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Abstract Background Guidelines recommended remote monitoring (RM) in managing patients with Cardiac Implantable Electronic Devices. In recent years, smart device (phone or tablet) monitoring‐based RM (SM‐RM) was introduced. This study aims to systematically review SM‐RM versus bedside monitor RM (BM‐RM) using radiofrequency in terms of compliance, connectivity, and episode transmission time. Methods We conducted a systematic review, searching three international databases from inception until July 2023 for studies comparing SM‐RM (intervention group) versus BM‐RM (control group). Results Two matched studies (21 978 patients) were retrieved (SM‐RM arm: 9642 patients, BM‐RM arm: 12 336 patients). There is significantly higher compliance among SM‐RM patients compared with BM‐RM patients in both pacemaker and defibrillator patients. Manyam et al. found that more SM‐RM patients than BM‐RM patients transmitted at least once (98.1% vs. 94.3%, p

Abstract Drug-eluting stents are a commonly used treatment for coronary artery disease. However, the coatings used in drug-eluting stents have some limitations such as poor biocompatibility and drug loading capacity. In recent years, self-assembly methods have emerged as a promising alternative for stent coatings. Self-assembled coatings employ biomaterials and offer several advantages over traditional coatings, including thinner thickness, stronger binding capacity, and better biocompatibility. This review discusses the latest research on self-assembled biomaterial-based coatings for drug-eluting stents. We explore how layer-by-layer coatings and composite coating films have been utilized to load and release drugs with high drug loading capacity and biocompatibility, as well as how they promote endothelial adhesion and growth. Additionally, we examine how self-assembled coatings have been used to release active molecules for anti-coagulation and deliver gene therapy. Moreover, we discuss the potential of self-assembled coatings for future development, including intelligent targeted drug delivery, bionic stent coatings, and 3D printed stent coatings. These advancements have the potential to further improve the effectiveness of drug-eluting stents in treating coronary artery disease.

Abstract In heterogeneous catalysis catalyst activation is often observed during the reaction process, which is mostly attributed to the induction by reactants. In this work we report that surface structure of molybdenum nitride (MoN x ) catalyst exhibits a high dependency on the partial pressure or concentration of reaction products i.e., CO and H2O in reverse water gas-shift reaction (RWGS) (CO2:H2 = 1:3) but not reactants of CO2 and H2. Molybdenum oxide (MoO x ) overlayers formed by oxidation with H2O are observed at reaction pressure below 10 mbar or with low partial pressure of CO/H2O products, while CO-induced surface carbonization happens at reaction pressure above 100 mbar and with high partial pressure of CO/H2O products. The reaction products induce restructuring of MoN x surface into more active molybdenum carbide (MoC x ) to increase the reaction rate and make for higher partial pressure CO, which in turn promote further surface carbonization of MoN x . We refer to this as the positive feedback between catalytic activity and catalyst activation in RWGS, which should be widely present in heterogeneous catalysis.

Emphysema is a respiratory disease that causes the progressive loss of lung extracellular matrix (ECM) organisation, subsequently undermining lung integrity and reducing lung function. Fibroblasts must constantly repair damage to the lungs to preserve lung health, however, fibroblast ECM repair is reduced during emphysema, causing ECM damage to outweigh fibroblast ECM maintenance. Current treatments for emphysema fail to address the root causes of emphysematous progression, highlighting the need for novel methods of treating emphysema. Nitrofurantoin is a broad-spectrum antibiotic indicated for the treatment of urinary tract infections that also displays potential as a novel avenue of emphysema treatment. Nitrofurantoin is known to potentially cause fibrotic effects that could be repurposed to increase fibroblast repair and outweigh the progressive ECM damage of the emphysematous lung. Therefore, this study examined the effects of nitrofurantoin treatment on primary human lung fibroblasts derived from emphysema patients to determine if the drug holds potential as a novel treatment for emphysema. Nitrofurantoin was shown to stimulate migration and alter fibroblast morphology by increasing cell area and reducing roundness, suggesting that it could induce an ECM-repair primed phenotype in fibroblasts. Interestingly, nitrofurantoin treatment did not alter collagen-IV, perlecan, periostin or tenascin-C deposition, though fibronectin deposition was significantly upregulated at a higher dosage (20 μg/mL). This study highlighted the nitrofurantoin induced changes to fibroblast motility and morphology that facilitate ECM repair. Thus, nitrofurantoin induced pulmonary fibrosis could be caused by a change in cell phenotype that subsequently upregulates ECM repair, indicating its potential as a treatment for emphysema.

