Fusion of a rice endogenous N-methylpurine DNA glycosylase to a plant adenine base transition editor ABE8e enables A-to-K base editing in rice plants.

Engineering of a new type of plant base editor for simultaneous adenine transition and transversion within the editing window will greatly expand the scope and potential of base editing in directed evolution and crop improvement. Here, we isolated a rice endogenous hypoxanthine excision protein, N-methylpurine DNA glycosylase (OsMPG), and engineered two plant A-to-K (K = G or T) base editors, rAKBE01 and rAKBE02, for simultaneous adenine transition and transversion base editing in rice by fusing OsMPG or its mutant mOsMPG to a plant adenine transition base editor, ABE8e. We further coupled either OsMPG or mOsMPG with a transactivation factor VP64 to generate rAKBE03 and rAKBE04, respectively. Testing these four rAKBEs, at five endogenous loci in rice protoplasts, indicated that rAKBE03 and rAKBE04 enabled higher levels of A-to-G base transitions when compared to ABE8e and ABE8e-VP64. Furthermore, whereas rAKBE01 only enabled A-to-C/T editing at one endogenous locus, in comparison with rAKBE02 and rAKBE03, rAKBE04 could significantly improve the A-to-C/T base transversion efficiencies by up to 6.57- and 1.75-fold in the rice protoplasts, respectively. Moreover, although no stable lines with A-to-C transversion were induced by rAKBE01 and rAKBE04, rAKBE04 could enable simultaneous A-to-G and A-to-T transition and transversion base editing, at all the five target loci, with the efficiencies of A-to-G transition and A-to-T transversion editing ranging from 70.97 to 92.31% and 1.67 to 4.84% in rice stable lines, respectively. Together, these rAKBEs enable different portfolios of editing products and, thus, now expands the potential of base editing in diverse application scenario for crop improvement. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00138-8.

The Functional Mechanism of BP9 in Promoting B Cell Differentiation and Inducing Antigen Presentation.

The Bursa of Fabricius, an avian unique humoral immune organ, is instrumental to B cell development. Bursal-derived peptide BP9 fosters B-cell development and formation. Yet, the exact mechanism wherein BP9 impacts B cell differentiation and antigenic presentation remains undefined. In this paper, B cell activation and differentiation in the spleen cells from mice immunized with the AIV vaccine and BP9 were detected following flow cytometry (FCM) analysis. Furthermore, the molecular mechanism of BP9 in B cell differentiation in vivo was investigated with RNA sequencing technology. To verify the potential functional mechanism of BP9 in the antigenic presentation process, the transcriptome molecular basis of chicken macrophages stimulated by BP9 was measured via high-throughput sequencing technology. The results proved that when given in experimental dosages, BP9 notably accelerated total B cells, and enhanced B-cell differentiation and plasma cell production. The gene expression profiles of B cells from mice immunized with 0.01 mg/mL BP9 and AIV vaccine disclosed that 0.01 mg/mL BP9 initiated the enrichment of several biological functions and significantly stimulated key B-cell pathways in immunized mice. Crucially, a total of 4093 differentially expressed genes were identified in B cells with BP9 stimulation, including 943 upregulated genes and 3150 downregulated genes. Additionally, BP9 induced various cytokine productions in the chicken macrophage HD11 cells and activated 9 upregulated and 20 downregulated differential miRNAs, which were involved in various signal and biological processes. Furthermore, BP9 stimulated the activation of multiple transcription factors in HD11 cells, which was related to antigen presentation processes. In summary, these results suggested that BP9 might promote B cell differentiation and induce antigen presentation, which might provide the valuable insights into the mechanism of B cell differentiation upon bursal-derived immunomodulating peptide stimulation and provide a solid experimental groundwork for enhancing vaccine-induced immunity.

Unraveling the Dynamic Molecular Motions of a Twin-Cavity Cage with Slow Configurational but Rapid Conformational Interconversions.

