Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13.

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

Methylation changes of liver DNA during the formation of gallstones.

Aim: To explore the overall methylation changes in liver tissues during the formation of gallstones, as well as the key pathways and genes involved in the process. Methods: Reduced-representation bisulfite sequencing and RNA sequencing were conducted on the liver tissues of mice with gallstones and control normal mice. Results: A total of 8705 differentially methylated regions in CpG and 1410 differentially expressed genes were identified. The joint analysis indicated that aberrant DNA methylation may be associated with dysregulated gene expression in key pathways such as cholesterol metabolism and bile secretion. Conclusion: We propose for the first time that methylation changes in some key pathway genes in liver tissue may be involved in the formation of gallstones.

A single 24 h maternal separation at PND 9 promotes behavioral resilience of female C57BL/6J mice and the possible role of hippocampal Homer1a.

Early life stress (ELS) has been thought to increase vulnerability to developing psychiatric disorders later in life, while some researchers have found that adversity early in life may promote stress resilience. Studies investigating the resilient effect of maternal separation (MS) are still relatively few, and the underlying mechanisms remain unknown. In the current study, the effect of a single 24 h MS paradigm at postnatal day 9 (PND 9) in female C57BL/6J mice was investigated by assessing behavioral performance in middle adolescence. We demonstrated that, mice in MS group displayed decreased anxiety-like behavior and increased exploratory behavior than controls in the open field test and elevated plus maze test. Furthermore, MS mice exhibited improved hippocampal-dependent spatial learning in the Morris water maze test. This performance indicated behavioral resilience to early life stress. The protein expression levels of Homer1 isoforms, which are implicated in a variety of neuropsychiatric disorders, were evaluated using Western blot analysis. A significant increase in hippocampal Homer1a protein expression was observed immediately after MS, which subsequently decreased until adolescence (PND 27-42), when a significant increase was observed again. This distinctive change of hippocampal Homer1a protein expression pattern indicated that hippocampal Homer1a might play a role in behavioral resilience to MS in female C57BL/6J mice. In conclusion, this study demonstrated that exposure to a single 24 h MS at PND 9 promoted behavioral resilience of female C57BL/6J mice in middle adolescence. This behavioral resilience might be related to increased expression of hippocampal Homer1a.

Amphoteric Chelating Ultrasmall Colloids for FAPbI3 Nanodomains Enable Efficient Near-Infrared Light-Emitting Diodes.

Perovskite light-emitting diodes (PeLEDs) are the next promising display technologies because of their high color purity and wide color gamut, while two classical emitter forms, i.e., polycrystalline domains and quantum dots, are encountering bottlenecks. Weak carrier confinement of large polycrystalline domains leads to inadequate radiative recombination, and surface ligands on quantum dots are the main annihilation sites for injected carriers. Here, pinpointing these issues, we screened out an amphoteric agent, namely, 2-(2-aminobenzoyl)benzoic acid (2-BA), to precisely control the in situ growth of FAPbI3 (FA: formamidine) nanodomains with enhanced space confinement, preferred crystal orientation, and passivated trap states on the transport-layer substrate. The amphoteric 2-BA performs bidentate chelating functions on the formation of ultrasmall perovskite colloids (<1 nm) in the precursor, resulting in a smoother FAPbI3 emitting layer. Based on monodispersed and homogeneous nanodomain films, a near-infrared PeLED device with a champion efficiency of >22% plus enhanced T80 operational stability was achieved. The proposed perovskite nanodomain film tends to be a mainstream emitter toward the performance breakthrough of PeLED devices covering visible wavelengths beyond infrared.

NR2F6 is essential for brown adipocyte differentiation and systemic metabolic homeostasis.

OBJECTIVE: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. METHODS: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. RESULTS: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. CONCLUSIONS: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.

MUC1-EGFR crosstalk with IL-6 by activating NF-κB and MAPK pathways to regulate the stemness and paclitaxel-resistance of lung adenocarcinoma.

