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Leaf senescence is the last stage of leaf development, manifested by leaf yellowing due to the loss of chlorophyll, along with the degradation of macromolecules and facilitates nutrient translocation from the sink to the source tissues, which is essential for the plants' fitness. Leaf senescence is controlled by a sophisticated genetic network that has been revealed through the study of the molecular mechanisms of hundreds of senescence-associated genes (SAGs), which are involved in multiple layers of regulation. Leaf senescence is primarily regulated by plant age, but also influenced by a variety of factors, including phytohormones and environmental stimuli. Phytohormones, as important signaling molecules in plant, contribute to the onset and progression of leaf senescence. Recently, peptide hormones have been reported to be involved in the regulation of leaf senescence, enriching the significance of signaling molecules in controlling leaf senescence. This review summarizes recent advances in the regulation of leaf senescence by classical and peptide hormones, aiming to better understand the coordinated network of different pathways during leaf senescence.

Leaf senescence is a highly coordinated, complicated process involving the integration of numerous internal and environmental signals. Salicylic acid (SA) and reactive oxygen species (ROS) are two well-defined inducers of leaf senescence whose contents progressively and interdependently increase during leaf senescence via an unknown mechanism. Here, we characterized the transcription factor WRKY75 as a positive regulator of leaf senescence in Arabidopsis thaliana. Knockdown or knockout of WRKY75 delayed age-dependent leaf senescence, while overexpression of WRKY75 accelerated this process. WRKY75 transcription is induced by age, SA, H2O2, and multiple plant hormones. Meanwhile, WRKY75 promotes SA production by inducing the transcription of SA INDUCTION-DEFICIENT2 (SID2) and suppresses H2O2 scavenging, partly by repressing the transcription of CATALASE2 (CAT2). Genetic analysis revealed that the mutation of SID2 or an increase in catalase activity rescued the precocious leaf senescence phenotype evoked by WRKY75 overexpression. Based on these results, we propose a tripartite amplification loop model in which WRKY75, SA, and ROS undergo a gradual but self-sustained rise driven by three interlinking positive feedback loops. This tripartite amplification loop provides a molecular framework connecting upstream signals, such as age and plant hormones, to the downstream regulatory network executed by SA- and H2O2-responsive transcription factors during leaf senescence.

Background Fibrinogen-like protein 1 (FGL1)—Lymphocyte activating gene 3 (LAG-3) pathway is a promising immunotherapeutic target and has synergistic effect with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1). However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unknown. Methods The levels of LAG-3, FGL1, PD-L1 and cytotoxic T (CD8 + T) cells in 143 HCC patients were assessed by multiplex immunofluorescence. Associations between the marker’s expression and clinical significances were studied. Results We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3 + cells but not PD-L1. CD8 + T cells densities had positive correlation with PD-L1 levels and negative association with FGL1 expression. Elevated densities of LAG-3 + cells and low levels of CD8 + T cells were correlated with poor disease outcome. Moreover, LAG-3 + cells deteriorated patient stratification based on the abundance of CD8 + T cells. Patients with positive PD-L1 expression on tumor cells (PD-L1 TC + ) tended to have an improved survival than that with negative PD-L1 expression on tumor cells (PD-L1 TC − ). Furthermore, PD-L1 TC − in combination with high densities of LAG-3 + cells showed the worst prognosis, and PD-L1 TC + patients with low densities of LAG-3 + cells had the best prognosis. Conclusions LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3 + cells and CD8 + T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively.

This study aims to evaluate the association between the Weight-Adjusted Waist Index (WWI) and osteoarthritis (OA) utilizing cross-sectional data from the 2005–2014 National Health and Nutrition Examination Survey (NHANES). The study analyzed data from 12,696 participants across the 2005–2014 NHANES cycles to examine differences in demographic, socioeconomic, lifestyle, and health-related variables across WWI quartiles. Multivariable logistic regression models were employed to assess the relationship between WWI and the risk of OA. Receiver Operating Characteristic (ROC) curve analysis was conducted to evaluate and compare the predictive ability of WWI, BMI, waist circumference, and weight in identifying OA risk. Scatter plots were generated to visualize the association between WWI and OA, with linear regression lines illustrating trends and statistical significance. Restricted cubic spline (RCS) analysis was used to further explore the nonlinear relationship between WWI and OA risk. Forest plots were used to display the impact of WWI on OA risk across subgroups such as gender, age, and race, showing that individuals with higher WWI generally exhibit a significantly increased risk of OA. After adjusting for multiple covariates, the findings indicated a significant association between higher WWI and an increased risk of OA. Subgroup analyses, including gender, age, and race, further reinforced the consistent association between WWI and OA risk. In the U.S. adult population, an elevated WWI is significantly associated with an increased risk of OA, suggesting that WWI could serve as a potential indicator for assessing OA risk.