Featuring diverse structural motions/changes, dynamic molecular systems hold promise for executing complex tasks. However, their structural complexity presents formidable challenge in elucidating their kinetics, especially when multiple structural motions are intercorrelated. We herein introduce a twin-cavity cage that features interconvertible C3- and C1-configurations, with each configuration exhibiting interchangeable P- and M-conformations. This molecule is therefore composed of four interconnected chiral species (P)-C3, (M)-C3, (P)-C1, (M)-C1. We showcase an effective approach to decouple these sophisticated structural changes into two kinetically distinct pathways. Utilizing time-dependent 1H NMR spectroscopy at various temperatures, which disregards the transition between mirror-image conformations, we first determine the rate constant (kc) for the C3- to C1-configuration interconversion, while time-dependent circular dichroism spectroscopy at different temperatures quantifies the observed rate constant (kobs) of the ensemble of all the structural changes. As kobs ≫ ${{\rm { \gg }}}$ kc, it allows us to decouple the overall molecular motions into a slow configurational transformation and rapid conformational interconversions, with the latter further dissected into two independent conformational interchanges, namely (P)-C3 ← → ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ (M)-C3 and (P)-C1 ← → ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ (M)-C1. This work, therefore, sheds light on the comprehensive kinetic study of complex molecular dynamics, offering valuable insights for the rational design of smart dynamic materials for applications of sensing, separation, catalysis, molecular machinery, etc.

Surgical treatment of distal radius fractures: impact on forearm rotation in non-elderly patients.

Forearm rotation restriction (FRR) is common after surgery for distal radius fractures (DRFs). The aim of the current study was to investigate the effect of DRFs on forearm rotation. This retrospective study reviewed patients with DRFs who underwent surgical treatment from January 2019 to December 2021. The patients' basic data and radiographic parameters were analyzed. Forearm rotation, including pronation and supination, was assessed using a standard goniometer. The Patient-Rated Wrist Evaluation (PRWE) score was evaluated, and the incidence of FRR at the 6-month follow-up was recorded. Univariate and multivariate logistic regression analyses were performed to identify risk factors correlated with FRR. A total of 127 patients with DRFs were included in this study. After surgery, 46 cases were considered to have FRR, with a rate of 36.2%, while the remaining 81 cases (63.8%) did not have FRR. The PRWE scores were 22.8 ± 5.2 and 17.9 ± 4.2 in the FRR group and non-FRR group, respectively, and the difference was statistically significant (P < 0.05). Multivariate analysis showed that the involvement of the sigmoid notch (OR, 2.88; 95% CI 1.49-5.56), post-operative volar tilt < 0° (OR, 2.16; 95% CI 1.34-3.50), and post-operative ulnar variance > 0 mm (OR, 1.37; 95% CI 1.06-1.78) were independently associated with the incidence of FRR. The FRR is associated with an increased PRWE score and may have had some impact on the patient's daily life. Fractures involving the sigmoid notch, dorsal angulation, and radial shortening deformity were found to be correlated with the incidence of FRR. Preoperative risk notification and intraoperative preventive measures are necessary for these patients.

Protocol for photocatalytic upcycling of non-biodegradable plastics into platform chemicals at ambient conditions.

Upcycling plastics presents an opportunity not only to reduce plastic waste, but also to provide an alternative carbon source to fossil fuels. Herein, we present a protocol to upcycle plastics with resin codes 2-7 using a commercially available base-metal photocatalyst. We first conducted batch reactions, followed by a continuous, segmented flow system for gram-scale upcycling into value-added platform chemicals. This protocol, employing tandem carbon-hydrogen bond oxidation/carbon-carbon bond cleavage reactions, can be useful for photocatalytically transforming plastics at ambient conditions. For complete details on the use and execution of this protocol, please refer to Li et al. (2023).1.

TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury.