Abstract Understanding flower developmental processes is a prerequisite for improving flowering ‘plants’ production. Adonis amurensis is a fascinating spring ephemeral plant that develops its flower organs underground. Nevertheless, knowledge of the molecular mechanisms driving this particular process is scarce. Herein, we examined transcriptional changes during underground flower differentiation in A. amurensis and unveiled key differently regulated genes and pathways. High-throughput RNA sequencing of meristems at different flower developmental stages, including flower primordium (FP), sepal stage (SE), perianth primordium (PE), stamen stage (ST), and pistil stage (PI), identified 303,234 unigenes that showed 44.79% similarity with sequences in Aquilegia coerulea. Correlations, principal component, and differentially expressed genes (DEGs) analyses revealed that few molecular changes occurred during the transition from PE to ST. Many DEGs exhibited stage-specific regulations. Transcription factor (TF) and phytohormone family genes are critical regulators of the floral differentiation process in A. amurensis. The most differentially regulated TFs were MADS, FAR1, MYBs, AP2/ERF, B3, C2H2, and LOBs. We filtered out 186 candidate genes for future functional studies, including 18 flowering/circadian-related, 32 phytohormone-related, and TF family genes. Our findings deepen our understanding of the underground flower differentiation process and offer critical resources to dissect its regulatory network in A. amurensis. These findings establish a foundational platform for researchers dedicated to exploring the unique phenotypic characteristics of this specific flowering modality and delving into the intricate molecular mechanisms underpinning its regulation and expression.

Summary: Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).

ABSTRACTThe LMNA gene encoding lamin A/C is amplified in some clear cell renal cell carcinoma (ccRCC) samples. Our data showed that depletion of the tumor suppressor PBRM1 can upregulate lamin A/C levels, and lamin A/C could interact with PBRM1. However, the role of lamin A/C in ccRCC is not yet fully understood. Our functional assays showed that although the proliferation ability was slightly impaired after LMNA depletion, the migration and invasion of ccRCC cells were significantly inhibited. This suppression was accompanied by a reduction in MMP2, MMP9, AKT/p-AKT, and Wnt/β-catenin protein levels. Our data therefore suggest that lamin A/C, as an interaction partner of the tumor suppressor PBRM1, plays a crucial role in tumor invasion and metastasis in ccRCC.

Abstract Background Diabetes mellitus is one of the causes of poor ventricular remodelling and poor cardiac recovery after myocardial infarction (MI). We previously reported that tissue factor pathway inhibitor-2 (TFPI2) was downregulated in response to hyperglycaemia and that it played a pivotal role in extracellular matrix (ECM) degradation and cell migration. Nonetheless, the function and mechanism of TFPI2 in post-MI remodelling under diabetic conditions remain unclear. Therefore, in the present study, we investigated the role of TFPI2 in post-MI effects in a diabetic mouse model. Results TFPI2 expression was markedly decreased in the infarcted myocardium of diabetic MI mice compared with that in non-diabetic mice. TFPI2 knockdown in the MI mouse model promoted fibroblast activation and migration as well as matrix metalloproteinase (MMP) expression, leading to disproportionate fibrosis remodelling and poor cardiac recovery. TFPI2 silencing promoted pro-inflammatory M1 macrophage polarization, which is consistent with the results of TFPI2 downregulation and M1 polarization under diabetic conditions. In contrast, TFPI2 overexpression in diabetic MI mice protected against adverse cardiac remodelling and functional deterioration. TFPI2 overexpression also inhibited MMP2 and MMP9 expression and attenuated fibroblast activation and migration, as well as excessive collagen production, in the infarcted myocardium of diabetic mice. TFPI2 promoted an earlier phenotype transition of pro-inflammatory M1 macrophages to reparative M2 macrophages via activation of peroxisome proliferator-activated receptor gamma. Conclusions This study highlights TFPI2 as a promising therapeutic target for early resolution of post-MI inflammation and disproportionate ECM remodelling under diabetic conditions.

