DELLA-mediated gene repression is maintained by chromatin modification in rice.

DELLA proteins are master regulators of gibberellic acid (GA) signaling through their effects on gene expression. Enhanced DELLA accumulation in rice and wheat varieties has greatly contributed to grain yield increases during the green revolution. However, the molecular basis of DELLA-mediated gene repression remains elusive. In this work, we show that the rice DELLA protein SLENDER RICE1 (SLR1) forms a tripartite complex with Polycomb-repressive complex 2 (PRC2) and the histone deacetylase HDA702 to repress downstream genes by establishing a silent chromatin state. The slr1 mutation and GA signaling resulted in dissociation of PRC2 and HDA702 from GA-inducible genes. Loss-of-function or downregulation of the chromatin regulators impaired SLR1-dependent histone modification and gene repression. Time-resolved analysis of GA signaling revealed that GA-induced transcriptional activation was associated with a rapid increase of H3K9ac followed by H3K27me3 removal. Collectively, these results establish a general epigenetic mechanism for DELLA-mediated gene repression and reveal details of the chromatin dynamics during transcriptional activation stimulated by GA signaling.

MethBank 4.0: an updated database of DNA methylation across a variety of species.

DNA methylation, as the most intensively studied epigenetic mark, regulates gene expression in numerous biological processes including development, aging, and disease. With the rapid accumulation of whole-genome bisulfite sequencing data, integrating, archiving, analyzing, and visualizing those data becomes critical. Since its first publication in 2015, MethBank has been continuously updated to include more DNA methylomes across more diverse species. Here, we present MethBank 4.0 (https://ngdc.cncb.ac.cn/methbank/), which reports an increase of 309% in data volume, with 1449 single-base resolution methylomes of 23 species, covering 236 tissues/cell lines and 15 biological contexts. Value-added information, such as more rigorous quality evaluation, more standardized metadata, and comprehensive downstream annotations have been integrated in the new version. Moreover, expert-curated knowledge modules of featured differentially methylated genes associated with biological contexts and methylation analysis tools have been incorporated as new components of MethBank. In addition, MethBank 4.0 is equipped with a series of new web interfaces to browse, search, and visualize DNA methylation profiles and related information. With all these improvements, we believe the updated MethBank 4.0 will serve as a fundamental resource to provide a wide range of data services for the global research community.

LRRK2 regulates ferroptosis through the system Xc-GSH-GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease.

Parkinson's disease (PD) is the most prevalent neurodegenerative disorder. Neuroinflammation mediated by activated microglia and apoptosis of dopaminergic (DA) neurons in the midbrain are its primary pathological manifestations. Leucine-rich repeat protein kinase 2 (LRRK2) kinase has been observed to increase expression during neuroinflammation, however, the effect of LRRK2 on microglia activation remains poorly understood. In this study, we have established lipopolysaccharide (LPS) treated BV2 cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models for both in vivo and in vitro investigation. Our data in vivo reveal that LRRK2 can promote microglia activation by regulating ferroptosis and activating nuclear factor-κB. Inhibition of LRRK2 expression effectively suppressed the LPS-induced pro-inflammatory cytokines and facilitated the secretion of neuroprotective factors. Importantly, by co-overexpressing LRRK2 and glutathione peroxidase 4 (GPX4), we identified the system Xc-GSH-GPX4 pathway as a crucial component in LRRK2-mediated microglial ferroptosis and inflammatory responses. Using a microglial culture supernatant (MCS) transfer model, we found that inhibiting LRRK2 or downregulating ferroptosis in BV2 cells prevented SH-SY5Y cell apoptosis. Additionally, we observed abundant expression of LRRK2 and P-P65 in the midbrain, which was elevated in the MPTP-induced PD model, along with microglia activation. LRRK2 and P-P65 expression inhibition with PF-06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP-treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc-GSH-GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis.

Direct Observation of Enhanced Iodine Binding within a Series of Functionalized Metal-Organic Frameworks with Exceptional Irradiation Stability.