BACKGROUND: Transient receptor potential (TRP) ankyrin 1 (TRPA1) could mediate ozone-induced lung injury. Optic Atrophy 1 (OPA1) is one of the significant mitochondrial fusion proteins. Impaired mitochondrial fusion, resulting in mitochondrial dysfunction and ferroptosis, may drive the onset and progression of lung injury. In this study, we examined whether TRPA1 mediated ozone-induced bronchial epithelial cell and lung injury by activating PI3K/Akt with the involvement of OPA1, leading to ferroptosis. METHODS: Wild-type, TRPA1-knockout (KO) mice (C57BL/6 J background) and ferrostatin-1 (Fer-1)-pretreated mice were exposed to 2.5 ppm ozone for 3 h. Human bronchial epithelial (BEAS-2B) cells were treated with 1 ppm ozone for 3 h in the presence of TRPA1 inhibitor A967079 or TRPA1-knockdown (KD) as well as pharmacological modulators of PI3K/Akt-OPA1-ferroptosis. Transcriptome was used to screen and decipher the differential gene expressions and pathways. Oxidative stress, inflammation and ferroptosis were measured together with mitochondrial morphology, function and dynamics. RESULTS: Acute ozone exposure induced airway inflammation and airway hyperresponsiveness (AHR), reduced mitochondrial fusion, and enhanced ferroptosis in mice. Similarly, acute ozone exposure induced inflammatory responses, altered redox responses, abnormal mitochondrial structure and function, reduced mitochondrial fusion and enhanced ferroptosis in BEAS-2B cells. There were increased mitochondrial fusion, reduced inflammatory responses, decreased redox responses and ferroptosis in ozone-exposed TRPA1-KO mice and Fer-1-pretreated ozone-exposed mice. A967079 and TRPA1-KD enhanced OPA1 and prevented ferroptosis through the PI3K/Akt pathway in BEAS-2B cells. These in vitro results were further confirmed in pharmacological modulator experiments. CONCLUSION: Exposure to ozone induces mitochondrial dysfunction in human bronchial epithelial cells and mouse lungs by activating TRPA1, which results in ferroptosis mediated via a PI3K/Akt/OPA1 axis. This supports a potential role of TRPA1 blockade in preventing the deleterious effects of ozone.

A donor-acceptor cage for circularly polarized TADF emission.

Herein, we report the first example of chiral donor-acceptor cage DA-2 displaying efficient circularly polarized thermally activated delayed fluorescence (CP-TADF) with |glum| values up to 2.1 × 10-3 and PLQY of 32%. A small ΔEST of 0.051 eV and quasi-parallel (θ = 6°) transition electric and magnetic dipole moments were realized from the through-space charge transfer interaction between the parallelly aligned donor and acceptor in DA-2. This D-A cage configuration has provided a novel design strategy for discovering potential efficient CP-TADF emitters.

Effectiveness of Acupoint Application in Patients with Pharyngeal Pain: Evidence from CHUNBO, A Prospective Real-World Study.

OBJECTIVE: To assess the outcomes after acupoint application in patients with pharyngeal pain in a real-world settings, and analyze the characteristics of effective population and prescription characteristics of acupoint application. METHODS: Based on CHUNBO platform, patients with pharyngeal pain who were candidates for acupoint application on the basis of physician-evaluation, were enrolled in a nationwide, prospective, 69-week multicenter observational study from August 2020 to February 2022. Propensity score matching (PSM) was used to match the confounding factors and the association rules were used to analyze the characteristics of effective population and prescription characteristics of acupoint application. Outcome assessments included the disappearance rate of pharyngeal pain (within 3, 7, and 14 days), disappearance time of pharyngeal pain, as well as adverse events. RESULTS: Of 7,699 enrolled participants, 6,693 (86.9%) received acupoint application and 1,450 (21.7%) with non-acupoint application. After PSM, there were 1,004 patients each in the application group (AG) and non-application group (NAG). The disappearance rate of pharyngeal pain in the AG at 3, 7, and 14 days were all higher than those in the NAG (P<0.05). The disappearance time of pharyngeal pain in the AG were shorter than that in the NAG (logrank P<0.001, hazard ratio=1.51, 95% confidence interval: 1.41-1.63). The median age of effective cases was 4 years, mainly 3-6 years old (40.21%). The disappearance rate of pharyngeal pain in the application group with tonsil diseases was 2.19 times higher than that in the NAG (P<0.05). The commonly used acupoints for the effective cases were Tiantu (RN 22), Shenque (RN 8) and Dazhui (DU 14). The commonly used herbs for the effective cases were Natrii sulfas, Radix et Rhizoma Rhei, and Herba Ephedrae. Among them, Natrii sulfas was applied to RN 8 most frequently (support 84.39%). A total of 1,324 (17.2%) patients experienced AEs, and mainly occurred in the AG, with significant difference in the incidence of AEs between goups (P<0.05). All AEs reported were the first grade, and the average regression days of AEs was 2.8 days. CONCLUSIONS: Acupoint application in patients with pharyngeal pain resulted in improved effective rate and shortened duration, especially children aged 3-6 years old, and those with tonsil diseases. Acupoint of RN 22, RN 8 and DU 14, Natrii sulfas, Radix et Rhizoma Rhei, and Herba Ephedrae were the most commonly used herbs in the treatment of pharyngeal pain.