The apical hook protects the meristems of dicot seedlings as they protrude through the soil; multiple factors, including phytohormones and light, mediate apical hook development. HOOKLESS1 (HLS1) plays an indispensable role, as HLS1 mutations cause a hookless phenotype. The ETHYLENE INSENSITIVE3 (EIN3) and EIN3-LIKE1 (EIL1) transcription factors integrate multiple signals (ethylene, gibberellins, and jasmonate) and activate HLS1 expression to enhance hook development. Here, we found that Arabidopsis thaliana PHYTOCHROME INTERACTING FACTOR (PIF) transcription factors act in parallel with EIN3/EIL1 and promote hook curvature by activating HLS1 transcription at a distinct binding motif. EIN3/EIL1 and PIFs can promote hook formation in the absence of the other. Jasmonate represses PIF function to inhibit hook development. Like EIN3 and EIL1, MYC2 interacts with PIF4 and hampers its activity. Acting together, EIN3/EIL1 and PIFs alleviate the negative effects of jasmonate/light and facilitate the positive effects of ethylene/gibberellins. Mutating EIN3/EIL1 and PIFs causes a complete hookless phenotype, marginal HLS1 expression, and insensitivity to upstream signals. Transcriptome profiling revealed that EIN3/EIL1 and PIFs additively and distinctly regulate a wide array of processes, including apical hook development. Together, our findings identify an integrated framework underlying the regulation of apical hook development and show that EIN3/EIL1 and PIFs fine-tune adaptive growth in response to hormone and light signals.

Gut microbiota is closely related to age. Studies from Europe and the U.S. identified featured microbiota in different age groups for the elderly. Asian studies mainly focused on people living in longevity areas. Featured microbiota for the elderly people of different age groups, especially in the centenarian in the general population, has not been well investigated in China. We conducted a comparative study by including 198 subjects of three age groups (65-70, 90-99, and 100+ years) in East China. Information regarding age, sex, height, weight, waist circumference, hip circumference, food preference, smoking status and alcohol consumption were collected by using a structured questionnaire. Fecal samples for each participant were collected as well. 16S rRNA gene sequencing were employed to analyze the gut microbiota composition. Logistic regression with LASSO feature selection was used to identify featured taxa in different age groups and to assess their potential interactions with other factors such as lifestyle. The gut microbiota of the 90-99 year and 100+ year age groups showed more diversity, robustness, and richness compared with the 65-70 year age group. PCoA analysis showed a clear separation between the 65-70 and 100+ year age groups. At the species level, Bacteroides fragilis, Parabacteroides merdae, Ruminococcus gnavus, Coprococcus and Clostridium perfringens increased, but Bacteroides vulgatus, Ruminococcus sp.5139BFAA and Clostridium sp.AT5 decreased in the 90-99 year age group. The age differences in gut microbiota were similar across the strata of smoking, alcohol consumption status and food preference. Our study demonstrated age differences in many aspects of gut microbiota, such as overall diversity, microbiota structure, and relative abundance of key taxa. Moreover, the gut microbiota of centenarian was significantly different from those of younger age groups of the elderly.

Objective. Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with a poor prognosis and limited treatment. Cisplatin with gemcitabine is used as the standard first-line chemotherapy regimen; however, there is still no robust evidence for second-line and successive treatments. Although preliminary evidence suggests a vital role of precision therapy or immunotherapy in a subset of patients, the gene alteration rate is relatively low. Herein, we explored the second-line and successive treatments using hepatic arterial infusion chemotherapy (HAIC) based on FOLFIRI after the failure of gemcitabine and platinum combined with target and immunotherapy in refractory CCAs. Methods. Advanced patients with iCCAs confirmed by diagnostic pathology, who progressed at least on a gemcitabine/platinum doublet and/or other systemic chemotherapy combined with target therapy and immune checkpoint inhibitor, were included. All patients received infusional 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) via HAIC until progression or unacceptable toxicity. The primary objective was the feasibility of treatment, with secondary objectives of disease control rate (DCR) and 6-month survival rate. Results. A total of 9 iCCA patients treated between Dec 2020 and May 2021 were enrolled; 2 patients suffered from distant metastasis, while 7 had local lymph node metastasis and portal vein or hepatic vein invasion. HAIC was delivered as second-line therapy in 6/9 patients, while a third or successive therapy in 3/9 patients. The patients accepted an average of 2.90 ± 1.69 cycles of HAIC. The objective response rate was 22.2%; the disease control rate was 55.5% (5/9); median progression-free survival was 5 months; and 6-month survival rate was 66.7% (6/9). Conclusions. Our results provide preliminary evidence that HAIC based on FOLFIRI regimen is efficient and safe in some patients progressing after previous treatment. Therefore, HAIC may be a promising and valuable complementary therapy for advanced CCAs as a second-line and successive therapy. Otherwise, the combination of HAIC with precision medicine may improve clinical benefits (clinical registration number: 2021BAT4857).