Cardiovascular diseases (CVDs) are multifactorial chronic diseases and have the highest rates of morbidity and mortality worldwide. The ubiquitin–proteasome system (UPS) plays a crucial role in posttranslational modification and quality control of proteins, maintaining intracellular homeostasis via degradation of misfolded, short-lived, or nonfunctional regulatory proteins. Noncoding RNAs (ncRNAs, such as microRNAs, long noncoding RNAs, circular RNAs and small interfering RNAs) serve as epigenetic factors and directly or indirectly participate in various physiological and pathological processes. NcRNAs that regulate ubiquitination or are regulated by the UPS are involved in the execution of target protein stability. The cross-linked relationship between the UPS, ncRNAs and CVDs has drawn researchers’ attention. Herein, we provide an update on recent developments and perspectives on how the crosstalk of the UPS and ncRNAs affects the pathological mechanisms of CVDs, particularly myocardial ischemia/reperfusion injury, myocardial infarction, cardiomyopathy, heart failure, atherosclerosis, hypertension, and ischemic stroke. In addition, we further envision that RNA interference or ncRNA mimics or inhibitors targeting the UPS can potentially be used as therapeutic tools and strategies.

A series of chalcone derivatives containing piperidine sulfonamide were designed and synthesized from natural chalones, and their structures were characterized on NMR and HRMS. In vitro antifungal activity test results showed that most of the target compounds exhibited good antifungal activities against a variety of fungi in vitro. X17 showed an excellent antifungal activity against S. sclerotiorum, Phomopsis sp, P. capsica with EC50 values of 10.43, 10.78, 12.02 µg/mL, respectively. It was better than those of azoxystrobin (19.34, 18.21, 63.44 µg/mL). In vivo antifungal activity test showed that X17 at the concentration of 200 µg/mL had better curative activities on rape leaves (90.8 %) than that of azoxystrobin (86.6 %). The protective activities on kiwifruits (88.3 %) were better than that of azoxystrobin (86.1 %). Mechanical studies showed that X17 inhibited the normal hypha growth by disrupting the cell membrane of S. sclerotiorum.

19 myricetin derivatives containing thiazole were designed and synthesized. Their fungicidal activities in vitro against ten species of plant pathogenic fungi were evaluated. Bioassay results indicated that some of compounds exhibited remarkable antifungal activities. Among them, Z17 showed the strongest antifungal activity against Phomopsis sp, with in vitro EC50 of 12.3 µg/mL, which was superior to those of the control drug azoxystrobin (32.2 µg/mL) and fluopyram (77.7 µg/mL). In addition, Z18 also had the inhibitory activity against the Alternaria brassicae, with an EC50 value of 32.5 µg/mL, which was much higher than azoxystrobin (49.3 µg/mL). Z17 exhibited good protective activity (62.5 %) against Phomopsis sp on kiwifruit in vivo at 200 µg/mL. The results of in vivo experiments revealed that Z18 could effectively defend against the infestation of cabbage by Alternaria brassicae, and improve the protection ability of the crop. Scanning electron microscopy (SEM) and fluorescence microscopy (FM) demonstrated that Z17 could destroy the integrity of cell membrane of pathogen Phomopsis sp, thus affecting the normal growth of mycelia. The results of the mechanism research further confirmed that the action of Z17 changed the mycelial morphology of Phomopsis sp, affected the permeability of cells, increased the leakage of cytoplasm and MDA contents. Molecular docking simulation results revealed that compound Z17 could readily bind with the active site of SDH and could be a potential SDH inhibitor. In summary, this study provides new ideas for effectively controlling plant fungal diseases and developing new green chemical pesticide products.

