Association between acute exacerbation and progressive pulmonary fibrosis in interstitial lung disease: a retrospective cohort study.

BACKGROUND: Acute exacerbation (AE) refers to rapidly progressive respiratory deterioration in the clinical course of interstitial lung disease (ILD). Progressive pulmonary fibrosis (PPF) is the chronic progressive phenotype of ILD. No study has investigated the relationship between AE and PPF in ILD. OBJECTIVES: We aimed to determine the association between AE and PPF in ILD patients. DESIGN: A retrospective cohort study. METHODS: A total of 414 patients hospitalised for ILD were included in our study. The clinical presentations, radiographic features and laboratory findings of the patients were reviewed. RESULTS: AE was present in 120 (29.0%) ILD patients and was associated with a higher risk of death than non-AE patients in the whole cohort (HR 2.893; 95% CI, 1.847-4.529; p < 0.001). However, the significant difference disappeared when stratified by PPF (HR 1.192; 95% CI, 0.633-2.247; p = 0.586) and non-PPF (HR 1.113; 95% CI, 0.384-3.223; p = 0.844). In addition, the adverse effect of PPF on prognosis remained consistent in both AE and non-AE patients. Multivariable logistic regression analysis showed that compared with non-PPF patients, only age was a risk factor for PPF in AE-ILD, while the risk factors for PPF in the non-AE group were age, definite usual interstitial pneumonia and mediastinal lymph node enlargement. CONCLUSION: In the context of ILD, both AE and PPF were found to be associated with poor prognosis. However, the adverse effect of AE on prognosis disappeared when PPF was considered as a stratification feature, whereas the adverse effect of PPF on prognosis persisted in both AE and non-AE individuals. Therefore, it is important to investigate effective strategies to prevent disease progression after AE. Increased recognition and attention to PPF and early antifibrotic therapy at the appropriate time is also warranted.

Association between acute exacerbation and progressive pulmonary fibrosis in interstitial lung diseaseWhy was the study done? Acute exacerbation (AE) is an acute respiratory worsening of interstitial lung disease (ILD). Progressive pulmonary fibrosis (PPF) is a chronic progressive-fibrosing form of ILD. The relationship between AE and PPF in ILD remained unclear. We aimed to determine the association between AE and PPF in ILD patients.What did the researchers do? The researchers studied 414 patients with ILD to see how AE and PPF affect the outcome of ILD and explored the risk factors for PPF in ILD.What did the researchers find? AE was present in 120 (29.0%) ILD patients and was associated with higher risk of death than non-AE patients in the whole cohort. However, the significant difference disappeared when stratified by PPF and non-PPF. In addition, the adverse effect of PPF on prognosis remained consistent in both AE and non-AE patients. In AE-ILD patients, age was the only risk factor for PPF. In the non-AE group, age, definite usual interstitial pneumonia and mediastinal lymph node enlargement were risk factors for PPF.What do the findings mean? The findings suggest that it is important to investigate effective strategies to prevent disease progression after AE. Increased recognition and attention to PPF and early antifibrotic therapy at the appropriate time is also necessary.

A shifted ratio spectrum strategy for effective subtraction of fluorescence interference in Raman spectra.

Raman spectroscopy is an important technique for analyzing the chemical composition of samples in many fields. A severe challenge often encountered in Raman measurements is the presence of a concurrent fluorescence background, especially in biological samples. In order to obtain accurate Raman spectra, the fluorescence background must be subtracted from the original Raman spectra. We proposed a shifted ratio spectrum method to subtract the strong fluorescence background from the original Raman spectrum. First, the original Raman spectrum is divided into multiple regions according to the spectral shape of the shifted ratio spectra, and then, Gaussian fitting is performed in each region. The fitting results are stitched together in order to obtain the complete fluorescence background. Finally, this fluorescence background is subtracted from the original spectrum to obtain a pure Raman spectrum. This method can accurately subtract the fluorescence background of Rhodamine 6G (R6G)/ethanol solution and serum. This highlights the great potential of this method for applications in both biological and non-biological samples.

Dendrimer nanoclusters loaded with gold nanoparticles for enhanced tumor CT imaging and chemotherapy via an amplified EPR effect.

