve for predicting non-healing compared with GLIM criteria (0·70 (0·65-0·75) v. 0·63 (0·58-0·65), P < 0·01). These findings suggest that both nutritional assessment tools effectively identify patients with DFU at increased risk, with SGA showing superior performance in predicting non-healing ulcers.

Enhancing the Carbon Monoxide Oxidation Performance through Surface Defect Enrichment of Ceria-Based Supports for Platinum Catalyst.

Effective synthesis and application of single-atom catalysts on supports lacking enough defects remain a significant challenge in environmental catalysis. Herein, we present a universal defect-enrichment strategy to increase the surface defects of CeO2-based supports through H2 reduction pretreatment. The Pt catalysts supported by defective CeO2-based supports, including CeO2, CeZrOx, and CeO2/Al2O3 (CA), exhibit much higher Pt dispersion and CO oxidation activity upon reduction activation compared to their counterpart catalysts without defect enrichment. Specifically, Pt is present as embedded single atoms on the CA support with enriched surface defects (CA-HD) based on which the highly active catalyst showing embedded Pt clusters (PtC) with the bottom layer of Pt atoms substituting the Ce cations in the CeO2 surface lattice can be obtained through reduction activation. Embedded PtC can better facilitate CO adsorption and promote O2 activation at PtC-CeO2 interfaces, thereby contributing to the superior low-temperature CO oxidation activity of the Pt/CA-HD catalyst after activation.

Design of vilazodone-donepezil chimeric derivatives as acetylcholinesterase inhibitors by QSAR, molecular docking and molecular dynamics simulations.

Alzheimer's disease (AD) is a disease that affects the cognitive abilities of older adults, and it is one of the biggest global medical challenges of the 21st century. Acetylcholinesterase (AChE) can increase acetylcholine concentrations and improve cognitive function in patients, and is a potential target to develop small molecule inhibitors for the treatment of Alzheimer's disease (AD). In this study, 29 vilazodone-donepezil chimeric derivatives are systematically studied using 3D-QSAR modeling, and a robust and reliable Topomer CoMFA model was obtained with: q2 = 0.720, r2 = 0.991, F = 287.234, N = 6, and SEE = 0.098. Based on the established model and combined with the ZINC20 database, 33 new compounds with ideal inhibitory activity are successfully designed. Molecular docking and ADMET property prediction also show that these newly designed compounds have a good binding ability to the target protein and can meet the medicinal conditions. Subsequently, four new compounds with good comprehensive ability are selected for molecular dynamics simulation, and the simulation results confirm that the newly designed compounds have a certain degree of reliability and stability. This study provides guidance for vilazodone-donepezil chimeric derivatives as a potential AChE inhibitor and has certain theoretical value.

Ergone Derivatives from the Deep-Sea-Derived Fungus Aspergillus terreus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (1-10) and five known analogues (11-15) were isolated from the deep-sea-derived fungus Aspergillus terreus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus. Structurally, compound 2 bearing a 15-carbonyl group and compounds 5-7 possessing a 15ß-OH/OCH3 group are rarely encountered in ergone derivatives. Bioassay results showed that compounds 1 and 11 demonstrated cytotoxic effects on human colon cancer SW620 cells with IC50 values of 8.4 and 3.1 µM, respectively. Notably, both compounds exhibited negligible cytotoxicity on the human normal lung epithelial cell BEAS-2B. Compound 11 was selected for preliminary mechanistic study and was found to inhibit cell proliferation and induce apoptosis in human colon cancer SW620 cells. In addition, compound 1 displayed cytotoxic activity against five human leukemia cell lines with IC50 values ranging from 5.7 to 8.9 µM. Our study demonstrated that compound 11 may serve as a potential candidate for the development of anticolorectal cancer agents.

Effect of early serum phosphate disorder on in-hospital and 28-day mortality in sepsis patients: a retrospective study based on MIMIC-IV database.