BACKGROUND: The chemotherapy resistance often leads to chemotherapy failure. This study aims to explore the molecular mechanism by which MUC1 regulates paclitaxel resistance in lung adenocarcinoma (LUAD), providing scientific basis for future target selection. METHODS: The bioinformatics method was used to analyse the mRNA and protein expression characteristics of MUC1 in LUAD. RT-qPCR and ELISA were used to detect the mRNA and protein expression, flow cytometry was used to detect CD133+ cells, and cell viability was detected by CCK-8 assay. The mRNA-seq was performed to analyse the changes in expression profile, GO and KEGG analysis were used to explore the potential biological functions. RESULTS: MUC1 is highly expressed in LUAD patients and is associated with a higher tumour infiltration. In paclitaxel resistance LUAD cells (A549/TAX cells), the expression of MUC1, EGFR/p-EGFR and IL-6 were higher than that of A549 cells, the proportion of CD133+ cells was significantly increased, and the expression of cancer stem cell (CSCs) transcription factors (NANOG, OCT4 and SOX2) were significantly up-regulated. After knocking down MUC1 in A549/Tax cells, the activity of A549/Tax cells was significantly decreased. Correspondingly, the expression of EGFR, IL-6, OCT4, NANOG, and SOX2 were significantly down-regulated. The mRNA-seq showed that knocking down MUC1 affected the gene expression, DEGs mainly enriched in NF-κB and MAPK signalling pathway. CONCLUSION: MUC1 was highly expressed in A549/TAX cells, and MUC1-EGFR crosstalk with IL-6 may be due to the activation of NF-κB and MAPK pathways, which promote the enrichment of CSCs and lead to paclitaxel resistance.

Long noncoding RNA LINC00921 serves as a predictive biomarker for lung adenocarcinoma: An observational study.

Lung adenocarcinoma (LUAD) is usually diagnosed at advanced stages. Hence, there is an urgent need to seek an effective biomarker to predict LUAD status. Long noncoding RNAs (lncRNAs) play key roles in the development of tumors. However, the relationship between LINC00921 and LUAD remains unclear. The gene expression data of LUAD were downloaded from the Cancer Genome Atlas database to investigate the expression level of LINC00921 in LUAD. Diagnostic ability analysis, survival analysis, tumor mutational burden analysis, and immune cell infiltration analysis of LINC00921 in LUAD patients were performed simultaneously. According to the median expression value of LINC00921, patients were divided into LINC00921 high- and low-expression groups. The function of LINC00921 in LUAD was identified through difference analysis and enrichment analysis. Moreover, drugs that may be relevant to LUAD treatment were screened. Finally, blood samples were collected for real-time polymerase chain reaction. LINC00921 was significantly lower in LUAD tumor tissues. Notably, patients with low expression of LINC00921 had a shorter median survival time. Decreased immune cell infiltration in the tumor microenvironment in the low LINC00921 expression group may contribute to poorer patient outcomes. Tumor mutational burden was significantly different in survival between the LINC00921 high- and low-expression groups. In addition, LINC00921 may exert an influence on cancer development through its regulation of target genes transcription. Glyceraldehyde-3-phosphate dehydrogenase-related drugs may be more likely to be therapeutically effective in LUAD. LINC00921 was able to be used as the potential diagnostic indicator for LUAD.

Enhancement of the production of TEMPO-mediated oxidation cellulose nanofibrils by kneading.

The industrial use of TEMPO-mediated oxidation (TMO) reaction to produce highly fibrillated cellulose nanofibrils has been hindered by high catalyst costs, long reaction times and high reaction volumes. The hypothesis that cellulose concentration during TMO process is key to increase the process of efficiency has been confirmed. The novelty of this research is the proof-of-concept for a significant enhancement of the TMO reaction by kneading the cellulose to work in concentrations above 120 g/L. Results show that the increase of the cellulose concentration in the TMO reaction, from the traditional 10 g/L to 120 g/L, increase not only the production for the same reaction volume (1200 %) but also the pulp recovery (up to 94 %). Moreover, the oxidation time can be reduced from 42 min to only 4 min while properties of both the oxidized pulps and the final nanocellulose are similar. On the other hand, the use of buffers in the TMO reaction allows us to keep the pH constant without using NaOH, and to improve the selectivity of the carboxyl groups production. The proposed process also minimizes the final environmental impact.