The design of efficient multifunctional nanomedicines to overcome adverse side effects within biological systems and to achieve desirable computed tomography (CT) imaging and therapeutics of tumors remains challenging. Herein, we report the design of multifunctional nanoclusters (NCs) based on generation 3 (G3) poly(amidoamine) (PAMAM) dendrimers. In brief, G3 dendrimers were crosslinked with 4,4'-dithiodibutryic acid (DA) to generate disulfide-bond-containing dendrimer nanoclusters (DNCs), functionalized with 1,3-propane sultone (1,3-PS) to be zwitterionic, in situ loaded with gold nanoparticles (Au NPs), and finally encapsulated with the drug doxorubicin (DOX). The designed DOX/Au@DNCs-PS possess a favorable colloidal stability with a hydrodynamic size of 249.4 nm, a redox-responsive drug release profile, and enhanced cellular uptake in vitro. We show that DOX/Au@DNCs-PS have a greater DOX penetration and growth inhibition of three-dimensional (3D) tumor spheroids than the single dendrimer counterpart in vitro. Furthermore, the developed Au@DNCs-PS enable a better Au-mediated X-ray attenuation property than the single dendrimer counterpart material. Likely due to the amplified enhanced permeability and retention (EPR) effect, the created Au@DNCs-PS and DOX/Au@DNCs-PS enable better CT imaging and chemotherapeutic effect of a mouse breast tumor model, respectively, than the single dendrimer counterparts. With its proven biocompatibility, the constructed formulation may hold promising potential for development for different cancer nanomedicine applications.

Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration.

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

Inosine reverses multidrug resistance in Gram-negative bacteria carrying mobilized RND-type efflux pump gene cluster tmexCD-toprJ.

Antimicrobial resistance is rapidly increasing worldwide, highlighting the urgent need for pharmaceutical and nonpharmaceutical interventions to tackle different-to-treat bacterial infections. Tigecycline, a semi-synthesis glycylcycline for parenteral administration, is widely recognized as one of the few effective therapies available against pan-drug resistant Gram-negative pathogens. Regrettably, the efficacy of multiple drugs, including tigecycline, is currently being undermined due to the emergence of a recently discovered mobilized resistance-nodulation-division-type efflux pump gene cluster tmexCD1-toprJ1. Herein, by employing untargeted metabolomic approaches, we reveal that the expression of tmexCD1-toprJ1 disrupts bacterial purine metabolism, with inosine being identified as a crucial biomarker. Notably, the supplementation of inosine effectively reverses tigecycline resistance in tmexCD1-toprJ1-positive bacteria. Mechanistically, exogenous inosine enhanced bacterial proton motive force, which promotes the uptake of tigecycline. Furthermore, inosine enhances succinate biosynthesis by stimulating the tricarboxylic acid cycle. Succinate interacts with the two-component system EnvZ/OmpR and upregulates OmpK 36, thereby promoting the influx of tigecycline. These actions collectively lead to the increased intracellular accumulation of tigecycline. Overall, our study offers a distinct combinational strategy to manage infections caused by tmexCD-toprJ-positive bacteria. IMPORTANCE: TMexCD1-TOprJ1, a mobilized resistance-nodulation-division-type efflux pump, confers phenotypic resistance to multiple classes of antibiotics. Nowadays, tmexCD-toprJ has disseminated among diverse species of clinical pathogens, exacerbating the need for novel anti-infective strategies. In this study, we report that tmexCD1-toprJ1-negative and -positive bacteria exhibit significantly different metabolic flux and characteristics, especially in purine metabolism. Intriguingly, the addition of inosine, a purine metabolite, effectively restores the antibacterial activity of tigecycline by promoting antibiotic uptake. Our findings highlight the correlation between bacterial mechanism and antibiotic resistance, and offer a distinct approach to overcome tmexCD-toprJ-mediated multidrug resistance.

A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation.

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

Protective effects of Gumibao recipe on glucocorticoid-included bone microcirculatory endothelial cell injury and the underlying mechanism.