Predictive factors of distal radioulnar joint instability after surgical treatment of distal radius fractures.

Distal radioulnar joint (DRUJ) instability is a common postoperative complication of distal radius fractures, seriously impacting patients' quality of life. This study investigated its possible influencing factors to determine prognosis and to guide treatment better. We retrospectively included a series of patients with distal radius fractures that underwent volar locking plate fixation. Basic patient information and imaging parameters were collected. The incidence of DRUJ instability during follow-up was recorded, and factors associated with DRUJ instability were determined using univariate analysis and multifactorial logistic regression analysis. A total of 159 patients were enrolled in this study. At 6 months of follow-up, 54 patients (34.0%) had DRUJ instability, and multivariate analysis showed coronal plane displacement (OR, 1.665; 95% CI, 1.091-2.541), fracture classification (OR, 0.679; 95% CI, 0.468-0.984) and DRUJ interval (OR, 1.960; 95% CI, 1.276-3.010) were associated with DRUJ instability after volar locking plate. DRUJ interval, coronal plane displacement, and fracture classification are associated with DRUJ instability during follow-up. Therefore, preoperative risk communication and intraoperative attention to recovering relevant imaging parameters are necessary for these patients.

Role of mitochondrial fusion proteins MFN2 and OPA1 on lung cellular senescence in chronic obstructive pulmonary disease.

BACKGROUND: Mitochondrial dysfunction and lung cellular senescence are significant features involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) stands as the primary contributing factor to COPD. This study examined mitochondrial dynamics, mitophagy and lung cellular senescence in COPD patients and investigated the effects of modulation of mitochondrial fusion [mitofusin2 (MFN2) and Optic atrophy 1 (OPA1)] on CS extract (CSE)-induced lung cellular senescence. METHODS: Senescence-associated secretory phenotype (SASP) component mRNAs (IL-1ß, IL-6, CXCL1 and CXCL8), mitochondrial morphology, mitophagy and mitochondria-related proteins (including phosphorylated-DRP1(p-DRP1), DRP1, MFF, MNF2, OPA1, PINK1, PARK2, SQSTM1/p62 and LC3b) and senescence-related proteins (including P16, H2A.X and Klotho) were measured in lung tissues or primary alveolar type II (ATII) cells of non-smokers, smokers and COPD patients. Alveolar epithelial (A549) cells were exposed to CSE with either pharmacologic inducer (leflunomide and BGP15) or genetic induction of MFN2 and OPA1 respectively. RESULTS: There were increases in mitochondrial number, and decreases in mitochondrial size and activity in lung tissues from COPD patients. SASP-related mRNAs, DRP1 phosphorylation, DRP1, MFF, PARK2, SQSTM1/p62, LC3B II/LC3B I, P16 and H2A.X protein levels were increased, while MFN2, OPA1, PINK1 and Klotho protein levels were decreased in lung tissues from COPD patients. Some similar results were identified in primary ATII cells of COPD patients. CSE induced increases in oxidative stress, SASP-related mRNAs, mitochondrial damage and dysfunction, mitophagy and cellular senescence in A549 cells, which were ameliorated by both pharmacological inducers and genetic overexpression of MFN2 and OPA1. CONCLUSIONS: Impaired mitochondrial fusion, enhanced mitophagy and lung cellular senescence are observed in the lung of COPD patients. Up-regulation of MFN2 and OPA1 attenuates oxidative stress, mitophagy and lung cellular senescence, offering potential innovative therapeutic targets for COPD therapy.