BACKGROUND: This study aims to assess the influence of early serum phosphate fluctuation on the short-term prognosis of sepsis patients. METHODS: This retrospective study used the Medical Information Mart for Intensive Care IV database to analyze serum phosphate levels in sepsis patients within 3 days of ICU admission. According to the absolute value of delta serum phosphate (the maximum value minus the minimum value of serum phosphorus measured within three days), the patients were divided into four groups, 0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl. Meanwhile, the direction of delta serum phosphate was compared. With the serum phosphate change group of 0-1.3 mg/dl as the reference group, the relationship between delta serum phosphate and in-hospital mortality and 28-day mortality was analyzed by multivariate Logistics regression analysis. RESULTS: The study involved 1375 sepsis patients. Serum phosphate changes (0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl) correlated with in-hospital and 28-day mortality variations (p = 0.005, p = 0.008). Much higher serum phosphate fluctuation elevated in-hospital and 28-day mortality. Compared to the 0-1.3 mg/dl change group, adjusted odds ratios (OR) in other groups for in-hospital mortality were 1.25 (0.86-1.81), 1.28 (0.88-1.86), and 1.63 (1.10-2.43), and for 28-day mortality were 1.21 (0.86-1.72), 1.10 (0.77-1.57), and 1.49 (1.03-2.19). Under the trend of increasing serum phosphate, the ORs of in-hospital mortality and 28-day mortality in ≥ 3.2 mg/dl group were 2.52 and 2.01, respectively. CONCLUSION: In conclude, the delta serum phosphate ≥ 3.2 mg/dl was associated with in-hospital mortality and 28-day mortality in patients with sepsis.

Novel, high accuracy models for hepatocellular carcinoma prediction based on longitudinal data and cell-free DNA signatures.

BACKGROUND & AIMS: Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures. METHODS: A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development. RESULTS: We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p = 0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001). CONCLUSIONS: aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance. IMPACT AND IMPLICATIONS: In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.

Metal-responsive elements confer cadmium response in Arabidopsis.

MAIN CONCLUSION: Molecular, biochemical, and genetic experiments demonstrate that metal-responsive elements (MREs), initially identified in animals, confer the cadmium transcriptional response in Arabidopsis, thus providing deep functional insights of MREs in plants. Cadmium (Cd) is highly toxic to all organisms including plants. Cd-responsive gene transcription is a fundamental aspect of the Cd response, in which Cd stress regulatory cis-acting elements are essential. However, little is known regarding such elements in plants. Metal-responsive elements (MREs, 5'-TGCRCNC-3', R: A or G, N: any base) are essential for transcriptional induction of Cd in animals. MREs are also contained in the promoters of some Cd-regulated plant genes, but whether MREs confer Cd responses in plants is poorly defined. Herein, we used a previously identified MRE of the tobacco feedback-insensitive anthranilate synthase α-2 chain gene as a representative MRE (named as MREa, 5'-TGCACAC-3') to explore the roles of MREs in the transcriptional response to Cd stress in Arabidopsis thaliana. First, we showed that MREa conferred Cd stress responsiveness on a minimal promoter in both concentration- and time-dependent manners, whereas the mutated MREa did not. Second, MREa specifically bound nuclear extracts, displaying a biochemical characteristic of cis-acting elements. We screened and identified four MREa-binding transcription factors, including ethylene response factor 13 (AtERF13). At last, MREa could mediate AtERF13 to activate the ß-glucuronidase (GUS) reporter expression. Overall, these molecular, biochemical, and genetic data suggest that MREa is instrumental in the Cd response in Arabidopsis, thus providing deep functional insights of MREs in plants.

Early gut microbiological changes and metabolomic changes in patients with sepsis: a preliminary study.

The gut microbiota is closely related to the development of sepsis. The aim of this study was to explore changes in the gut microbiota and gut metabolism, as well as potential relationships between the gut microbiota and environmental factors in the early stages of sepsis. Fecal samples were collected from 10 septic patients on the first and third days following diagnosis in this study. The results showed that in the early stages of sepsis, the gut microbiota is dominated by microorganisms that are tightly associated with inflammation, such as Escherichia-Shigella, Enterococcus, Enterobacteriaceae, and Streptococcus. On sepsis day 3 compared to day 1, there was a significant decrease in Lactobacillus and Bacteroides and a significant increase in Enterobacteriaceae, Streptococcus, and Parabacteroides. Culturomica_massiliensis, Prevotella_7 spp., Prevotellaceae, and Pediococcus showed significant differences in abundance on sepsis day 1, but not on sepsis day 3. Additionally, 2-keto-isovaleric acid 1 and 4-hydroxy-6-methyl-2-pyrone metabolites significantly increased on sepsis day 3 compared to day 1. Prevotella_7 spp. was positively correlated with phosphate and negatively correlated with 2-keto-isovaleric acid 1 and 3-hydroxypropionic acid 1, while Prevotella_9 spp. was positively correlated with sequential organ failure assessment score, procalcitonin and intensive care unit stay time. In conclusion, the gut microbiota and metabolites are altered during sepsis, with some beneficial microorganisms decreasing and some pathogenic microorganisms increasing. Furthermore, Prevotellaceae members may play different roles in the intestinal tract, with Prevotella_7 spp. potentially possessing beneficial health properties and Prevotella_9 spp. potentially playing a promoting role in sepsis.