Promoting molten calcium–magnesium–alumina–silicate (CMAS) crystallization can highly reduce the melt penetration into thermal barrier coatings (TBCs), which alleviates its corrosion to TBCs. In marine environments, many salts are coupled with CMAS. In this study, we investigated the crystallization behavior of CMAS + NaCl/NaSO4, and pointed out its influence on the corrosion behavior of TBCs. At 1200 ℃, CMAS + NaCl was crystalized into CaMgSi2O6, CaSiO3 and CaAl2Si2O8, while the crystallization products of CMAS + NaSO4 depended on NaSO4 content, i.e., 4 wt.% and 10 wt.% NaSO4 addition leading to CaAl2Si2O8 and Ca2Al(AlSiO7) phases, respectively, in addition to CaMgSi2O6 and CaSiO3. At 1100 ℃, CMAS + NaSO4 crystalized, while CMAS + NaCl had no crystallization. At lower temperatures, both NaCl and NaSO4 additions could suppress CMAS crystallization. It reveals that CMAS coupled with molten salt is hard to crystallize, which is detrimental to corrosion protection.

In the context of resource utilization, the applications of waste biomass have attracted increasing attention.Previous studies have shown that forming biochar by heat treatment of sludge could replace the traditional sludge disposal methods, and sludge biochar is proved to be efficient in wastewater treatment. In this work, the pyrolysis, hydrothermal carbonization and microwave pyrolysis methods for preparing sludge biochar were reviewed, and the effects of different modification methods on the performance of sludge biochar in the synthesis process were comprehensively analyzed. This review also summarized the risk control of heavy metal leaching in sludge biochar, increasing the pyrolysis temperature and use of the fractional pyrolysis or co-pyrolysis were usually effectively meathods to reduce the leaching risk of heavy metal in the system, which is crucial for the wide application of sludge biochar in sewage treatment. At the same time, the adsorption mechanism of sludge biochar and the catalytic mechanism as the catalytic material in AOPs reaction, the process of radical and non-radical pathway and the possible impacts in the sludge biochar catalytic process were also analyzed in this paper

Gestational diabetes mellitus is a growing global health problem. Inadequate management during pregnancy can lead to maternal and foetal complications. Currently, mobile health (mHealth) delivers healthcare services, playing an increasingly important role in the management of blood glucose in GDM. This study aimed to systematically evaluate the effectiveness of mHealth intervention in pregnant women with GDM. Based on randomised controlled trials of mHealth application in GDM patients searched from the database, literature screening, data extraction, and quality evaluation were conducted independently by two researchers. Statistical analysis was performed using Review Manager 5.4 software. The review included 27 studies with a total of 3483 patients. The results showed a significant improvement in glycemic control. In addition, mHealth interventions could reduce the occurrence of adverse pregnancy outcomes and improve self-management ability. In a subgroup analysis, recording of delivery mode and WeChat combined phone call indicated significant differences with mHealth interventions. It was suggested that mHealth interventions imposed a positive effect on glycemic control and reduction of adverse pregnancy outcomes in GDM patients. Our results demonstrated that the application of mHealth interventions can act as an effective and feasible approach to self-management to promote the self-management level and awareness of GDM patients.