Mapping the path towards novel treatment strategies: a bibliometric analysis of Hashimoto's thyroiditis research from 1990 to 2023.

Background: Hashimoto's thyroiditis (HT), a common form of thyroid autoimmunity, is strongly associated with deteriorating clinical status and impaired quality of life. The escalating global prevalence, coupled with the complexity of disease mechanisms, necessitates a comprehensive, bibliometric analysis to elucidate the trajectory, hotspots, and future trends in HT research. Objective: This study aims to illuminate the development, hotspots, and future directions in HT research through systematic analysis of publications, institutions, authors, journals, references, and keywords. Particular emphasis is placed on novel treatment strategies for HT and its complications, highlighting the potential role of genetic profiling and immunomodulatory therapies. Methods: We retrieved 8,726 relevant documents from the Web of Science Core Collection database spanning from 1 January 1990 to 7 March 2023. Following the selection of document type, 7,624 articles were included for bibliometric analysis using CiteSpace, VOSviewer, and R software. Results: The temporal evolution of HT research is categorized into three distinct phases: exploration (1990-1999), rapid development (1999-2000), and steady growth (2000-present). Notably, the United States, China, Italy, and Japan collectively contributed over half (54.77%) of global publications. Among the top 10 research institutions, four were from Italy (4/10), followed by China (2/10) and the United States (2/10). Recent hotspots, such as the roles of gut microbiota, genetic profiling, and nutritional factors in HT management, the diagnostic dilemmas between HT and Grave's disease, as well as the challenges in managing HT complicated by papillary thyroid carcinoma and type 1 diabetes mellitus, are discussed. Conclusion: Although North America and Europe have a considerable academic impact, institutions from emerging countries like China are demonstrating promising potential in HT research. Future studies are anticipated to delve deeper into the differential diagnosis of HT and Grave's disease, the intricate relationship between gut microbiota and HT pathogenesis, clinical management of HT with papillary thyroid carcinoma or type 1 diabetes, and the beneficial effects of dietary modifications and micronutrients supplementation in HT. Furthermore, the advent of genetic profiling and advanced immunotherapies for managing HT offers promising avenues for future research.

MDA5 with Complete CARD2 Region Inhibits the Early Replication of H9N2 AIV and Enhances the Immune Response during Vaccination.

Chicken melanoma differentiation-associated gene 5 (MDA5) is a member of the RLRs family that recognizes the viral RNAs invading cells and activates downstream interferon regulatory pathways, thereby inhibiting viral replication. The caspase activation and recruitment domain (CARD) is the most important region in MDA5 protein. However, the antiviral and immune enhancement of MDA5 with the CARD region remains unclear. In this study, two truncated MDA5 genes with different CARD regions, namely MDA5-1 with CARD1 plus partial CARD2 domain and MDA5-2 with CARD1 plus complete CARD2 domain, were cloned via reverse transcription PCR and ligated into plasmid Flag-N vector to be Flag-MDA5-1 and Flag-MDA5-2 plasmids. DF-1 cells were transfected with two plasmids for 24 h and then inoculated with H9N2 virus (0.1 MOI) for 6 h to detect the levels of IFN-ß, PKR, MAVS, and viral HA, NA, and NS proteins expression. The results showed that MDA5-1 and MDA5-2 increased the expression of IFN-ß and PKR, activated the downstream molecule MAVS production, and inhibited the expression of HA, NA, and NS proteins. The knockdown of MDA5 genes confirmed that MDA5-2 had a stronger antiviral effect than that of MDA5-1. Furthermore, the recombinant proteins MDA5-1 and MDA5-2 were combined with H9N2 inactivated vaccine to immunize SPF chickens subcutaneously injected in the neck three times. The immune response of the immunized chicken was investigated. It was observed that the antibody titers and expressions of immune-related molecules from the chicken immunized with MDA5-1 and MDA5-2 group were increased, in which the inducing function of MDA5-2 groups was the highest among all immunization groups. These results suggested that the truncated MDA5 recombinant proteins with complete CARD2 region could play vital roles in antiviral and immune enhancement. This study provides important material for the further study of the immunoregulatory function and clinical applications of MDA5 protein.