Identification of Signature Genes of Dilated Cardiomyopathy Using Integrated Bioinformatics Analysis.

Dilated cardiomyopathy (DCM) is characterized by left ventricular or biventricular enlargement with systolic dysfunction. To date, the underlying molecular mechanisms of dilated cardiomyopathy pathogenesis have not been fully elucidated, although some insights have been presented. In this study, we combined public database resources and a doxorubicin-induced DCM mouse model to explore the significant genes of DCM in full depth. We first retrieved six DCM-related microarray datasets from the GEO database using several keywords. Then we used the "LIMMA" (linear model for microarray data) R package to filter each microarray for differentially expressed genes (DEGs). Robust rank aggregation (RRA), an extremely robust rank aggregation method based on sequential statistics, was then used to integrate the results of the six microarray datasets to filter out the reliable differential genes. To further improve the reliability of our results, we established a doxorubicin-induced DCM model in C57BL/6N mice, using the "DESeq2" software package to identify DEGs in the sequencing data. We cross-validated the results of RRA analysis with those of animal experiments by taking intersections and identified three key differential genes (including BEX1, RGCC and VSIG4) associated with DCM as well as many important biological processes (extracellular matrix organisation, extracellular structural organisation, sulphur compound binding, and extracellular matrix structural components) and a signalling pathway (HIF-1 signalling pathway). In addition, we confirmed the significant effect of these three genes in DCM using binary logistic regression analysis. These findings will help us to better understand the pathogenesis of DCM and may be key targets for future clinical management.

Discovery of Novel Hybrid-Type Strigolactone Mimics Derived from Cinnamic Amide.

Strigolactones (SLs) are a class of plant hormones and rhizosphere communication signals of great interest. They perform diverse biological functions including the stimulation of parasitic seed germination and phytohormonal activity. However, their practical use is limited by their low abundance and complex structure, which requires simpler SL analogues and mimics with maintained biological function. Here, new, hybrid-type SL mimics were designed, derived from Cinnamic amide, a new potential plant growth regulator with good germination and rooting-promoting activities. Bioassay results indicated that compound 6 not only displayed good germination activity against the parasitic weed O. aegyptiaca with an EC50 value of 2.36 × 10-8 M, but also exhibited significant inhibitory activity against Arabidopsis root growth and lateral root formation, as well as promoting root hair elongation, similar to the action of GR24. Further morphological experiments on Arabidopsis max2-1 mutants revealed that 6 possessed SL-like physiological functions. Furthermore, molecular docking studies indicated that the binding mode of 6 was similar to that of GR24 in the active site of OsD14. This work provides valuable clues for the discovery of novel SL mimics.

A Potential Lead for Insect Growth Regulator: Design, Synthesis, and Biological Activity Evaluation of Novel Hexacyclic Pyrazolamide Derivatives.

Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) hexacyclic pyrazolamide derivatives were designed and synthesized by reducing the heptacycle and inserting small flexible linkers on the basis of the previously discovered dual-target compound D-27 acting simultaneously on EcR and Ostrinia furnacalis chitinase (OfChtI). Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda, and Ostrinia furnacalis larvae were evaluated. The results revealed that the insecticidal activity was not significantly enhanced when the heptacycle on the pyrazole ring was reduced to a hexacycle. However, the insertion of an additional methylene spacer between the substituted phenyl ring and the amide bond can improve the insecticidal activity. Among the derivatives, the most potent compound, 6j, exhibited promising insecticidal activities against P. xylostella and S. frugiperda. Further protein binding assays and molecular docking indicated that 6j could target both EcR and OfChtI, and is a potential lead compound for IGRs. The present work provides valuable clues for the development of new dual-target IGRs.