Moving morphable component (MMC) topology optimization with different void structure scaling factors.

The explicit topology optimization method based on moving morphable component (MMC) has attracted more and more attention, and components are the basic building blocks of the implementation of MMC method. In the present work, a MMC topology optimization method based on component with void structure is followed with interest. On the basis of analyzing the characteristics of components used by MMC method, the topology description function for component with void structure is presented, where a quantitative scaling factor is introduced without increasing the number of design variables. Taking the minimum flexibility as the optimization objective, an example of short beam is analyzed with different void structure scaling factors. The results show that different scaling factors have a greater impact on the final topology optimization structure, and an ideal topology structure can be obtained with an appropriate scaling factor. Finally, some problems in the optimization process are analyzed and indicate that appropriate mesh density should be chose for component with void structure in order to achieve good optimization results.

Buried-Metal-Grid Electrodes for Efficient Parallel-Connected Perovskite Solar Cells.

The limited conductivity of existing transparent conducting oxide (TCO) greatly restricts the further performance improvement of perovskite solar cells (PSCs), especially for large-area devices. Herein, buried-metal-grid tin-doped indium oxide (BMG ITO) electrodes are developed to minimize the power loss caused by the undesirable high sheet resistance of TCOs. By burying 140-nm-thick metal grids into ITO using a photolithography technique, the sheet resistance of ITO is reduced from 15.0 to 2.7 Ω sq-1 . The metal step of BMG over ITO has a huge impact on the charge carrier transport in PSCs. The PSCs using BMG ITO with a low metal step deliver power conversion efficiencies (PCEs) significantly better than that of their counterparts with higher metal steps. Moreover, compared with the pristine ITO-based PSCs, the BMG ITO-based PSCs show a smaller PCE decrease when scaling up the active area of devices. The parallel-connected large-area PSCs with an active area of 102.8 mm2 reach a PCE of 22.5%. The BMG ITO electrodes are also compatible with the fabrication of inverted-structure PSCs and organic solar cells. The work demonstrates the great efficacy of improving the conductivity of TCO by BMG and opens up a promising avenue for constructing highly efficient large-area PSCs.

Seed-Mediated Growth for High-Efficiency Perovskite Solar Cells: The Important Role of Seed Surface.

Additive engineering has emerged as one of the most promising strategies to improve the performance of perovskite solar cells (PSCs). Among additives, perovskite nanocrystals (NCs) have a similar chemical composition and matched lattice structure with the perovskite matrix, which can effectively enhance the efficiency and stability of PSCs. However, relevant studies remain limited, and most of them focus on bromide-involved perovskite NCs, which may undergo dissolution and ion exchange within the FAPbI3 host, potentially resulting in an enlarged band gap. In this work, we employ butylamine-capped CsPbI3 NCs (BPNCs) as additives in PSCs, which can be well maintained and serve as seeds for regulating the crystallization and growth of perovskite films. The resultant perovskite film exhibits larger domain sizes and fewer grain boundaries without compromising the band gap. Moreover, BPNCs can alleviate lattice strain and reduce defect densities within the active layer. The PSCs incorporating BPNCs show a champion power conversion efficiency (PCE) of up to 25.41 %, well over both Control of 22.09 % and oleic acid/oleylamine capped CsPbI3 NC (PNC)-based devices of 23.11 %. This work illustrates the key role of nanosized seed surfaces in achieving high-performance photovoltaic devices.

Development and validation of a blood routine-based extent and severity clinical decision support tool for ulcerative colitis.