Optimization of active sites and stability under irradiation are important targets for sorbent materials that might be used for iodine (I2) storage. Herein, we report the direct observation of I2 binding in a series of Cu(II)-based isostructural metal-organic frameworks, MFM-170, MFM-172, MFM-174, NJU-Bai20, and NJU-Bai21, incorporating various functional groups (-H, -CH3, - NH2, -C≡C-, and -CONH-, respectively). MFM-170 shows a reversible uptake of 3.37 g g-1 and a high packing density of 4.41 g cm-3 for physiosorbed I2. The incorporation of -NH2 and -C≡C- moieties in MFM-174 and NJU-Bai20, respectively, enhances the binding of I2, affording uptakes of up to 3.91 g g-1. In addition, an exceptional I2 packing density of 4.83 g cm-3 is achieved in MFM-174, comparable to that of solid iodine (4.93 g cm-3). In situ crystallographic studies show the formation of a range of supramolecular and chemical interactions [I···N, I···H2N] and [I···C≡C, I-C═C-I] between -NH2, -C≡C- sites, respectively, and adsorbed I2 molecules. These observations have been confirmed via a combination of solid-state nuclear magnetic resonance, X-ray photoelectron, and Raman spectroscopies. Importantly, γ-irradiation confirmed the ultraresistance of MFM-170, MFM-174, and NJU-Bai20 suggesting their potential as efficient sorbents for cleanup of radioactive waste.

Antimicrobial efficacy of aloe-emodin mediated photodynamic therapy against antibiotic-resistant Pseudomonas aeruginosa in vitro.

Multidrug-resistant Pseudomonas aeruginosa is a common pathogen that causes topical infections following burn injuries. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach for treating antibiotic-resistant bacterial infections. The objective of this study was to evaluate the aPDT efficacy of aloe-emodin (AE), which is a photosensitizer extracted from traditional Chinese herbs, on antibiotic-sensitive and antibiotic-resistant P. aeruginosa in vitro. In this study, we confirmed the effectiveness of AE-mediated aPDT against both standard and MDR P. aeruginosa, explored the effects of irradiation time and AE concentration on bacterial survival in AE-mediated aPDT, and observed the structural damage of P. aeruginosa by using transmission electron microscope. Our results showed that neither AE nor light irradiation alone caused cytotoxic effects on P. aeruginosa. However, AE-mediated aPDT effectively inactivated both antibiotic-sensitive and antibiotic-resistant P. aeruginosa. The transmission electron microscope investigation showed that aPDT mediated by AE primarily caused damage to the cytoplasm and cell membrane. Our findings suggest that AE is a photosensitizer in the aPDT of MDR P. aeruginosa-caused topical infections following burn injuries. Future investigations will concentrate on the safety and efficacy of AE-mediated aPDT in animal models and clinical trials.

A novel flavobacterial phage abundant during green tide, representing a new viral family, Zblingviridae.

Flavobacteriia are the dominant and active bacteria during algal blooms and play an important role in polysaccharide degradation. However, little is known about phages infecting Flavobacteriia, especially during green tide. In this study, a novel virus, vB_TgeS_JQ, infecting Flavobacteriia was isolated from the surface water of the Golden Beach of Qingdao, China. Transmission electron microscopy demonstrated that vB_TgeS_JQ had the morphology of siphovirus. The experiments showed that it was stable from -20°C to 45°C and pH 5 to pH 8, with latent and burst periods both lasting for 20 min. Genomic analysis showed that the phage vB_TgeS_JQ contained a 40,712-bp dsDNA genome with a GC content of 30.70%, encoding 74 open-reading frames. Four putative auxiliary metabolic genes were identified, encoding electron transfer-flavoprotein dehydrogenase, calcineurin-like phosphoesterase, phosphoribosyl-ATP pyrophosphohydrolase, and TOPRIM nucleotidyl hydrolase. The abundance of phage vB_TgeS_JQ was higher during Ulva prolifera (U. prolifera) blooms compared with other marine environments. The phylogenetic and comparative genomic analyses revealed that vB_TgeS_JQ exhibited significant differences from all other phage isolates in the databases and therefore was classified as an undiscovered viral family, named Zblingviridae. In summary, this study expands the knowledge about the genomic, phylogenetic diversity and distribution of flavobacterial phages (flavophages), especially their roles during U. prolifera blooms. IMPORTANCE: The phage vB_TgeS_JQ was the first flavobacterial phage isolated during green tide, representing a new family in Caudoviricetes and named Zblingviridae. The abundance of phage vB_TgeS_JQ was higher during the Ulva prolifera blooms. This study provides insights into the genomic, phylogenetic diversity, and distribution of flavophages, especially their roles during U. prolifera blooms.

