Ancient Chinese Character Recognition with Improved Swin-Transformer and Flexible Data Enhancement Strategies.

The decipherment of ancient Chinese scripts, such as oracle bone and bronze inscriptions, holds immense significance for understanding ancient Chinese history, culture, and civilization. Despite substantial progress in recognizing oracle bone script, research on the overall recognition of ancient Chinese characters remains somewhat lacking. To tackle this issue, we pioneered the construction of a large-scale image dataset comprising 9233 distinct ancient Chinese characters sourced from images obtained through archaeological excavations. We propose the first model for recognizing the common ancient Chinese characters. This model consists of four stages with Linear Embedding and Swin-Transformer blocks, each supplemented by a CoT Block to enhance local feature extraction. We also advocate for an enhancement strategy, which involves two steps: firstly, conducting adaptive data enhancement on the original data, and secondly, randomly resampling the data. The experimental results, with a top-one accuracy of 87.25% and a top-five accuracy of 95.81%, demonstrate that our proposed method achieves remarkable performance. Furthermore, through the visualizing of model attention, it can be observed that the proposed model, trained on a large number of images, is able to capture the morphological characteristics of ancient Chinese characters to a certain extent.

Protein disulfide isomerase 1 is required for RodA assembling-based conidial hydrophobicity of Aspergillus fumigatus.

The hydrophobic layer of Aspergillus conidia, composed of RodA, plays a crucial role in conidia transfer and immune evasion. It self-assembles into hydrophobic rodlets through intramolecular disulfide bonds. However, the secretory process of RodA and its regulatory elements remain unknown. Since protein disulfide isomerase (PDI) is essential for the secretion of many disulfide-bonded proteins, we investigated whether PDI is also involved in RodA secretion and assembly. By gene knockout and phenotypic analysis, we found that Pdi1, one of the four PDI-related proteins of Aspergillus fumigatus, determines the hydrophobicity and integrity of the rodlet layer of the conidia. Preservation of the thioredoxin-active domain of Pdi1 was sufficient to maintain conidial hydrophobicity, suggesting that Pdi1 mediates RodA assembly through its disulfide isomerase activity. In the absence of Pdi1, the disulfide mismatch of RodA in conidia may prevent its delivery from the inner to the outer layer of the cell wall for rodlet assembly. This was demonstrated using a strain expressing a key cysteine-mutated RodA. The dormant conidia of the Pdi1-deficient strain (Δpdi) elicited an immune response, suggesting that the defective conidia surface in the absence of Pdi1 exposes internal immunogenic sources. In conclusion, Pdi1 ensures the correct folding of RodA in the inner layer of conidia, facilitating its secretion into the outer layer of the cell wall and allowing self-assembly of the hydrophobic layer. This study has identified a regulatory element for conidia rodlet assembly.IMPORTANCEAspergillus fumigatus is the major cause of invasive aspergillosis, which is mainly transmitted by the inhalation of conidia. The spread of conidia is largely dependent on their hydrophobicity, which is primarily attributed to the self-assembly of the hydrophobic protein RodA on the cell wall. However, the mechanisms underlying RodA secretion and transport to the outermost layer of the cell wall are still unclear. Our study identified a critical role for Pdi1, a fungal protein disulfide isomerase found in regulating RodA secretion and assembly. Inhibition of Pdi1 prevents the formation of correct S-S bonds in the inner RodA, creating a barrier to RodA delivery and resulting in a defective hydrophobic layer. Our findings provided insight into the formation of the conidial hydrophobic layer and suggested potential drug targets to inhibit A. fumigatus infections by limiting conidial dispersal and altering their immune inertia.

Novel aromatic moieties-modified poly(glycidyl amine)s with potent siRNA delivery and cancer treatment effect.