28 chalcone derivatives containing thiazole fragment were synthesized. The results of antifungal bioactivity tests suggested that most of the compounds possessed superior in vitro antifungal activities against nine plant pathogenic fungi. T17 showed excellent bioactivity against Sclerotinia sclerotiorum (S. sclerotiorum) with an EC50 value of 12.9 μg/mL, which was better than that of azoxystrobin (15.1 μg/mL). Further than that, T11 exhibited good bioactivity against Phytophthora capsici (P. capsici) with an EC50 value of 15.8 μg/mL, which was superior to that of azoxystrobin (40.2 μg/mL). The bioactivity test was carried out in oilseed rape in vivo. The protective and curative activities of T17 on oilseed rape infected with S. sclerotiorum were 86.5 and 75.2 %, respectively, which were higher than those of azoxystrobin (71.4 and 68.6 %) at 200 μg/mL. Scanning electron microscopy results indicated that the mycelium collapsed and folded after T17 treatment, which changed the mycelial morphology, inhibiting the growth of mycelium, thus achieving an inhibitory effect on S. sclerotiorum. In addition, the mechanism of action studies manifested that the results were further verified by performing in vivo antifungal activity assay, fluorescence microscopy, light microscopy, cell membrane permeability, leakage of cellular contents, and malondialdehyde content assay. This study demonstrates that compound T17 has the potential to become a novel fungicide.

Brillouin microscopy has recently emerged as a new bio-imaging modality that provides information on the microscale mechanical properties of biological materials, cells and tissues. The data collected in a typical Brillouin microscopy experiment represents the high-dimensional set of spectral information, i.e. each pixel within a 2D/3D Brillouin image is associated with hundreds of points of spectral data. Its analysis requires non-trivial approaches due to subtlety in spectral variations as well as spatial and spectral overlaps of measured features. This article offers a guide to the application of Principal Component Analysis (PCA) for processing Brillouin imaging data. Being unsupervised multivariate analysis, PCA is well-suited to tackle processing of complex Brillouin spectra from heterogeneous biological samples with minimal a priori information requirements. We point out the importance of data pre-processing steps in order to improve outcomes of PCA. We also present a strategy where PCA combined with k -means clustering method can provide a working solution to data reconstruction and deeper insights into sample composition, structure and mechanics.

Cardiac hypertrophy, a kind of cardiomyopathic abnormality, might trigger heart contractile and diastolic dysfunction, and even heart failure. Currently, bisphenols (BPs) including bisphenol A (BPA), and its alternatives bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol S (BPS) are ubiquitously applied in various products and potentially possess high cardiovascular risks for humans. However, the substantial experimental evidences of BPs on heart function, and their structure-related effects on cardiomyocyte hypertrophy are still urgently needed. DNA methylation, a typical epigenetics, play key roles in BPs-induced transcription dysregulation, thereby affecting human health including cardiovascular system. Thus, in this study, we performed RNA-seq and reduced representation bisulfite sequencing (RRBS) to profile the landscapes of BPs-induced cardiotoxicity and to determine the key roles of DNA methylation in the transcription. Further, the capabilities of three BPA analogues, together with BPA, in impacting heart function and changing DNA methylation and transcription were compared. We concluded that similar to BPA, BPAF, BPF and BPS exposure deteriorated heart function in a mouse model, and induced cardiomyocyte hypertrophy in a H9c2 cell line. BPAF, BPF and BPS all played BPA-like roles in both transcriptive and methylated hierarchies. Moreover, we validated the expression levels of four cardiomyocyte hypertrophy related candidate genes, Psmc1, Piptnm2, Maz and Dusp18, which were all upregulated and with DNA hypomethylation. The findings on the induction of BPA analogues on cardiomyocyte hypertrophy and DNA methylation revealed their potential detrimental risks in heart function of humans.