SnRK1 stimulates the histone H3K27me3 demethylase JMJ705 to regulate a transcriptional switch to control energy homeostasis.

Plant SNF1-Related Kinase1 (SnRK1) is an evolutionarily conserved energy-sensing protein kinase that orchestrates transcriptional networks to maintain cellular energy homeostasis when energy supplies become limited. However, the mechanism by which SnRK1 regulates this gene expression switch to gauge cellular energy status remains largely unclear. In this work, we show that the rice histone H3K27me3 demethylase JMJ705 is required for low energy stress tolerance in rice plants. The genetic inactivation of JMJ705 resulted in similar effects as those of the rice snrk1 mutant on the transcriptome, which impairs not only the promotion of the low energy stress-triggered transcriptional program but also the repression of the program under an energy-sufficient state. We show that the α-subunit of OsSnRK1 interacts with and phosphorylates JMJ705 to stimulate its H3K27me3 demethylase activity. Further analysis revealed that JMJ705 directly targets a set of low energy stress-responsive transcription factor genes. These results uncover the chromatin mechanism of SnRK1-regulated gene expression in both energy-sufficient and -limited states in plants and suggest that JMJ705 functions as an upstream regulator of the SnRK1α-controlled transcriptional network.

Therapeutic potential of Pien Tze Huang in colitis-associated colorectal cancer: mechanistic insights from a mouse model.

BACKGROUND: Pien Tze Huang (PZH), a traditional Chinese medicine formulation, is recognized for its therapeutic effect on colitis and colorectal cancer. However, its protective role and underlying mechanism in colitis-associated colorectal cancer (CAC) remain to be elucidated. METHODS: A CAC mouse model was established using AOM/DSS. Twenty mice were randomly divided into four groups (n = 5/group): Control, PZH, AOM/DSS, and AOM/DSS + PZH groups. Mice in the PZH and AOM/DSS + PZH group were orally administered PZH (250 mg/kg/d) from the first day of experiment, while the control and AOM/DSS group received an equivalent volume of distilled water. Parameters such as body weight, disease activity index (DAI), colon weight, colon length, colon histomorphology, intestinal tumor formation, serum concentrations of pro-inflammatory cytokines, proliferation and apoptosis in colon tissue were assessed. RNA sequencing was employed to identify the differentially expressed transcripts (DETs) in colonic tissues and related signaling pathways. Wnt/ß-Catenin Pathway-Related genes in colon tissue were detected by QPCR and immunohistochemistry (IHC). RESULTS: PZH significantly attenuated AOM/DSS-induced weight loss, DAI elevation, colonic weight gain, colon shortening, histological damage, and intestinal tumor formation in mice. PZH also notably decreased serum concentration of IL-6, IL-1ß, and TNF-α. Furthermore, PZH inhibited cell proliferation and promote apoptosis in tumor tissues. RNA-seq and KEGG analysis revealed key pathways influenced by PZH, including Wnt/ß-catenin signaling pathway. IHC staining confirmed that PZH suppressed the expression of ß-catenin, cyclin D1 and c-Myc in colonic tissues. CONCLUSIONS: PZH ameliorates AOM/DSS-induced CAC in mice by suppressing the activation of Wnt/ß-catenin signaling pathway.