OBJECTIVE: To investigate the protective effects of Gumibao recipe on glucocorticoid-included bone microcirculatory endothelial cell (BMEC) injury, and elucidate the possible underlying mechanism. METHODS: BMECs were treated with different concentrations of hydrocortisone at different time points, and the viability as well as migration of BMECs were evaluated; furthermore, the release of LDH, levels of VEGF, PAI-1, t-PA, and the content of NO by BMECs have been evaluated by commercially available kits; moreover, the expressions of eNOS, p-PI3K, p-Akt and p-mTOR in BMECs were examined by WB methods. Next, hydrocortisone treated BMECs were co-treated with Gumibao recipe, and the viability, migration and autophagy of BMECs were evaluated. RESULTS: 0.2 mg/ml and 0.3 mg/ml hydrocortisone significantly decreased viability and migration ability of BMECs, and also impeded the endothelial function of BMECs by decreasing the levels of VEGF, t-PA, the content of NO, and increasing the level of PAI-1. Gumibao medicated serum markedly increased the viability and migration of BMECs, and also increased the levels of VEGF, t-PA, the content of NO, meanwhile decreased the level of PAI-1 in 0.3 mg/ml hydrocortisone treated BMECs; moreover, glucocorticoids inhibited the autophagy of BMECs, and Gumibao recipe significantly increased the autophagy of BMECs; meanwhile, autophagy inhibitor 3-MA partially blocked the protective effects of Gumibao recipe. Finally, gumibao recipe partially abrogated the inhibitory effects of hydrocortisone on the activation of PI3K/Akt/mTOR singling, and these effects were further counteracted by PI3K and mTOR inhibitor NVP-BEZ235. CONCLUSIONS: We reported for the first time the protective effects of Gumibao recipe on glucocorticoid-included BMECs injury, and the possible underlying mechanism may be regulating the autophagy of BMECs via PI3K/AKT/mTOR signaling pathway.

Preoperative HIFU ablation combined with femoral bone marrow nailing for the treatment of pathological fracture of femur: a case report.

Introduction and importance: Bone is one of the common sites of metastasis in lung cancer. Pathological fractures of the femur significantly reduce patients' quality of life and increase the risk of death. However, there is still no consensus on the optimal treatment of pathological femoral fractures. The authors' report provides a treatment method for a patient with pathological fracture of lung cancer with preoperative HIFU lesion ablation followed by combined intramedullary nail fixation. Case presentation: A 61-year-old Chinese woman was hospitalized with severe pain in her right thigh. X-ray and CT examination at admission considered pathological fracture of the right femur. MRI showed a comminuted fracture of the middle and lower part of the right femur, swelling of the surrounding soft tissue, and effusion. WBS showed an abnormal concentration of imaging agent at the right femoral fracture end and abnormal bone metabolism. After a lung biopsy, it was diagnosed as lung cancer with femoral metastasis and pathological fracture. Clinical discussion: The patient underwent HIFU ablation before surgery to reduce the lesion, and a re-examination MRI showed that the signal at the lesion was significantly reduced, and the lesion volume was significantly reduced. The operation was performed by open reduction and intramedullary nail fixation, focal excision, and bone cement filling. After 6 months of follow-up, the patient's bone metastasis was not aggravated, and there was no loosening or fracture of the right femoral intramedullary nail. Conclusion: This is a case of pathological fracture of the femur caused by bone metastases from pulmonary cancer. The patient used HIFU to reduce the lesion before the operation and combined it with intramedullary nail internal fixation to treat the pathological fracture. A satisfactory therapeutic effect was obtained. The authors believe that this is a safe and effective treatment. This case may be beneficial to the treatment of pathological fracture of bone metastasis of lung cancer.

Exposure to bisphenol compounds accelerates the conjugative transfer of antibiotic resistance plasmid.

Antimicrobial resistance poses the most formidable challenge to public health, with plasmid-mediated horizontal gene transfer playing a pivotal role in its global spread. Bisphenol compounds (BPs), a group of environmental contaminants with endocrine-disrupting properties, are extensively used in various plastic products and can be transmitted to food. However, the impact of BPs on the plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) has not yet been elucidated. Herein, we demonstrate that BPs could promote the conjugative transfer frequency of RP4-7 and clinically multidrug-resistant plasmids. Furthermore, the promoting effect of BPs on the plasmid transfer was also confirmed in a murine model. Microbial diversity analysis of transconjugants indicated an increase in α diversity in the BPAF-treated group, along with the declined richness of some beneficial bacteria and elevated richness of Faecalibaculum rodentium, which might serve as an intermediate repository for resistance plasmids. The underlying mechanisms driving the enhanced conjugative transfer upon BPAF treatment include exacerbated oxidative stress, disrupted membrane homeostasis, augmented energy metabolism, and the increased expression of conjugation-related genes. Collectively, our findings highlight the potential risk associated with the exacerbated dissemination of AMR both in vitro and in vivo caused by BPs exposure.