The development of safe and effective delivery systems is critical for the clinical applications of siRNA-based therapeutics. Polymer-based vectors have garnered significant attention owing to their structural flexibility and functional tunability. Polyethyleneimine (PEI) has been extensively studied for nucleic acid delivery; nevertheless, its high cytotoxicity has posed challenges for clinical applications. In this study, we have reported poly(glycidyl amine) (PGAm), a linear PEI analogue, demonstrating remarkable siRNA delivery efficacy and improved biocompatibility. By introducing three aromatic moieties (tyrosine, p-hydroxybenzenepropanoic acid, and phenylalanine) at varying ratios to further modify PGAms, we successfully constructed a library comprising 36 PGAm-based carriers. In vitro evaluations revealed that PGAm-based carriers exhibited significantly enhanced biocompatibility and reduced non-specific protein absorption in comparison to PEI25k. Among them, 10 modified PGAms achieved a knockdown of target gene expressions exceeding 80%, and 26 modified PGAms maintained over 70% cell viability when utilized for the in vitro delivery of siRNA to HeLa cells. Explorations into the structure-activity relationship of PGAm-based polyplex nanoparticles (NPs) indicated that the siRNA delivery efficacy of NPs depended on factors such as the molecular weight of PGAm precursors, the type of modifying moieties, and the modification ratio. Furthermore, it was demonstrated that two top-performing NPs, namely 2T100/siLuc and 2A50/siLuc, exhibited potent silencing of target genes in tumors following i.v. injection into mice bearing HeLa-Luc xenografts. The in vivo efficacy of the selected NPs was further validated by a remarkable anti-cancer effect when employed for the delivery of siRNA targeting polo-like kinase 1 (siPLK1) to mice with PC-3 xenograft tumors. The intravenous administration of NPs resulted in a substantial inhibition of tumor growth without significant toxicity. These findings demonstrate the feasibility of employing PGAm in siRNA delivery and provide valuable insights for the development of efficient siRNA carriers based on PGAm.

Percutaneous Coronary Intervention Offers Clinical Benefits to Diabetic Patients With Stable Chronic Total Occlusion.

Whether percutaneous coronary intervention for chronic total occlusion (CTO-PCI) in diabetic patients offers more benefits compared with initial medical therapy (CTO-MT) is unclear. In this study, diabetic patients with one CTO (clinical manifestations: stable angina or silent ischemia) were enrolled. Consecutively, enrolled patients (n = 1605) were assigned to different groups: CTO-PCI (1044 [65.0%]) and initial CTO-MT (561 [35%]). After a median follow-up of 44 months, CTO-PCI tended to be superior to initial CTO-MT in major adverse cardiovascular events (adjusted hazard-ratio [aHR]: .81, 95% conference-interval: .65-1.02) and significantly superior in cardiac death (aHR: .58 [.39-.87]) and all-cause death (aHR: .678[.473-.970]). Such superiority mainly attributed to a successful CTO-PCI. CTO-PCI tended to be performed in patients with younger age, good collaterals, left anterior descending branch CTO, and right coronary artery CTO. While, those with left circumflex CTO and severe clinical/angiographic situations were more likely to be assigned to initial CTO-MT. However, none of these variables influenced the benefits of CTO-PCI. Thus, we concluded that for diabetic patients with stable CTO, CTO-PCI (mainly successful CTO-PCI) offered patients survival benefits over initial CTO-MT. These benefits were consistent regardless of clinical/angiographic characteristics.

Determinants of device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic stenosis.

Background: Clinical evidence of transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve was relatively scarce. Aims: Our goal was to explore determinants of device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve morphology. Methods: In this retrospective multicenter analysis, we included 59 patients with symptomatic severe aortic stenosis with type-0 bicuspid aortic valve morphology who underwent transcatheter aortic valve replacement. Type-0 bicuspid aortic valve was identified with multidetector computed tomography scans. The technical success rate was 89.8%, and the device success rate was 81.4%. Patients were divided into a device success group and a device failure group according to Valve Academic Research Consortium- 3 criteria. Results: When we compared the two groups, we found that the ellipticity index of the aortic root and the presence of bulky calcifications at the commissure were statistically different (ellipticity index 35.7 ± 1.7 vs. 29.7 ± 1.1, p = 0.018; bulky calcification at the commissure, 54.5% vs. 4.5%, p < 0.001). Further multivariate logistic analysis showed that bulky calcification at the commissure had a negative correlation with device success (odds ratio 0.030, 95% confidence interval 0.003-0.285, p = 0.002). Yet there was no statistical correlation between the ellipticity index and device success (odds ratio 0.818, 95% confidence interval 0.667-1.003, p = 0.053). Conclusions: The presence of bulky calcifications at the commissure is negatively correlated with device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve.