The tolerability and efficacy of antifibrotic therapy in patients with idiopathic pulmonary fibrosis: Results from a real-world study.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive and fatal lung disease lacking effective therapeutics. Treatment with pirfenidone or nintedanib is recommended for patients to delay the progression of their disease. Adverse reactions caused by anti-fibrosis drugs can sometimes interrupt treatment and even change the progression of the disease. OBJECTIVE: This study aimed to investigate the clinical use, adverse reactions, tolerability of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and the efficacy of antifibrotic therapy in a real world. METHODS: We recruited patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib at China-Japan Friendship Hospital from February 2017 to February 2022. We investigated the medication situation, adverse reactions, tolerability and survival of patients taking medications. RESULTS: A total of 303 patients with idiopathic pulmonary fibrosis were enrolled in the study. Treatment was divided between 205 patients receiving pirfenidone and 98 patients receiving nintedanib. Baseline data between the two groups were not significantly different. Patients treated with nintedanib had a higher overall discontinuation rate than those treated with pirfenidone (61.22 vs. 32.68 %, p < 0.001). Across all patient groups, the most common reason for discontinuing treatment was medication-related adverse effects. Compared to pirfenidone, nintedanib had a significantly higher discontinuation rate due to adverse events (48.98 % vs 27.80 %, p < 0.001). The most common side effect of both drugs was diarrhea. Pirfenidone was associated with a higher rate of extra-digestive adverse effects than nintedanib. Survival was not significantly different between the two drugs and using pirfenidone above 1200 mg/day did not confer significant survival benefits. The survival rate of patients who adhere to anti-fibrosis therapy for more than 6 months can be significantly improved (HR = 0.323, p = 0.0015). CONCLUSION: Gastrointestinal adverse effects were the most common adverse effects and the main reason of discontinuation of antifibrotic therapy, especially nintedanib. Consistent adherence to antifibrotic therapy may make the patients benefit from adjusting their antifibrotic medications, dosage, and active management of side effects.

Frank-Kasper phases in charge transfer complexes enable tunable photoelectronic properties.

Understanding how particles pack in space and the mechanisms underlying symmetry selection across soft matter is challenging. The Frank-Kasper (F-K) phase of complex spherical packing is amongst the most fascinating phases; however, it has not been observed in discotic liquid crystals until now. Herein, we report the first observation of F-K phases of charge transfer complexes (CTCs) obtained from triphenylene derivatives as donors and 2,4,7-trinitro-9-fluorenone as the acceptor. The CTCs were characterized using experimental and theoretical calculations, indicating that the F-K A15 cubic lattice possesses a unit cell containing 8 sphere-like supramolecules, each of which was self-assembled from 3 CTC complexes. The lattice constant was only 3.2 nm, which is by far the smallest for the A15 phase. Interestingly, the supramolecular assembly can be regarded as the molecular column splitting into isolated spherical fragments, impeding charge transfer and turning it into one insulator. This provides a simple and effective method for preparing asymmetric complex compounds for the design of unconventional self-assembled nanostructures.

Modeling Ion Transport across Thin-Film Composite Membranes During Saltwater Electrolysis.

Affordable thin-film composite (TFC) membranes are a potential alternative to more expensive ion exchange membranes in saltwater electrolyzers used for hydrogen gas production. We used a solution-friction transport model to study how the induced potential gradient controls ion transport across the polyamide (PA) active layer and support layers of TFC membranes during electrolysis. The set of parameters was simplified by assigning the same size-related partition and friction coefficients for all salt ions through the membrane active layer. The model was fit to experimental ion transport data from saltwater electrolysis with 600 mM electrolytes at a current density of 10 mA cm-2. When the electrolyte concentration and current density were increased, the transport of major charge carriers was successfully predicted by the model. Ion transport calculated using the model only minimally changed when the negative active layer charge density was varied from 0 to 600 mM, indicating active layer charge was not largely responsible for controlling ion crossover during electrolysis. Based on model simulations, a sharp pH gradient was predicted to occur within the supporting layer of the membrane. These results can help guide membrane design and operation conditions in water electrolyzers using TFC membranes.

Nanoscale Sequential Reactor Design Achieves Effective Removal of Disinfection Byproduct Precursors in Catalytic Ozonation.