Global patterns and controlling factors of tree bark C : N : P stoichiometry in forest ecosystems consistent with biogeochemical niche hypothesis.

Bark serves crucial roles in safeguarding trees physically and chemically, while also contributing to nutrient cycling and carbon sequestration. Despite its importance, the broader biogeographical patterns and the potential factors influencing bark C : N : P stoichiometry in forest ecosystems remain largely unknown. In this study, we compiled a comprehensive dataset comprising carbon (C), nitrogen (N), and phosphorus (P) concentrations in bark with 1240 records from 550 diverse forest sites to systematically analyze the large-scale patterns and the factors controlling bark C : N : P stoichiometry. The geometric means of bark C, N, and P concentrations were found to be 493.17 ± 1.75, 3.91 ± 0.09, and 0.2 ± 0.01 mg g-1, respectively. Correspondingly, the C : N, C : P, and N : P mass ratios were 135.51 ± 8.11, 3313.19 ± 210.16, and 19.16 ± 0.6, respectively. Bark C : N : P stoichiometry exhibited conspicuous latitudinal trends, with the exception of N : P ratios. These patterns were primarily shaped by the significant impacts of climate, soil conditions, and plant functional groups. However, the impact of evolutionary history in shaping bark C : N : P stoichiometry outweigh climate, soil, and plant functional group, aligning with the biogeochemical niche (BN) hypothesis. These finding enhance our understanding of the spatial distribution of bark nutrient stoichiometry and have important implications for modeling of global forest ecosystem nutrient cycles in a changing environment.

Allocation of nitrogen and phosphorus in the leaves, stems, and roots of Artemisia: a case study in phylogenetic control.

Introduction: The allocation of nitrogen (N) and phosphorus (P) among plant organs is an important strategy affecting growth and development as well as ecological processes in terrestrial ecosystems. However, due to lack of systematic investigation data, the allocation strategies of N and P in the three primary plant organs (e.g., leaves, stems and roots) are still unclear. Methods: A total of 912 individuals of 62 Artemisia species were examined across a broad environmental expanse in China, and the N and P concentrations of leaves, stems and roots were measured to explore the allocation strategies in different subgenera, ecosystem types, and local sites. Results and discussion: Across all 62 species, the N vs. P scaling exponents for leaves, stems and roots were 0.67, 0.59 and 0.67, respectively. However, these numerical values differed among subgenera, ecosystem types, and local sites. Overall, the numerical values of N vs. P scaling exponents comply with a 2/3-power function for each Artemisia organ-type reflecting a phylogenetically conserved allocation strategy that has nevertheless diversified with respect to local environmental conditions. These results inform our understanding of N and P stoichiometric patterns and responses to abiotic factors in an ecologically broadly distributed angiosperm genus.

NRF2 inhibitors: Recent progress, future design and therapeutic potential.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor involved in oxidative stress response, which controls the expression of various cytoprotective genes. Recent research has indicated that constitutively activated NRF2 can enhance patients' resistance to chemotherapy drugs, resulting in unfavorable prognosis. Therefore, the development of NRF2 inhibitors has emerged as a promising approach for overcoming drug resistance in cancer treatment. However, there are limited reports and reviews focusing on NRF2 inhibitors. This review aims to provide a comprehensive analysis of the structure and regulation of the NRF2 signaling pathway, followed by a comprehensive review of reported NRF2 inhibitors. Moreover, the current design strategies and future prospects of NRF2 inhibitors will be discussed, aiming to establish a foundation for the development of more effective NRF2 inhibitors.

Sustainable chitin-derived elastomers via grafting strategy with tunable mechanical and adhesion properties.