Single femoral artery access is safe and feasible during transcatheter aortic valve replacement: a propensity score matched analysis.

Background: Transcatheter aortic valve replacement (TAVR) potentially may be significantly simplified by using the single artery access (SA) technique, which does not require a secondary artery access. Nevertheless, the safety and efficacy of this technique remains unclear. Our goal was to determine if single artery access TAVR (without upgrading the sheath size) is a feasible, minimally invasive procedure. Methods: Patients with symptomatic severe aortic stenosis who underwent TAVR via the femoral artery were consecutively enrolled in this study. Eligible individuals were divided into 2 groups: the SA group and the dual artery access (DA) group. The primary end point was device success (defined by the valve academic research consortium 3, VARC 3). A 6-month follow-up and propensity score matching analyses were performed. Results: After propensity score matching analysis, a total of 130 patients were included: 65 in the SA group and 65 in the DA group. The SA procedure achieved similar device success (95.4% vs. 87.7%; P = 0.115) compared with the DA procedure. The SA procedure shortened the operating time (102 min vs. 125 min; P = 0.001) but did not increase the x-ray time or dose. Both a 20 Fr and a 22 Fr sheath (without upgrading the sheath size) could be used for the SA procedure. There was no major vascular complication occurred in both groups. The incidence of minor main vascular and access complications in the SA group was comparable to those of the DA procedure (0.0% vs. 3.1%; P = 0.156). Conclusions: The SA access procedure is a promising minimally invasive TAVR technique with a low incidence of vascular complications and a high incidence of device success. It is safe and possibly applicable in all TAVR procedures.

Respiration-driven methanotrophic growth of diverse marine methanogens.

Anaerobic marine environments are the third largest producer of the greenhouse gas methane. The release to the atmosphere is prevented by anaerobic 'methanotrophic archaea (ANME) dependent on a symbiotic association with sulfate-reducing bacteria or direct reduction of metal oxides. Metagenomic analyses of ANME are consistent with a reverse methanogenesis pathway, although no wild-type isolates have been available for validation and biochemical investigation. Herein is reported the characterization of methanotrophic growth for the diverse marine methanogens Methanosarcina acetivorans C2A and Methanococcoides orientis sp. nov. Growth was dependent on reduction of either ferrihydrite or humic acids revealing a respiratory mode of energy conservation. Acetate and/or formate were end products. Reversal of the well-characterized methanogenic pathways is remarkably like the consensus pathways for uncultured ANME based on extensive metagenomic analyses.

Branched hydrophobic tails in lipid nanoparticles enhance mRNA delivery for cancer immunotherapy.

Efficient and safe delivery of vulnerable mRNA is a long-standing challenge for the broad application of the emerging mRNA-based therapeutics. Herein, a combinatorial library containing 119 novel lipids was constructed via sequential aza-Michael addition reactions of arylates and varying amines to tackle the ongoing challenge in mRNA delivery. Through in vitro screening of the lipid library on IGROV 1 cells, we identified several synthetic lipids with superior mRNA delivery efficacy. The delivery capability of these lipids was verified by the potent expression of luciferase in BALB/c mice upon intravenous administration of luciferase-encoding mRNA lipid nanoparticles (LNPs). Further investigations on the structure-activity relationship revealed that lipids with branched hydrophobic tails were better at delivering mRNA than those containing linear tails at the similar total number of carbons. In comparison to linear tails, the branched tails endowed LNPs with less inner hydrophobicity, fewer surface charges, and proper stability, which benefits the cellular uptake of LNPs and the intracellular trafficking of mRNA, thus improves the delivery efficacy of mRNA. The therapeutical potential of the lead LNPs was evaluated by delivering ovalbumin (OVA)-encoding mRNA to mice bearing B16-OVA melanoma tumors. The results demonstrated that the administration of OVA mRNA LNPs significantly activated CD8+ T cells in tumor microenvironment and substantially prohibited the growth of the aggressive B16-OVA tumors. The robust antitumor efficacy highlights the great potential of these LNPs in cancer immunotherapy.