Background Transarterial chemoembolization (TACE) is commonly used to treat patients with unresectable hepatocellular carcinoma (HCC); however, TACE alone has demonstrated unsatisfactory survival benefits. Our previous studies suggested that TACE plus oral medication of thalidomide, carmofur and compound mylabris capsule (TCC cocktail) may be a better therapeutic option. Methods In this randomized, open-label, multicenter clinical trial, 72 treatment-naive HCC patients were randomly assigned to receive cTACE alone or cTACE plus oral TCC cocktail between July 2018 and October 2019. The primary endpoint of this trial was the 1-, 2- and 3-year overall survival (OS) rates. The second endpoints of this trial included 1-, 2- and 3-year progression-free survival (PFS) rates, objective response rates (ORR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety with adverse events (AEs). Results The 1-, 2- and 3-year OS rates were significantly higher in the cTACE plus TCC group than in the cTACE group (83.2% vs 54.3%, 63.1% vs 30.1%, 37.7% vs 18.1%; p  = 0.008), with a significantly longer median OS (29.0 vs 15.0 months; p  < 0.001). Regarding the 1-, 2- and 3-year PFS rates, HCC patients in the cTACE plus TCC group also demonstrated significantly higher rates (66.3% vs 34.4%, 35.8% vs 18.8%, 31.8% vs 15.6%; p  = 0.014) and had a longer median PFS (16.0 vs 8.0 months; p  < 0.001) compared with cTACE group. All treatment-related AEs were tolerated. Conclusions For patients with unresectable HCC, TACE combined with TCC cocktail was well tolerated and significantly improved clinical outcomes. Trial registration The trial was registered at https://www.chictr.org.cn/showproj.html?proj=27493 as ChiCTR1800016335 on 25th May 2018 named an open-label, multicenter, randomized, prospective clinical trial of thalidomide based triple oral regimen for low-dose maintenance therapy after TACE in advanced hepatocellular carcinoma.

Although several studies have evaluated the relationship between bisphenol A (BPA) and thyroid functions, their results are not entirely consistent. Little is known about BPA in relation to thyroid volume and structure. We examined the association of BPA with thyroid volume and thyroid nodules using data from 718 Chinese children living in the East Coast of China in 2012. First morning urine samples were collected for the determination of urinary BPA, creatinine, and urinary iodine concentrations (UIC). Thyroid volume (TV) and nodules were assessed by thyroid ultrasonography. The median of TV was 3.14ml. 459(63.9%) children took iodized salt at home and the median of UIC was 159μg/l. BPA was detected in 99.9% of the urine samples and the medians for boys and girls were 2.64 and 2.35μg/g creatinine, respectively. Of all participants 14.0% had thyroid nodules. Urinary BPA concentration was inversely associated with thyroid volume (β = -0.033, 95% CI: -0.053, -0.013) and the risk for multiple nodules (OR = 0.78; 95% CI: 0.63, 0.97). The associations above were similar for children who consumed iodized salt and those consumed non-iodized salt. The data suggest that BPA may be one of the influencing factors for TV and thyroid nodules and its effects are independent of iodine nutrition status in children.

Zero-shot event detection aims to involve the automatic discovery and classification of new events within unstructured text. Current zero-shot event detection methods have not considered addressing the problem more effectively from the perspective of improving event representations. In this paper, we propose dual-contrastive prompting (COPE) model for learning event representations to address zero-shot event detection, which leverages prompts to assist in generating event embeddings using a pretrained language model, and employs a contrastive fusion approach to capture complex interaction information between trigger representations and sentence embeddings to obtain enhanced event representations. Firstly, we introduce a sample generator to create ordered contrastive sample sequences with varying degrees of similarity for each event instance, aiding the model in better distinguishing different types of events. Secondly, we design two distinct prompts to obtain trigger representations and event sentence embeddings separately. Thirdly, we employ a contrastive fusion module, where trigger representations and event sentence embeddings interactively fuse in vector space to generate the final event representations. Experiments show that our model is more effective than the most advanced methods.