Coronavirus is a type of acute atypical respiratory disease representing the leading cause of death worldwide. Eucalyptol (EUC) known also as 1,8-cineole is a potential inhibitor candidate for COVID-19 (main protease-Mpro) with effective antiviral properties but undergoes physico-chemical instability and poor water solubility. Nano-emulsion (NE) is a promising drug delivery system to improve the stability and efficacy of drugs. This work focuses on studying the anti- COVID-19 activity of EUC by developing nebulized eucalyptol nano-emulsion (EUC-NE) as a potentially effective treatment for COVID-19. The EUC -NE formulation was prepared using Tween 80 as a surfactant. In vitro evaluation of the EUC-NE formulation displayed an entrapment efficiency of 77.49 %, a droplet size of 122.37 nm, and an EUC % release of 84.7 %. The aerodynamic characterization and cytotoxicity of EUC-NE formulation were assessed, and results showed high lung deposition and low inhibitory concentration. The antiviral mechanism of the EUC-NE formulation was performed, and it was found that it exerts its action by virucidal, viral replication, and viral adsorption. Our results confirmed the antiviral activity of the EUC-NE formulation against COVID-19 and the efficacy of nano-emulsion as a delivery system, which can improve the cytotoxicity and inhibitory activity of EUC.

Novel Ti-xNb-yCu alloys containing various Cu and Nb concentrations have been developed through heat treatment and rapid quenching. The effects of Cu and Nb content on microstructure, corrosion properties and bacterial inhibitory ability of the novel alloys have been systematically investigated with various characterisation methods. Results revealed that Ti3Cu alloy showed a typical eutectoid structure (α-Ti and Ti2Cu), Ti10Nb3Cu alloy exhibited three-phase coexistence microstructure (α+β+Ti2Cu), Ti30Nb alloy comprised of α+β phases, and Ti30Nb5Cu and Ti30Nb3Cu alloys comprised of single β phase. The corrosion behaviour of novel Ti-xNb-yCu alloys were studied in details using electrochemical measurements and immersion testing. It has been found that corrosion resistance of novel Ti-xNb-yCu alloys was improved with increasing Nb content, while the addition of Cu exhibited opposite trend on corrosion resistance. Higher Cu content (5%) in Ti30Nb alloy decreased its corrosion resistance while lower Cu content (3%) improved its corrosion resistance, probably due to the single-phase transition and less Cu-containing precipitates on the grain boundary of Ti30Nb3Cu. Besides, Cu-containing Ti alloys exhibited significantly better bacterial inhibitory properties. This study suggests that, Ti30Nb3Cu alloy with high corrosion resistance and excellent bacterial inhibitory property is promising for biomedical implant applications.

Myocardial infarction (MI) is defined as cardiomyocyte death in a clinical context consistent with ischemic insult. MI remains one of the leading causes of morbidity and mortality worldwide. Although there are a number of effective clinical methods for the diagnosis and treatment of MI, further investigation of novel biomarkers and molecular therapeutic targets is required. Circular RNAs (circRNAs), novel non-coding RNAs, have been reported to function mainly by acting as microRNA (miRNA) sponges or binding to RNA-binding proteins (RBPs). The circRNA-miRNA-mRNA (protein) regulatory pathway regulates gene expression and affects the pathological mechanisms of various diseases. Undoubtedly, a more comprehensive understanding of the relationship between MI and circRNA will lay the foundation for the development of circRNA-based diagnostic and therapeutic strategies for MI. Therefore, this review summarizes the pathophysiological process of MI and various approaches to measure circRNA levels in MI patients, tissues, and cells; highlights the significance of circRNAs in the regulation MI pathogenesis and development; and provides potential clinical insight for the diagnosis, prognosis, and treatment of MI.

Abstract Organizing pneumonia (OP) promptly responds to corticosteroids. However, a minority of patients demonstrate corticosteroid resistance or relapse on corticosteroid tapering. We describe post COVID‐19 OP patients with clinically inadequate response to corticosteroids but that improved after the addition of Mycophenolate Mofetil (MMF). Case 1: A gentleman was diagnosed with post COVID‐19 OP but had suboptimal clinico‐physiologic‐radiologic response and steroid toxicity during outpatient reviews. MMF was initiated resulting in marked clinical response and quick weaning from corticosteroids. Case 2: A gentleman with post COVID‐19 OP relapsed during tapering of steroids. Clarithromycin and MMF were added to his regimen, which improved his clinico‐physiologic parameters and allowed corticosteroid tapering. Unfortunately, he developed MMF‐related colitis needing therapy cessation. Currently, no studies have reported on MMF utilization in difficult post COVID‐19 OP patients. Nevertheless, we believe, similar as in non‐COVID OPs, MMF or other immunomodulators, potentially have a role in treating difficult or steroid‐resistant OPs.