With increasing environmental awareness and the pursuit of sustainable development goals, environmentally friendly sustainable thermoplastic elastomers (TPEs) derived from natural resources are highly desired to replace traditional TPEs. However, preparing sustainable TPEs with high mechanical properties and multifunctionality from biobased feedstocks remains a significant challenge. In this work, a series of chitin-graft-poly(acrylamide-co-2-ethylhexyl acrylate) (Chitin-g-P(AM-co-EHA)) copolymers were synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. The tensile strength of Chitin-g-P(AM-co-EHA) copolymers can be tuned over a wide range from 1.0 to 7.3 MPa by adjusting the chitin and PAM contents. Benefiting from the brush-like architecture, Chitin-g-P(AM-co-EHA) copolymer exhibits improved mechanical properties over its linear counterparts. Moreover, these Chitin-g-P(AM-co-EHA) copolymers show good adhesion performance on different substrates. The shear strength can achieve 7.5 MPa for Chitin0.8-PAM50, which is high enough for commercial applications. The combination of chitin and grafting strategy can promote the development of strong chitin-based sustainable elastomers. This approach can be further utilized to design novel high-performance biobased elastomers and adhesives derived from natural resources.

Conventional versus high-voltage, long-term pulse Radiofrequency of ganglion impar in perineal pain with advanced rectal cancer: a Randomized, double-blind controlled trial.

STUDY OBJECTIVE: Advanced rectal cancer is a common cause of perineal pain and research on the use of radiofrequency therapy for the treatment of this pain is limited. In the present study, we aimed to compare the effectiveness and safety of conventional radiofrequency (CRF) and high-voltage long-term pulsed radiofrequency (H-PRF) of radiofrequency therapy in the management of perineal pain in advanced rectal cancer. DESIGN: Randomized, Double-Blind Controlled Trial. SETTING: Sichuan Cancer Hospital & Institute and Yanjiang District People's Hospital in Sichuan, China. PARTICIPANTS: A total of 72 patients with advanced rectal cancer experiencing perineal pain who were accepted for radiofrequency treatment. INTERVENTIONS: Patients were assigned randomly (1:1) assigned to either the group CRF or H-PRF in a double-blind trial. MEASUREMENTS AND MAIN RESULTS: The primary focus was on assessing perineal pain using numeric rating scales (NRS) scores at various time points. Secondary outcomes included the duration of maintaining a sitting position, depression scores, sleep quality, consumption of Oral Morphine Equivalent and Pregabalin, and the incidence of perineal numbness. A total of 57 patients (28 patients in the group CRF and 29 patients in the group H-PRF) were investigated. At all observation time points postoperatively, both groups of patients exhibited significant reductions in pain, enhancements in depression, improvements in sleep quality, and increased duration of sitting compared to their baseline measurements (P<0.05). During the 3 months and 6 months follow-up period, the group CRF exhibited significant reduction in pain, improvement in depression, sleep quality, and increased the time of keeping a sitting position compared with the group H-PRF (P<0.05). The consumption of oral morphine equivalent and Pregabalin as well as the incidence of perineal numbness were not significantly different between groups (P > 0.05). CONCLUSION: Our results demonstrate that application of CRF and H-PRF in ganglion impar to reduce perineal pain and improve the quality of life of patients with advanced rectal cancer is safe and effective. However, the long-term effect of CRF is better compared with that of H-PRF. TRIAL REGISTRATION: https://www.chictr.org.cn/ (ChiCTR2200061800) on 02/07/2022. This study adheres to CONSORT guidelines.

Clarifying the Direct Generation of •OH Radicals in Photocatalytic O2 Reduction: Theoretical Prediction Combined with Experimental Validation.

This work systematically studied thermocatalytic and photocatalytic pathways of formaldehyde degradation and H-assisted O2 reduction over a Pt13/anatase-TiO2(101) composite via DFT calculations together with constrained molecular dynamics (MD) simulations. We show that photocatalytic O2 reduction on Pt/TiO2 can directly generate •OH radicals (*O2 → *OOH → •OH) via two hydrogenation steps with small barriers, and the product selectivity (*H2O2 or •OH) is decided by the relative position between catalyst Fermi level and •OH/*H2O2 redox potential (theoretical determination of 0.07 V referencing to the SHE). Such a novel reaction channel was furthermore validated at the liquid-solid interface via constrained MD simulations and experimental electron paramagnetic resonance detections, and a wide range of H resources, e.g., *HCHO, *HCO, *H (H+ + e-), can always drive the direct •OH generation. The additional portion of e--triggered •OH radicals are prone to diffuse into solution or the TiO2 surface and furthermore cooperate with the conventional h+-driven photooxidations.