IoT-Enabled Few-Shot Image Generation for Power Scene Defect Detection Based on Self-Attention and Global-Local Fusion.

Defect detection in power scenarios is a critical task that plays a significant role in ensuring the safety, reliability, and efficiency of power systems. The existing technology requires enhancement in its learning ability from large volumes of data to achieve ideal detection effect results. Power scene data involve privacy and security issues, and there is an imbalance in the number of samples across different defect categories, all of which will affect the performance of defect detection models. With the emergence of the Internet of Things (IoT), the integration of IoT with machine learning offers a new direction for defect detection in power equipment. Meanwhile, a generative adversarial network based on multi-view fusion and self-attention is proposed for few-shot image generation, named MVSA-GAN. The IoT devices capture real-time data from the power scene, which are then used to train the MVSA-GAN model, enabling it to generate realistic and diverse defect data. The designed self-attention encoder focuses on the relevant features of different parts of the image to capture the contextual information of the input image and improve the authenticity and coherence of the image. A multi-view feature fusion module is proposed to capture the complex structure and texture of the power scene through the selective fusion of global and local features, and improve the authenticity and diversity of generated images. Experiments show that the few-shot image generation method proposed in this paper can generate real and diverse defect data for power scene defects. The proposed method achieved FID and LPIPS scores of 67.87 and 0.179, surpassing SOTA methods, such as FIGR and DAWSON.

Cytosol Peroxiredoxin and Cell Surface Catalase Differentially Respond to H2O2 Stress in Aspergillus nidulans.

Both catalase and peroxiredoxin show high activities of H2O2 decomposition and coexist in the same organism; however, their division of labor in defense against H2O2 is unclear. We focused on the major peroxiredoxin (PrxA) and catalase (CatB) in Aspergillus nidulans at different growth stages to discriminate their antioxidant roles. The dormant conidia lacking PrxA showed sensitivity to high concentrations of H2O2 (>100 mM), revealing that PrxA is one of the important antioxidants in dormant conidia. Once the conidia began to swell and germinate, or further develop to young hyphae (9 h to old age), PrxA-deficient cells (ΔprxA) did not survive on plates containing H2O2 concentrations higher than 1 mM, indicating that PrxA is an indispensable antioxidant in the early growth stage. During these early growth stages, absence of CatB did not affect fungal resistance to either high (>1 mM) or low (<1 mM) concentrations of H2O2. In the mature hyphae stage (24 h to old age), however, CatB fulfills the major antioxidant function, especially against high doses of H2O2. PrxA is constitutively expressed throughout the lifespan, whereas CatB levels are low in the early growth stage of the cells developing from swelling conidia to early growth hyphae, providing a molecular basis for their different contributions to H2O2 resistance in different growth stages. Further enzyme activity and cellular localization analysis indicated that CatB needs to be secreted to be functionalized, and this process is confined to the growth stage of mature hyphae. Our results revealed differences in effectiveness and timelines of two primary anti-H2O2 enzymes in fungus.

Flash Nanoprecipitation Fabrication of PEI@Amorphous Calcium Carbonate Hybrid Nanoparticles for siRNA Delivery.

RNA interference (RNAi) is a promising approach for disease treatments. But the development of safe and effective delivery carriers remains a major challenge. Organic-inorganic hybrid nanoparticles (NPs), with the integration of functions from distinct materials, show great potential in small interfering RNA (siRNA) delivery. Herein, pH responsive amorphous calcium carbonate NPs (ACC NPs) are prepared using flash nanoprecipitation and hybrid NPs are constructed by coating ACC NPs with polyethyleneimine (PEI) for efficient siRNA delivery. PEI/ACC NPs show robust pH responsiveness and stability as well as effective siRNA loading and protection. Furthermore, siRNA-loaded PEI/ACC NPs demonstrate enhanced cellular uptake and efficient endosomal escape, mediating improved siRNA delivery compared to pure PEI. These findings suggest that PEI/ACC NPs may have great potential in siRNA delivery for RNAi-based therapy.