Abstract Background Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction. Methods This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model. Results Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan–Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (

Abstract Manufacturing and resource industries are the key drivers for economic growth with a huge environmental cost (e.g. discharge of industrial effluents and post-mining substrates). Pollutants from waste streams, either organic or inorganic (e.g. heavy metals), are prone to interact with their physical environment that not only affects the ecosystem health but also the livelihood of local communities. Unlike organic pollutants, heavy metals or trace metals (e.g. chromium, mercury) are non-biodegradable, bioaccumulate through food-web interactions and are likely to have a long-term impact on ecosystem health. Microorganisms provide varied ecosystem services including climate regulation, purification of groundwater, rehabilitation of contaminated sites by detoxifying pollutants. Recent studies have highlighted the potential of methanotrophs, a group of bacteria that can use methane as a sole carbon and energy source, to transform toxic metal (loids) such as chromium, mercury and selenium. In this review, we synthesise recent advances in the role of essential metals (e.g. copper) for methanotroph activity, uptake mechanisms alongside their potential to transform toxic heavy metal (loids). Case studies are presented on chromium, selenium and mercury pollution from the tanneries, coal burning and artisanal gold mining, respectively, which are particular problems in the developing economy that we propose may be suitable for remediation by methanotrophs. Video Abstract

In this paper, a series of derivatives were synthesized by introducing the pharmacophore pyrazole ring and piperazine ring into the structure of the natural product myricetin through an amide bond. The structures were determined using carbon spectrum and hydrogen spectrum high-resolution mass spectrometry. Biological activities of those compounds against bacteria, including Xac (Xanthomonas axonopodis pv. Citri), Psa (Pseudomonas syringae pv. Actinidiae) and Xoo (Xanthomonas oryzae pv. Oryzae) were tested. Notably, D6 exhibited significant bioactivity against Xoo with an EC50 value of 18.8 μg/mL, which was higher than the control drugs thiadiazole-copper (EC50 = 52.9 μg/mL) and bismerthiazol (EC50 = 69.1 μg/mL). Furthermore, the target compounds were assessed for their antifungal activity against ten plant pathogenic fungi. Among them, D1 displayed excellent inhibitory activity against Phomopsis sp. with an EC50 value of 16.9 μg/mL, outperforming the control agents azoxystrobin (EC50 = 50.7 μg/mL) and fluopyram (EC50 = 71.8 μg/mL). In vitro tests demonstrated that D1 possessed curative (60.6%) and protective (74.9%) effects on postharvest kiwifruit. To investigate the active mechanism of D1, its impact on SDH activity was evaluated based on its structural features and further confirmed through molecular docking. Subsequently, the malondialdehyde content of D1-treated fungi was measured, revealing that D1 could increase malondialdehyde levels, thereby causing damage to the cell membrane. Additionally, the EC50 value of D16 on P. capsici was 11.3 μg/mL, which was superior to the control drug azoxystrobin (EC50 = 35.1 μg/mL), and the scanning electron microscopy results indicated that the surface of drug-treated mycelium was ruffled, and growth was significantly affected.