The Food Additive Benzaldehyde Confers a Broad Antibiotic Tolerance by Modulating Bacterial Metabolism and Inhibiting the Formation of Bacterial Flagella.

The rise of antibiotic tolerance in bacteria harboring genetic elements conferring resistance to antibiotics poses an increasing threat to public health. However, the primary factors responsible for the emergence of antibiotic tolerance and the fundamental molecular mechanisms involved remain poorly comprehended. Here, we demonstrate that the commonly utilized food additive Benzaldehyde (BZH) possesses the capacity to induce a significant level of fluoroquinolone tolerance in vitro among resistant Escherichia coli. Our findings from animal models reveal that the pre-administration of BZH results in an ineffective eradication of bacteria through ciprofloxacin treatment, leading to similar survival rates and bacterial loads as observed in the control group. These results strongly indicate that BZH elicits in vivo tolerance. Mechanistic investigations reveal several key factors: BZH inhibits the formation of bacterial flagella and releases proton motive force (PMF), which aids in expelling antibiotics from within cells to reducing their accumulation inside. In addition, BZH suppresses bacterial respiration and inhibits the production of reactive oxygen species (ROS). Moreover, exogenous pyruvate successfully reverses BZH-induced tolerance and restores the effectiveness of antibiotics, highlighting how crucial the pyruvate cycle is in combating antibiotic tolerance. The present findings elucidate the underlying mechanisms of BZH-induced tolerance and highlight potential hazards associated with the utilization of BZH.

Identification of Highly Repetitive Enhancers with Long-range Regulation Potential in Barley via STARR-seq.

Enhancers are DNA sequences that can strengthen transcription initiation. However, the global identification of plant enhancers is complicated due to uncertainty in the distance and orientation of enhancers, especially in species with large genomes. In this study, we performed self-transcribing active regulatory region sequencing (STARR-seq) for the first time to identify enhancers across the barley genome. A total of 7323 enhancers were successfully identified, and among 45 randomly selected enhancers, over 75% were effective as validated by a dual-luciferase reporter assay system in the lower epidermis of tobacco leaves. Interestingly, up to 53.5% of the barley enhancers were repetitive sequences, especially transposable elements (TEs), thus reinforcing the vital role of repetitive enhancers in gene expression. Both the common active mark H3K4me3 and repressive mark H3K27me3 were abundant among the barley STARR-seq enhancers. In addition, the functional range of barley STARR-seq enhancers seemed much broader than that of rice or maize and extended to ±100 kb of the gene body, and this finding was consistent with the high expression levels of genes in the genome. This study specifically depicts the unique features of barley enhancers and provides available barley enhancers for further utilization.

Deletion of BTB and CNC homology 1 protects against Staphylococcus aureus-induced acute lung injury.

BTB and CNC homology 1 (BACH1) plays a crucial role in the pathogenesis of acute lung injury (ALI) caused by gram-negative bacteria. However, its exact mechanisms and roles in Staphylococcus aureus (SA)-induced ALI, a gram-positive bacterial infection, remain incompletely understood. In this study, we generated a BACH1-knockout mouse model (BACH1-/-) to investigate the role of BACH1 and its underlying mechanisms in regulating the development of sepsis-induced acute lung injury (ALI). Elevated levels of BACH1 were observed in both serum samples from septic patients and mouse models. Deletion of BACH1 alleviated ALI symptoms induced by sepsis. In bone marrow-derived macrophages, BACH1 deletion or knockdown suppressed NF-κB p65 phosphorylation and the induction of pro-inflammatory cytokines. Mechanistic studies demonstrated that BACH1 downregulated tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) mRNA expression by binding to its promoter region. These findings uncover inhibiting BACH1 may be a promising therapeutic strategy for treating gram-positive bacteria-induced ALI.