Feasibility study of temporary permanent pacemaker in patients with conduction block after TAVR.

Background: Limited data exist on the use of temporary permanent pacemaker (TPPM) to reduce unnecessary PPM in patients with high-degree atrioventricular block (HAVB) after transcatheter aortic valve replacement (TAVR). Objectives: This study aims to determine the feasibility of TPPM in patients with HAVB after TAVR to provide prolonged pacing as a bridge. Materials and methods: One hundred and eleven consecutive patients undergoing TAVR were screened from August 2021 to June 2022. Patients with HAVB eligible for PPM were included. TPPM were used in these patients instead of conventional temporary pacing or early PPM. Patients were followed up for 1 month. Holter and pacemaker interrogation were used to determine whether to implant PPM. Results: Twenty one patients met the inclusion criteria for TPPM, of which 14 patients were third-degree AVB, 1 patient was second-degree AVB, 6 patients were first degree AVB with PR interval > 240 ms and LBBB with QRS duration > 150 ms. TPPM were placed on the 21 patients for 35 ± 7 days. Among 15 patients with HAVB, 26.7% of them (n = 4) recovered to sinus rhythm; 46.7% (n = 7) recovered to sinus rhythm with bundle branch block. The remains of 26.7% patients (n = 4) still had third-degree AVB and received PPM. For patients with first-degree AVB and LBBB, PR interval shortened to < 200 ms in all 6 patients and LBBB recovered in 2 patients. TPPM were successfully removed from all patients and no procedure-related adverse events occurred. Conclusion: TPPM is reliable and safe in the small sample of patients with conduction block after TAVR to provide certain buffer time to distinguish whether a PPM is necessary. Future studies with larger sample are needed for further validation of the current results.

Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA.

The development of effective and safe delivery carriers is one of the prerequisites for the clinical translation of siRNA-based therapeutics. In this study, a library of 144 functional triblock polymers using ring-opening polymerization (ROP) and thiol-ene click reaction is constructed. These triblock polymers are composed of hydrophilic poly (ethylene oxide) (PEO), hydrophobic poly (ε-caprolactone) (PCL), and cationic amine blocks. Three effective carriers are discovered by high-throughput screening of these polymers for siRNA delivery to HeLa-Luc cells. In vitro evaluation shows that siLuc-loaded nanoparticles (NPs) fabricated with leading polymer carriers exhibit sufficient knockdown of luciferase genes and relatively low cytotoxicity. The chemical structure of polymers significantly affects the physicochemical properties of the resulting siRNA-loaded NPs, which leads to different cellular uptake of NPs and endosomal escape of loaded siRNA and thus the overall in vitro siRNA delivery efficacy. After systemic administration to mice with xenograft tumors, siRNA NPs based on P2-4.5A8 are substantially accumulated at tumor sites, suggesting that PEO and PCL blocks are beneficial for improving blood circulation and biodistribution of siRNA NPs. This functional triblock polymer platform may have great potential in the development of siRNA-based therapies for the treatment of cancers.

Improved paclitaxel delivery with PEG-b-PLA/zein nanoparticles prepared via flash nanoprecipitation.

Polymeric micelle is a promising vehicle to improve the bioavailability and clinical outcomes of paclitaxel (PTX) which has been proven effective in the treatment of a wide range of cancers. However, conventional PTX formulation with the amphiphilic PEG-b-PLA usually suffers from insufficient PTX loading, low stability of PTX-micelles, and rapid PTX release due to low compatibility between PTX and PLA, limiting its clinical application. In this study, a novel nanoparticle platform was developed to improve the stability of PTX-loaded nanoparticles (NPs) and the delivery efficacy of PTX by integrating the flash nanoprecipitation (FNP) technique and a combination of amphiphilic PEG-PLA and super hydrophobic zein. The incorporation of zein led to the formation of distinct hydrophobic interiors of NPs which enhanced the interaction between PTX and NPs, therefore improving the encapsulation efficiency of PTX and sustained drug release compared with PEG-PLA micelles without zein. In addition, FNP allowed facile fabrication of PTX-NPs with smaller sizes and higher stability. These PTX-NPs showed superior sustained release of PTX and good cancer cell-killing in vitro. Among them, PTX-5k-16k-1Z NPs exhibited excellent biosafety and anti-tumor efficacy in a xenograft tumor model in mice, suggesting great potential in the delivery of hydrophobic drugs for cancer therapy.