Transforming dissolved organic matter (DOM) is a crucial approach to alleviating the formation of disinfection byproducts (DBPs) in water treatment. Although catalytic ozonation effectively transforms DOM, increases in DBP formation potential are often observed due to the accumulation of aldehydes, ketones, and nitro compound intermediates during DOM transformation. In this study, we propose a novel strategy for the sequential oxidation of DOM, effectively reducing the levels of accumulation of these intermediates. This is achieved through the development of a catalyst with a tailored surface and nanoconfined active sites for catalytic ozonation. The catalyst features a unique confinement structure, wherein Mn-N4 moieties are uniformly anchored on the catalyst surface and within nanopores (5-20 Å). This design enables the degradation of the large molecular weight fraction of DOM on the catalyst surface, while the transformed smaller molecular weight fraction enters the nanopores and undergoes rapid degradation due to the confinement effect. The generation of *Oad as the dominant reactive species is essential for effectively reducing these ozone refractory intermediates. This resulted in over 70% removal of carbonaceous and nitrogenous DBP precursors as well as brominated DBP precursors. This study highlights the importance of the nanoscale sequential reactor design and provides new insights into eliminating DBP precursors by the catalytic ozonation process.

Combined applications of UV and chlorine on antibiotic resistance control: A critical review.

Environmental health problems caused by antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) have become a global concern. ARB and ARGs have been continuously detected in various water environments, which pose a new challenge for water quality safety assurance. Disinfection is a key water treatment process to eliminate pathogenic microorganisms in water, and combined chlorine and UV processes (the UV/Cl2 process, the UV-Cl2 process, and the Cl2-UV process) are considered potential disinfection methods to control antibiotic resistance. This review documented the efficacy and mechanism of combined UV and chlorine processes for the control of antibiotic resistance, as well as the effects of chlorine dose, solution pH, UV wavelength, and water matrix on the effectiveness of the processes. There are knowledge gaps in research on the combined chlorine and UV processes for antibiotic resistance control, in particular the UV-Cl2 process and the Cl2-UV process. In addition, changes in the structure of microbial communities and the distribution of ARGs, which are closely related to the spread of antibiotic resistance in the water, induced by combined processes were also addressed. Whether these changes could lead to the re-transmission of antibiotic resistance and harm human health may need to be further evaluated.

Numerical Simulation and Deformation Prediction of Deep Pit Based on PSO-BP Neural Network Inversion of Soil Parameters.

The finite element numerical simulation results of deep pit deformation are greatly influenced by soil layer parameters, which are crucial in determining the accuracy of deformation prediction results. This study employs the orthogonal experimental design to determine the combinations of various soil layer parameters in deep pits. Displacement values at specific measurement points were calculated using PLAXIS 3D under these varying parameter combinations to generate training samples. The nonlinear mapping ability of the Back Propagation (BP) neural network and Particle Swarm Optimization (PSO) were used for sample global optimization. Combining these with actual onsite measurements, we inversely calculate soil layer parameter values to update the input parameters for PLAXIS 3D. This allows us to conduct dynamic deformation prediction studies throughout the entire excavation process of deep pits. The results indicate that the use of the PSO-BP neural network for inverting soil layer parameters effectively enhances the convergence speed of the BP neural network model and avoids the issue of easily falling into local optimal solutions. The use of PLAXIS 3D to simulate the excavation process of the pit accurately reflects the dynamic changes in the displacement of the retaining structure, and the numerical simulation results show good agreement with the measured values. By updating the model parameters in real-time and calculating the pile displacement under different working conditions, the absolute errors between the measured and simulated values of pile top vertical displacement and pile body maximum horizontal displacement can be effectively reduced. This suggests that inverting soil layer parameters using measured values from working conditions is a feasible method for dynamically predicting the excavation process of the pit. The research results have some reference value for the selection of soil layer parameters in similar areas.

Response to the Comment on "Is Breast Magnetic Resonance Imaging Superior to Sonography in Gynecomastia Evaluation and Surgery Planning".

The chief aim of this paper is to response to the comment on "Is breast magnetic resonance imaging superior to sonography in gynecomastia evaluation and surgery planning" and reiterate the merit of breast MRI in gynecomastia treatment for its ability to improve our understanding of the anatomical structure of gynecomastia, which, in turn, aids in refining our surgical approach. All preliminary results shed light on the objective superiority of MRI over physical examination and sonography in evaluating the tissue components of gynecomastia. However, due to the inferiority of MRI over ultrasound in terms of cost, time consumption and accessibility, there is still a significant amount of progress to be made before MRI could be widely popularized.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Static and Dynamic Filler-Associated Tear Trough Deformities: Manifestations and Treatment Algorithm.