Normal Workflow and Key Strategies for Data Cleaning Toward Real-World Data: Viewpoint.

With the rapid development of science, technology, and engineering, large amounts of data have been generated in many fields in the past 20 years. In the process of medical research, data are constantly generated, and large amounts of real-world data form a "data disaster." Effective data analysis and mining are based on data availability and high data quality. The premise of high data quality is the need to clean the data. Data cleaning is the process of detecting and correcting "dirty data," which is the basis of data analysis and management. Moreover, data cleaning is a common technology for improving data quality. However, the current literature on real-world research provides little guidance on how to efficiently and ethically set up and perform data cleaning. To address this issue, we proposed a data cleaning framework for real-world research, focusing on the 3 most common types of dirty data (duplicate, missing, and outlier data), and a normal workflow for data cleaning to serve as a reference for the application of such technologies in future studies. We also provided relevant suggestions for common problems in data cleaning.

Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy.

INTRODUCTION: Targeted protein degradation represents a promising therapeutic approach, while diabetic cardiomyopathy (DCM) arises as a consequence of aberrant insulin secretion and impaired glucose and lipid metabolism in the heart.. OBJECTIVES: Considering that the Toll-like receptor 9 (TLR9) signaling pathway plays a pivotal role in regulating energy metabolism, safeguarding cardiomyocytes, and influencing glucose uptake, the primary objective of this study was to investigate the impact of TLR9 on diabetic cardiomyopathy (DCM) and elucidate its underlying mechanism. METHODS: Mouse model of DCM was established using intraperitoneal injection of STZ, and mice were transfected with adeno-associated virus serotype 9-TLR9 (AAV9-TLR9) to assess the role of TLR9 in DCM. To explore the mechanism of TLR9 in regulating DCM disease progression, we conducted interactome analysis and employed multiple molecular approaches. RESULTS: Our study revealed a significant correlation between TLR9 expression and mouse DCM. TLR9 overexpression markedly mitigated cardiac dysfunction, myocardial fibrosis, oxidative stress, and apoptosis in DCM, while inflammation levels remained relatively unaffected. Mechanistically, TLR9 overexpression positively modulated mitochondrial bioenergetics and activated the AMPK-PGC1a signaling pathway. Furthermore, we identified Triad3A as an interacting protein that facilitated TLR9's proteasomal degradation through K48-linked ubiquitination. Inhibiting Triad3A expression improved cardiac function and pathological changes in DCM by enhancing TLR9 activity. CONCLUSIONS: The findings of this study highlight the critical role of TLR9 in maintaining cardiac function and mitigating pathological alterations in diabetic cardiomyopathy. Triad3A-mediated regulation of TLR9 expression and function has significant implications for understanding the pathogenesis of DCM. Targeting TLR9 and its interactions with Triad3A may hold promise for the development of novel therapeutic strategies for diabetic cardiomyopathy. Further research is warranted to fully explore the therapeutic potential of TLR9 modulation in the context of cardiovascular diseases.

Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion.

BACKGROUND: Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 µm (PM2.5) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM2.5-induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively. METHODS: Alveolar epithelial (A549) cells were treated with PM2.5 (32 µg/ml) in the presence and absence of Mdivi-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or distilled water for two consecutive days. RESULTS: PM2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM2.5-induced celluar damage in A549 cells. Mdivi-1 and BGP-15 attenuated PM2.5-induced acute lung injury in mice. CONCLUSION: Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM2.5-induced alveolar epithelial cell damage in vitro and lung injury in vivo.

Main Group Molecular Switches with Swivel Bifurcated to Trifurcated Hydrogen Bond Mode of Action.