Microfluidic fabrication of tunable alginate-based microfibers for the stable immobilization of enzymes.

Immobilized enzymes have drawn extensive attention due to their enhanced stability, easy separation from reaction mixture, and prominent recyclability. Nevertheless, it is still an ongoing challenge to develop potent immobilization techniques which are capable of stable enzyme encapsulation, minimal loss of activity, and modulability for various enzymes and applications. These microfibers were able to efficiently encapsulate bovine serum albumin (BSA), glucose oxidase (GOx), and horseradish peroxidase (HRP). But the physically adsorbed enzymes readily diffused into the catalytic reaction system. The leakage of enzymes could be substantially inhibited by conjugating to poly(acrylic acid) (PAA) and incorporating into alginate-based microfibers, enabling stable immobilization, improved recyclability, and enhanced thermostability. In addition, GOx and HRP-loaded microfibers were fabricated under the optimized conditions for the visual detection of glucose using the cascade reaction of these enzymes, showing sensitive color change to glucose with concentration range of 0-2 mm. Due to the tunability and versatility, this microfluidic-based microfiber platform may provide a valuable approach to the enzyme immobilization for the cascade catalysis and diagnoses with multiple clinical markers.

Zwitterionic Modification of Polyethyleneimine for Efficient In Vitro siRNA Delivery.

Polyethylenimine (PEI) has been widely used in gene delivery. However, its high cytotoxicity and undesired non-specific protein adsorption hinder the overall delivery efficacy and the practical applications of PEI-based gene delivery systems. In this study, we prepared hydrophobically modified PEIs (H-PEIs) via the reaction of octanal with 40% of primary amines in PEI25k and PEI10k, respectively. Two common zwitterionic molecules, 1,3-propanesultone and ß-propiolactone, were then used for the modification of the resulting H-PEIs to construct polycationic gene carriers with zwitterionic properties (H-zPEIs). The siRNA delivery efficiency and cytotoxicity of these materials were evaluated in Hela-Luc and A549-Luc cell lines. Compared with their respective parental H-PEIs, different degrees of zwitterionic modification showed different effects in reducing cytotoxicity and delivery efficiency. All zwitterion-modified PEIs showed excellent siRNA binding capacity, reduced nonspecific protein adsorption, and enhanced stability upon nuclease degradation. It is concluded that zwitterionic molecular modification is an effective method to construct efficient vectors by preventing undesired interactions between polycationic carriers and biomacromolecules. It may offer insights into the modification of other cationic carriers of nucleic acid drugs.

Structural Exploration of Polycationic Nanoparticles for siRNA Delivery.

RNA interference (RNAi) is a promising approach to the treatment of genetic diseases by the specific knockdown of target genes. Functional polymers are potential vehicles for the effective delivery of vulnerable small interfering RNA (siRNA), which is required for the broad application of RNAi-based therapeutics. The development of methods for the facile modulation of chemical structures of polymeric carriers and an elucidation of detailed delivery mechanisms remain important areas of research. In this paper, we synthesized a series of methacrylate-based polymers with controllable structures and narrow distributions by atom transfer radical polymerization using various combinations of cationic monomers (2-dimethylaminoethyl methacrylate, 2-diethylaminoethyl methacrylate, and 2-dibutylaminoethyl methacrylate) and hydrophobic monomers (2-butyl methacrylate (BMA), cyclohexyl methacrylate, and 2-ethylhexyl methacrylate). These polymers exhibited varying hydrophobicities, charge densities, and pKa values, enabling the discovery of effective carriers for siRNA by in vitro delivery assays. For the polymers with BMA segments, 50% of cationic segments were beneficial to the formation of siRNA nanoparticles (NPs) and the in vitro delivery of siRNA. The optimal ratio varied for different combinations of cationic and hydrophobic segments. In particular, 20k PMB 0.5, PME 0.5, and PEB 1.0 showed >75% luciferase knockdown. Efficacious delivery was dependent on high siRNA binding, the small size of NPs, and balanced hydrophobicity and charge density. Cellular uptake and endosomal escape experiments indicated that carboxybetaine modification of 20k PMB 0.5 did not remarkably affect the internalization of corresponding NPs after incubation for 6 h but significantly reduced the endosomal escape of NPs, which leads to the notable decrease in delivery efficacy of polymers. These results provide insights into the mechanism of polymer-based siRNA delivery and may inspire the development of novel polymeric carriers.