Kinetics of ester-105 degradation by La/TiO2 photocatalysis.

Lanthanum-doped titanium (La/TiO2) nano-photocatalysts were prepared using the sol-gel method and characterized by X-ray diffraction (XRD), zeta potential, and low-temperature nitrogen adsorption analyses. Ester-105, a flotation collector from beneficiation wastewater, was chosen as the target pollutant. The influence of the initial ester-105 concentration, pH, and photocatalyst dosage on the photocatalytic degradation of ester-105 was investigated. To examine the kinetics of the adsorption and photocatalytic degradation of ester-105, a Langmuir adsorption model and Langmuir-Hinshelwood kinetic models were established and discussed. The synthesized photocatalyst comprised anatase-phase TiO2, with an isoelectric point of pH = 6.5, specific surface area of 56.1626 m2·g-1, and average pore size of 7.78 nm. The maximum adsorption and the adsorption equilibrium constant of La/TiO2 for ester-105 were determined as 0.338 mg·g-1 and 1.008 L·mg-1, respectively. The first-order kinetic reaction rate constant (k) exhibited a linear relationship with the initial ester-105 concentration. The optimal pH for ester degradation was theoretically determined to be 6.95, and the optimum photocatalyst dosage was found to be 0.2739 g·L-1. Experiments confirmed that the photocatalytic degradation of ester-105 using La/TiO2 followed the Langmuir-Hinshelwood kinetics model, thereby providing a theoretical foundation for the photocatalytic degradation of ester-105 for industrial application.

Formaldehyde oxidation on Pd/USY catalysts at room temperature: The effect of acid pretreatment on supports.

The complete catalytic oxidation of formaldehyde (HCHO) to CO2 and H2O at room temperature is a green route for indoor HCHO removal. Zeolite is an excellent carrier material for HCHO oxidation due to its large surface area, intricate pores and high adsorption capacity. However, the zeolite-supported noble metal catalysts have currently shown relatively low activity especially at room temperature. In this work, we present a facile acid treatment strategy for zeolite catalysts to improve the hydroxyl concentration and further enhance their catalytic activity for HCHO oxidation. Activity tests illustrated that HCHO could be completely oxidized to CO2 and H2O at a nearly 100% conversion rate with a weight hourly space velocity (WHSV) of 150,000 mL/(g∙hr) at 25°C, when the support of Pd/USY catalysts was pretreated by hydrochloric acid with a concentration of 0.20 mol/L. The characterization results revealed that the active hydroxyl groups originated from the dealumination in the acid treatment play a key role in the HCHO oxidation reaction. The deduced reaction mechanism suggests that bridging hydroxyl groups may oxidize HCHO to dioxymethylene (DOM) species and terminal hydroxyl groups are responsible for the transformation of DOM groups to formate (HCOO) species.

[Component identification and analysis in vivo of Sanhan Huashi formula].

Sanhan Huashi formula(SHF) is the intermediate of a newly approved traditional Chinese medicine(TCM) Sanhan Huashi Granules for the treatment of COVID-19 infection. The chemical composition of SHF is complex since it contains 20 single herbal medicines. In this study, UHPLC-Orbitrap Exploris 240 was used to identify the chemical components in SHF and in rat plasma, lung and feces after oral administration of SHF, and heat map was plotted for characterizing the distribution of the chemical components. Chromatographic separation was conducted on a Waters ACQUITY UPLC BEH C_(18)(2.1 mm×100 mm, 1.7 µm) using 0.1% formic acid(A)-acetonitrile(B) as mobile phases in a gradient elution. Electrospray ionization(ESI) source was used to acquire data in positive and negative mode. By reference to quasi-molecular ions and MS/MS fragment ions and in combination with MS spectra of reference substances and compound information in literature reports, 80 components were identified in SHF, including 14 flavonoids, 13 coumarins, 5 lignans, 12 amino-compounds, 6 terpenes and 30 other compounds; 40 chemical components were identified in rat plasma, 27 in lung and 56 in feces. Component identification and characterization of SHF in vitro and in vivo lay foundations for disclosure of its pharmacodynamic substances and elucidation of the scientific connotation.