Monitoring extent and severity is vital in the ulcerative colitis (UC) follow-up, however, current assessment is complex and low cost-effectiveness. We aimed to develop a routine blood-based clinical decision support tool, Jin's model, to investigate the extent and severity of UC. The multicentre retrospective cohort study recruited 975 adult UC inpatients and sub-grouped into training, internal validation and external validation set. Model was developed by logistics regression for the extent via Montreal classification and for the severity via Mayo score, Truelove and Witts score (TWS), Mayo endoscopic score (MES) and Degree of Ulcerative colitis Burden of Luminal Inflammation (DUBLIN) score. In Montreal classification, left-sided and extensive versus proctitis model achieved area under the receiver operating characteristic curve (AUROC) of 0.78 and 0.81 retrospectively. For severity, Mayo score model, TWS model, MES model and DUBLIN score model achieved an AUROC of 0.81, 0.70, 0.74 and 0.70 retrospectively. The models also were evaluated with satisfactory calibration and clinical unity. Jin's model was free with open access at http://jinmodel.com:3000/ . Jin's model is a noninvasive, convenient, and efficient approach to assess the extent and severity of UC.

Insights into the regulatory role of RNA methylation modifications in glioma.

Epitranscriptomic abnormalities, which are highly prevalent in primary central nervous system malignancies, have been identified as crucial contributors to the development and progression of gliomas. RNA epitranscriptomic modifications, particularly the reversible modification methylation, have been observed throughout the RNA cycle. Epitranscriptomic modifications, which regulate RNA transcription and translation, have profound biological implications. These modifications are associated with the development of several cancer types. Notably, three main protein types-writers, erasers, and readers, in conjunction with other related proteins, mediate these epitranscriptomic changes. This review primarily focuses on the role of recently identified RNA methylation modifications in gliomas, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N1-methyladenosine (m1A). We delved into their corresponding writers, erasers, readers, and related binding proteins to propose new approaches and prognostic indicators for patients with glioma.

The Association Between Sleep Duration and Sleep-Related Gene Methylation with Osteoporosis in Chinese Postmenopausal Women.

This study aims to investigate the association between sleep duration and osteoporosis. In addition, sleep-related gene methylation was also detected in this study and we explored its relationship with osteoporosis. The epidemiological investigation section of this study was designed as a retrospective cross-sectional study. We gathered 148 postmenopausal women from two communities and used questionnaires to collect data of sleep duration and other sleep patterns. Biochemical variables were tested, and bone mineral density was measured by dual-energy X-ray absorptiometry. In addition, sleep-related gene (PER2 and PER3) methylation was tested, and the association with osteoporosis was further studied. Twenty-nine of the 148 participants (aged from 65 to 86 years) who suffered from osteoporosis were tested for osteopenia. A significant difference was observed in the association between sleep duration and osteoporosis; the p-value was 0.013. In addition, in our study, we found that short sleep duration (<7 hours) may increase the risk of osteoporosis compared with longer sleep duration. Moreover, sleep-related genes such as PER2 and PER3 and their CpG island methylation were tested, and there was no significant difference between PER2 and PER3 CpG island methylation and osteoporosis. Short sleep duration may increase the risk of osteoporosis. However, the association between sleep-related gene methylation and osteoporosis was not found.

Serum anion gap is associated with mortality in intensive care unit patients with diastolic heart failure.

Serum anion gap (AG) is closely related to mortality in critically ill patients with several diseases. We aimed to determine the relationship between serum AG levels and 28-day intensive care unit (ICU) mortality in patients with diastolic heart failure (DHF). This cohort study enrolled critically ill patients with DHF from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Serum AG levels were calculated using the traditional and albumin-adjusted methods. Multivariate Cox proportional hazards regression and restricted cubic spline curves were used to determine the correlation between serum AG levels and 28-day ICU mortality. We used receiver operating characteristic (ROC) curves and area under the curve (AUC) to compare the ability of traditional and albumin-adjusted AG to predict mortality. Overall, 3290 patients were included. Multivariate analysis showed an association of high levels of traditional (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.1-1.98, p = 0.009) and albumin-adjusted AG (HR, 1.36; 95% CI, 1.02-1.79, p = 0.033) with higher risk of 28-day ICU mortality. Restricted cubic spline curves indicated a linear relationship between AG level and 28-day ICU mortality. Comparison of the ROC curves revealed that albumin-adjusted AG had a greater ability to predict 28-day ICU mortality compared with traditional AG (AUCs of 0.569 [95% CI, 0.536-0.601] and 0.619 [95% CI, 0.588-0.649], respectively). In ICU patients with DHF, higher levels of traditional and albumin-adjusted AG were associated with higher 28-day ICU mortality. Albumin-adjusted AG exhibited greater predictive ability for mortality compared with traditional AG.