Pioglitazone combined with atorvastatin promotes plaque stabilization in a rabbit model.

OBJECTIVE: It is not yet clear whether plaque inflammation and cardiovascular events are reduced further when pioglitazone and atorvastatin are combined. Our study aimed to determine whether pioglitazone combined with atorvastatin can restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model. METHOD AND RESULT: Thirty rabbits were randomly divided into an atherosclerosis group, an atorvastatin group, and an atorvastatin plus pioglitazone group. The atherosclerosis model was induced using balloon injury and feeding a high-fat diet. Plasma samples were then used to analyze glucose, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and matrix metalloproteinase-9 (MMP-9). The area percentage of atherosclerotic plaques was analyzed by hematoxylin-eosin staining. The relative reductions in TG and LDL-C and the increase in HDL-C levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (TG: -33.60 ± 7.17% vs -24.16 ± 8.04%, p < 0.001; LDL-C: -42.89 ± 1.63% vs -37.13 ± 1.35%, p < 0.001; and HDL-C: 25.18 ± 5.53% vs 10.43 ± 6.31%, p < 0.001). The relative reductions in hs-CRP and MMP-9 levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (-69.38 ± 1.06% vs-53.73 ± 1.92%, p < 0.001; -32.77 ± 2.49% vs -13.36 ± 1.66%, p < 0.001). The area percentage of atherosclerotic plaques was significantly smaller in the atorvastatin group (47.75%, p < 0.05) and in the atorvastatin plus pioglitazone group (22.57%, p < 0.05) than in the atherosclerosis group (84.08%, p < 0.05). CONCLUSION: We can thus conclude that the combination treatment of atorvastatin and pioglitazone provided additive benefits on inflammatory parameters and lipid metabolism. Pioglitazone combined with atorvastatin can further restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model.

Increasing NADPH impairs fungal H2O2 resistance by perturbing transcriptional regulation of peroxiredoxin.

NADPH provides the reducing power for decomposition of reactive oxygen species (ROS), making it an indispensable part during ROS defense. It remains uncertain, however, if living cells respond to the ROS challenge with an elevated intracellular NADPH level or a more complex NADPH-mediated manner. Herein, we employed a model fungus Aspergillus nidulans to probe this issue. A conditional expression of glucose-6-phosphate dehydrogenase (G6PD)-strain was constructed to manipulate intracellular NADPH levels. As expected, turning down the cellular NADPH concentration drastically lowered the ROS response of the strain; it was interesting to note that increasing NADPH levels also impaired fungal H2O2 resistance. Further analysis showed that excess NADPH promoted the assembly of the CCAAT-binding factor AnCF, which in turn suppressed NapA, a transcriptional activator of PrxA (the key NADPH-dependent ROS scavenger), leading to low antioxidant ability. In natural cell response to oxidative stress, we noticed that the intracellular NADPH level fluctuated "down then up" in the presence of H2O2. This might be the result of a co-action of the PrxA-dependent NADPH consumption and NADPH-dependent feedback of G6PD. The fluctuation of NADPH is well correlated to the formation of AnCF assembly and expression of NapA, thus modulating the ROS defense. Our research elucidated how A. nidulans precisely controls NADPH levels for ROS defense.