BACKGROUND: Fillers are popular substances for the correction of tear trough deformity. Despite well-documented complications increasing gradually, standardized treatment algorithm for deformity secondary to improper injection is still limited. METHODS: Between April 2020 and April 2023, a total of 22 patients with filler-associated tear trough deformity with static bulges or dynamic swells after injection of tear trough were enrolled. For patients who received hyaluronic acid (HA) and unknown fillers, hyaluronidase dissolution was performed. For patients who received non-HA fillers and unknown fillers that failed to dissolve, a magnetic resonance imaging (MRI) examination was conducted. Surgical approaches were selected based on the filler distribution and the condition of the lower eyelid. Ligament releasement and fat transposition were accomplished when fillers were excised. Aesthetic outcomes were evaluated by double-blind examiners using the Global Aesthetic Improvement Scale after patients were followed up. RESULTS: In total, the study included 3 patients with simple static deformities, 1 patient with simple dynamic, and 18 patients with both. Fourteen patients underwent transconjunctival surgery and 8 patients underwent transcutaneous surgery, among which 18 patients underwent hyaluronidase dissolution and 8 patients underwent MRI prior to surgery. A total of 4 patients with self-limited complications recovered after conservative treatment. 90.9% of patients expressed satisfaction or high satisfaction with the treatment results. CONCLUSION: Filler-associated tear trough deformities could be classified into static and dynamic deformities, which could appear separately or simultaneously. Treatment of deformities should be based on characteristics of fillers, in which MRI could serve as a promising tool. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Simultaneous Vertical Mastopexy During Aquafilling Removal: An Effective Way to Reshape the Breast with Ptosis.

BACKGROUND: Aquafilling was used to be a popular breast filler and was banned due to increasing reports of complications. Debridement surgery is the only available approach to treat complications caused by gel fillers, but it often leads to breast deformity and skin laxity. This study aims to present a new surgical strategy to reshape the breast immediately after Aquafilling removal. METHODS: Twelve patients who underwent Aquafilling removal at our institution were included, with five patients receiving the combined vertical mastopexy in group I and seven patients receiving Aquafilling removal alone in group II. Surgical data, complications and satisfaction were compared between the two groups. Satisfaction was assessed by using the BREAST-Q at least 6 months after surgery. RESULTS: The age range of the 12 patients was 41-56 years. Although the duration of surgery in group I was longer than that in group II (p = 0.011), the drainage duration and postoperative hospitalization between the two groups were comparable. All patients recovered well. Scarring was the only complication in group I, but there was no difference compared to group II (p = 0.711). Group II had a significantly higher incidence of postoperative depression deformity than group I (p = 0.008). Regarding satisfaction, patients in group I had significantly higher scores in satisfaction with breasts, psychosocial well-being and sexual well-being than those in group II. CONCLUSION: Combining Aquafilling removal with vertical mastopexy is an effective method of reshaping the shape of the ptotic breasts, offering superior esthetic outcomes without delaying postoperative recovery or increasing the risk of complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Impact of corticosteroid doses on prognosis of severe and critical COVID-19 patients with Omicron variant infection: a propensity score matching study.