Artificial molecular machines have captured the full attention of the scientific community since Jean-Pierre Sauvage, Fraser Stoddart, and Ben Feringa were awarded the 2016 Nobel Prize in Chemistry. The past and current developments in molecular machinery (rotaxanes, rotors, and switches) primarily rely on organic-based compounds as molecular building blocks for their assembly and future development. In contrast, the main group chemical space has not been traditionally part of the molecular machine domain. The oxidation states and valency ranges within the p-block provide a tremendous wealth of structures with various chemical properties. Such chemical diversity─when implemented in molecular machines─could become a transformative force in the field. Within this context, we have rationally designed a series of NH-bridged acyclic dimeric cyclodiphosphazane species, [(µ-NH){PE(µ-NtBu)2PE(NHtBu)}2] (E = O and S), bis-PV2N2, displaying bimodal bifurcated R21(8) and trifurcated R31(8,8) hydrogen bonding motifs. The reported species reversibly switch their topological arrangement in the presence and absence of anions. Our results underscore these species as versatile building blocks for molecular machines and switches, as well as supramolecular chemistry and crystal engineering based on cyclophosphazane frameworks.

Deep Learning Network of Amomum villosum Quality Classification and Origin Identification Based on X-ray Technology.

A machine vision system based on a convolutional neural network (CNN) was proposed to sort Amomum villosum using X-ray non-destructive testing technology in this study. The Amomum villosum fruit network (AFNet) algorithm was developed to identify the internal structure for quality classification and origin identification in this manuscript. This network model is composed of experimental features of Amomum villosum. In this study, we adopted a binary classification method twice consecutive to identify the origin and quality of Amomum villosum. The results show that the accuracy, precision, and specificity of the AFNet for quality classification were 96.33%, 96.27%, and 100.0%, respectively, achieving higher accuracy than traditional CNN under the condition of faster operation speed. In addition, the model can also achieve an accuracy of 90.60% for the identification of places of origin. The accuracy of multi-category classification performed later with the consistent network structure is lower than that of the cascaded CNNs solution. With this intelligent feature recognition model, the internal structure information of Amomum villosum can be determined based on X-ray technology. Its application will play a positive role to improve industrial production efficiency.

PCSK6 attenuates cardiac dysfunction in doxorubicin-induced cardiotoxicity by regulating autophagy.

Doxorubicin (DOX) is a chemotherapeutic drug widely used in the field of cancer, but its side effects on the heart hinder its clinical application. In cardiac injury caused by DOX, apoptosis and oxidative stress are both involved in cardiac damage, and autophagy is also one of the key responses. Both apoptosis and oxidative stress interact with autophagy. Proper promotion of autophagy effectively protects the myocardium and blocks cardiac injury. DOX mainly acts downstream of the autophagic flow and hinders the degradation process of autophagolysosomes, resulting in abnormal accumulation of autophagolysosomes in cells, which can prevent the timely removal of harmful substances and disrupt the normal function of cells. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is involved in the occurrence and development of various cardiovascular diseases, blood pressure regulation and the inflammatory response, but its role in DOX is still unclear. Here, we constructed cardiac PCSK6-overexpressing mice by injecting AAV9-PCSK6. Both in vivo and in vitro experiments confirmed that overexpression of PCSK6 effectively protected cardiac function, inhibited apoptosis and oxidative stress. We focused on the effect of PCSK6 overexpression on autophagy. We have detected an increase in autophagosomes production and a decrease in autophagolysosomes accumulation. This suggests that PCSK6 promotes the level of autophagy, while possibly acting on the sites where DOX inhibits degradation, so that the autophagic flux inhibited by DOX is restored and the degradation process of autophagolysosomes is restored. The effect of PCSK6 was dependent on FOXO3a, which promoted the nuclear translocation of Forkhead box O3 (FOXO3a), and Sirtuin 1 (SIRT1) regulated the expression of FOXO3a. When SIRT1 was inhibited, the protective effect of PCSK6 was diminished. In conclusion, overexpression of PCSK6 exerts a protective effect through SIRT1/FOXO3a in cardiac injury induced by DOX, suggesting that PCSK6 may be a therapeutic target for DOX cardiomyopathy.

Salidroside ameliorates pathological cardiac hypertrophy via TLR4-TAK1-dependent signaling.

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.