Pt Atomic Single-Layer Catalyst Embedded in Defect-Enriched Ceria for Efficient CO Oxidation.

The local coordination structure of metal sites essentially determines the performance of supported metal catalysts. Using a surface defect enrichment strategy, we successfully fabricated Pt atomic single-layer (PtASL) structures with 100% metal dispersion and precisely controlled local coordination environment (embedded vs adsorbed) derived from Pt single-atoms (Pt1) on ceria-alumina supports. The local coordination environment of Pt1 not only governs its catalytic activity but also determines the Pt1 structure evolution upon reduction activation. For CO oxidation, the highest turnover frequency can be achieved on the embedded PtASL in the CeO2 lattice, which is 3.5 times of that on the adsorbed PtASL on the CeO2 surface and 10-70 times of that on Pt1. The favorable CO adsorption on embedded PtASL and improved activation/reactivity of lattice oxygen within CeO2 effectively facilitate the CO oxidation. This work provides new insights for the precise control of the local coordination structure of active metal sites for achieving 100% atomic utilization efficiency and optimal intrinsic catalytic activity for targeted reactions simultaneously.

A Multicancer Malignant Pleural Effusion Diagnostic Test Using Hexokinase 2 and Single-Cell Sequencing.

BACKGROUND: Malignant pleural effusion (MPE) represents advanced malignant disease with poor prognosis. To date, pleural effusion cytology remains the best test to diagnose MPE but suffers from limited diagnostic sensitivity and high variation. We report a hexokinase 2-based method (HK2-seq) as a novel diagnostic method for multicancer MPE diagnosis. METHODS: HK2-seq employed HK2 as a new metabolic function-associated marker to detect disseminated tumor cells engaging increased glycolysis in pleural effusion from many cancer types. Single-cell sequencing was used to confirm the malignancy of HK2-derived high glycolytic tumor cells (hgTCs) at the single-cell level via surveying genome-wide copy number alterations (CNAs), leading to establishment of definitive MPE diagnosis. RESULTS: In a prospective cohort study including 111 patients with pleural effusion, the HK2 test showed diagnostic sensitivity, diagnostic specificity, positive predictive value, and negative predictive value of 91% (95% CI: 80%-97%), 84% (95% CI: 68%-93%), 90% (95% CI: 79%-96%), and 86% (95% CI: 70%-95%), respectively, in MPE diagnosis across 12 different cancer types. In contrast, pleural effusion cytology exhibits an overall diagnostic sensitivity of 45%. In addition to confirming the tumor origin of hgTCs, single-cell sequencing allowed identification of prognostic or targetable CNAs in hgTCs, especially CNAs found in liquid biopsies but absent in solid biopsies. CONCLUSIONS: HK2-seq establishes definitive MPE diagnosis across many cancer types with high diagnostic performance. It has the potential to be used for multicancer detection of circulating tumor cells in blood and other types of body fluids, as well as liquid biopsy-based genomic characterization for informative diagnosis.

MiR-143-3p Increases the Radiosensitivity of Breast Cancer Cells Through FGF1.

Breast cancer is a common malignant tumor in women. At present, the main treatment for breast cancer is radiotherapy. Due to the difference in radiosensitivity between individuals or tumor cells, the effect of radiotherapy is not good. Therefore, in radiotherapy, how to use various auxiliary means to reduce the radiation resistance of tumor, Therefore, it has become an important research topic to improve the radiosensitivity of the tumor. Fibroblast growth factor-1 (FGF1) plays an important role in tumor migration. Therefore, the study of miR-143-3p increasing the radiosensitivity of breast cancer cells through FGF1 is proposed in this paper. In this study, a control group experiment was set up to study. During the experiment, the relative expression of miR-143-3p was detected by fluorescent quantitative PCR of miRNA, and the cell irradiation experiment was created to analyze the radiosensitivity of breast cancer cells by comparing their survival fraction. The results of this study showed that when the radiation dose was 0, the survival scores of the three groups were all 1. The survival fraction of the experimental group decreased from 0.26 ± 0.045 to 0.068 ± 0.008 when the dose was added to 4Gy. The survival fraction of the experimental group was always greater than that of the two control groups. The results of this study show that miR-143-3p can increase the radiosensitivity of breast cancer cells through FGF1.