Aggravated hepatic fibrosis induced by phenylalanine and tyrosine was ameliorated by chitooligosaccharides supplementation.

Hepatic fibrosis is a classic pathological manifestation of metabolic chronic hepatopathy. The pathological process might either gradually deteriorate into cirrhosis and ultimately liver cancer with inappropriate nutrition supply, or be slowed down by several multifunctional nutrients, alternatively. Herein, we found diet with excessive phenylalanine (Phe) and tyrosine (Tyr) exacerbated hepatic fibrosis symptoms of liver dysfunction and gut microflora dysbiosis in mice. Chitooligosaccharides (COS) could ameliorate hepatic fibrosis with the regulation of amino acid metabolism by downregulating the mTORC1 pathway, especially that of Phe and Tyr, and also with the alleviation of the dysbiosis of gut microbiota, simultaneously. Conclusively, this work presents new insight into the role of Phe and Tyr in the pathologic process of hepatic fibrosis, while revealing the effectiveness and molecular mechanism of COS in improving hepatic fibrosis from the perspective of metabolites.

[Changes in Ozone Pollution Trend Characteristics and Sensitivity in Jinan from 2015 to 2020].

The surface ozone (O3) spatiotemporal distribution, variations, and its causes in Ji'nan from 2015 to 2020 were revealed based on the air quality monitoring network data and satellite retrievals from the Ozone Monitoring Instrument (OMI). The results showed that the ozone concentration in Ji'nan gradually increased from 2015 to 2020. The annual 90th percentile of the daily maximum 8-h average (MDA8) O3(namely the annual evaluation value) and the MDA8 O3(April-September) increased by 4.8 µg·(m3·a)-1 and 3.8 µg·(m3·a)-1, respectively. The trend of the ozone levels in the high-concentration range increased faster than that in the low-concentration range. The MDA8 in June increased by 7.4 µg·(m3·a)-1, and the rate range of increases was 2.6-3.9 µg·(m3·a)-1 in the cool seasons (December-February); thus, the O3 control in winter cannot be ignored. It is apparent from the diurnal variations in ozone from 2015 to 2020 in April-September that the average ozone levels have risen in recent years. The growth rate in the daytime was higher than that at night. The capacity of photochemical production has been increasing, especially in recent years. Additionally, it is noteworthy that the peak time for ozone levels occurred approximately 1-2 h earlier. The disparity of ozone concentrations among different stations gradually decreased in recent years. Compared with that in 2015, the range of areas with high O3 concentrations in 2019-2020 was further expanded. The significant positive trends in MDA8-90th and MDA8 (April-September) were observed in 16.1% and 22.6% of the monitoring sites in Ji'nan (P<0.05), most of which were located in urban areas and the suburbs close to urban areas. The temporal and spatial changes in ozone in Jinan had been affected by the changes in VOCs and NOx emissions since 2015. Satellite remote sensing data from 2015 to 2020 revealed that the NO2 tropospheric columns (April-September) showed reductions of 20.6%, with a decreasing rate of 0.3×1015 mole·(cm2·a)-1, especially in the urban areas and suburbs. The detected variation trends of tropospheric HCHO were weak and insignificant, which suggested that the decrease in NOx emissions was much greater than the decrease in VOCs emissions, and the gap had become more obvious in the urban areas. With responses to precursor emissions, the chemical sensitivity of O3 formation had been changing. The VOCs-limited regimes continuously decreased, and the mixed NOx/VOCs-sensitive regimes and NOx-limited regimes increased. In general, such an extremely inappropriate control ratio of ozone precursor NOx/VOCs led to an overall trend of slow increasing fluctuations of O3 in Ji'nan. The findings clearly indicate that the reduction of VOCs in Ji'nan was far from sufficient, and strengthening the current control of VOCs emissions is an effective measure to control the growth trend of O3 pollution in Ji'nan in the near future, especially in urban and surrounding suburban areas.