BACKGROUND: There is lack of research on corticosteroid use for severe and critical COVID-19 patients with Omicron variant infection. METHODS: This multi-center retrospective cohort study involved 1167 patients from 59 ICUs across the mainland of China diagnosed with severe or critical SARS-CoV-2 Omicron variant infection between November 1, 2022, and February 11, 2023. Patients were segregated into two groups based on their corticosteroid treatment-usual dose (equivalent prednisone dose 30-50 mg/day) and higher dose (equivalent prednisone dose > 50 mg/day). The primary outcome was 28-day ICU mortality. Propensity score matching was used to compare outcomes between cohorts. RESULTS: After propensity score matching, 520 patients in the usual dose corticosteroid group and 260 patients in the higher dose corticosteroid group were included in the analysis, respectively. The mortality was significantly higher in the higher dose corticosteroid group (67.3%, 175/260) compared to the usual dose group (56.0%, 291/520). Logistic regression showed that higher doses of corticosteroids were significantly associated with increased mortality at 28-day (OR = 1.62,95% CI 1.19-2.21, p = 0.002) and mortality in ICU stay (OR = 1.66,95% CI 1.21-2.28, p = 0.002). Different types of corticosteroids did not affect the effect. CONCLUSIONS: The study suggests that higher-dose corticosteroids may lead to a poorer prognosis for severe and critical COVID-19 patients with Omicron variant infection in the ICU. Further research is needed to determine the appropriate corticosteroid dosage for these patients.

ACBP4-WRKY70-RAP2.12 module positively regulates submergence-induced hypoxia response in Arabidopsis thaliana.

ACYL-CoA-BINDING PROTEINs (ACBPs) play crucial regulatory roles during plant response to hypoxia, but their molecular mechanisms remain poorly understood. Our study reveals that ACBP4 serves as a positive regulator of the plant hypoxia response by interacting with WRKY70, influencing its nucleocytoplasmic shuttling in Arabidopsis thaliana. Furthermore, we demonstrate the direct binding of WRKY70 to the ACBP4 promoter, resulting in its upregulation and suggesting a positive feedback loop. Additionally, we pinpointed a phosphorylation site at Ser638 of ACBP4, which enhances submergence tolerance, potentially by facilitating WRKY70's nuclear shuttling. Surprisingly, a natural variation in this phosphorylation site of ACBP4 allowed A. thaliana to adapt to humid conditions during its historical demographic expansion. We further observed that both phosphorylated ACBP4 and oleoyl-CoA can impede the interaction between ACBP4 and WRKY70, thus promoting WRKY70's nuclear translocation. Finally, we found that the overexpression of orthologous BnaC5.ACBP4 and BnaA7.WRKY70 in Brassica napus increases submergence tolerance, indicating their functional similarity across genera. In summary, our research not only sheds light on the functional significance of the ACBP4 gene in hypoxia response, but also underscores its potential utility in breeding flooding-tolerant oilseed rape varieties.

Qing Hua Chang Yin ameliorates chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and the NF-κB signalling pathway.

CONTEXT: Ulcerative colitis has been clinically treated with Qing Hua Chang Yin (QHCY), a traditional Chinese medicine formula. However, its precise mechanisms in mitigating chronic colitis are largely uncharted. OBJECTIVE: To elucidate the therapeutic efficiency of QHCY on chronic colitis and explore its underlying molecular mechanisms. MATERIALS AND METHODS: A total ion chromatogram fingerprint of QHCY was analysed. Chronic colitis was induced in male C57BL/6 mice using 2% dextran sodium sulphate (DSS) over 49 days. Mice were divided into control, DSS, DSS + QHCY (0.8, 1.6 and 3.2 g/kg/d dose, respectively) and DSS + mesalazine (0.2 g/kg/d) groups (n = 6). Mice were intragastrically administered QHCY or mesalazine for 49 days. The changes of disease activity index (DAI), colon length, colon histomorphology and serum pro-inflammatory factors in mice were observed. RNA sequencing was utilized to identify the differentially expressed transcripts (DETs) in colonic tissues and the associated signalling pathways. The expression of endoplasmic reticulum (ER) stress-related protein and NF-κB signalling pathway-related proteins in colonic tissues was detected by immunohistochemistry staining. RESULTS: Forty-seven compounds were identified in QHCY. Compared with the DSS group, QHCY significantly improved symptoms of chronic colitis like DAI increase, weight loss, colon shortening and histological damage. It notably reduced serum levels of IL-6, IL-1ß and TNF-α. QHCY suppressed the activation of PERK-ATF4-CHOP pathway of ER stress and NF-κB signalling pathways in colonic tissues. DISCUSSION AND CONCLUSIONS: The findings in this study provide novel insights into the potential of QHCY in treating chronic colitis patients.