Development of low-cost, high-temperature-resistant and salt-resistant fracturing fluids is a hot and difficult issue in reservoir fluids modification. In this study, an organic zirconium crosslinker that was synthesized and crosslinked with partially hydrolyzed polyacrylamide (HPAM) was employed as a cost-effective polymer thickener to synthesize a high-temperature-resistant and salt-resistant fracturing fluid. The rheological properties of HPAM in tap water solutions and 2 × 104 mg/L salt solutions were analyzed. The results demonstrated that addition of salt reduced viscosity and viscoelasticity of HPAM solutions. Molecular dynamics (MD) simulation results indicated that, due to electrostatic interaction, the carboxylate ions of HPAM formed an ionic bridge with metal cations, curling the conformation, decreasing the radius of rotation and thus decreasing viscosity. However, optimizing fracturing fluids formulation can mitigate the detrimental effects of salt on HPAM. The rheological characteristics of the HPAM fracturing fluid crosslinking process were analyzed and a crosslinking rheological kinetic equation was established under small-amplitude oscillatory shear (SAOS) test. The results of a large-amplitude oscillation shear (LAOS) test indicate that the heating effect on crosslinking is stronger than the shear effect on crosslinking. High-temperature-resistant and shear-resistant experiments demonstrated good performance of fracturing fluids of tap water and salt solution at 200 °C and 180 °C.

Glaesserella (Haemophilus) parasuis, the etiological agent of Glässer’s disease, is an economically significant pathogen commonly associated with serofibrinous polyserositis, arthritis, fibrinous bronchopneumonia and/or meningitis. This study is the first attempt to molecularly characterize and provide a detailed overview of the genetic variants of G. parasuis present in Malaysia, in reference to its serotype, virulence-associated trimeric autotransporters (vtaA) gene and outer membrane protein P2 (OmpP2) gene. The G. parasuis isolates (n = 11) from clinically sick field samples collected from two major pig producing states (Selangor and Perak) were selected for analysis. Upon multiplex PCR, the majority of the isolates (eight out of 11) were identified to be serotype 5 or 12, and interestingly, serotypes 3, 8 and 15 were also detected, which had never been reported in Malaysia prior to this. Generally, virulent vtaA was detected for all isolates, except for one, which displayed a nonvirulent vtaA. A phylogenetic analysis of the OmpP2 gene revealed that the majority of Malaysian isolates were clustered into genotype 1, which could be further divided into Ia and Ib, while only one isolate was clustered into genotype 2.

Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo. Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it may be a promising therapeutic target for the treatment of proliferative vascular diseases.

Abstract Y2O3 stabilized ZrO2 (YSZ) thermal barrier coatings (TBCs) are prone to hot corrosion by molten salts. In this study, the microstructure of atmospheric plasma spraying YSZ TBCs is modified by laser glazing in order to improve the corrosion resistance. By optimizing the laser parameters, a ∼18 µm smooth glazed layer with some vertical cracks was produced on the coating surfaces. The as-sprayed and modified coatings were both exposed to hot corrosion tests at 700 and 1000 °C for 4 h in V2O5 molten salt, and the results revealed that the modified one had improved corrosion resistance. After hot corrosion, the glazed layer kept structural integrity, with little evidence of dissolution. However, the vertical cracks in the glazed layer acted as the paths for molten salt penetration, accelerating the corrosion of the non-modified coating. Further optimization of the glazed layer is needed in the future work.

A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm; FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production.

Objective The predictors of in-hospital mortality for intensive care units (ICUs)-admitted heart failure (HF) patients remain poorly characterised. We aimed to develop and validate a prediction model for all-cause in-hospital mortality among ICU-admitted HF patients.Design A retrospective cohort study.Setting and participants Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-III) database. Data on 1177 heart failure patients were analysed.Methods Patients meeting the inclusion criteria were identified from the MIMIC-III database and randomly divided into derivation (n=825, 70%) and a validation (n=352, 30%) group. Independent risk factors for in-hospital mortality were screened using the extreme gradient boosting (XGBoost) and the least absolute shrinkage and selection operator (LASSO) regression models in the derivation sample. Multivariate logistic regression analysis was used to build prediction models in derivation group, and then validated in validation cohort. Discrimination, calibration and clinical usefulness of the predicting model were assessed using the C-index, calibration plot and decision curve analysis. After pairwise comparison, the best performing model was chosen to build a nomogram according to the regression coefficients.Results Among the 1177 admissions, in-hospital mortality was 13.52%. In both groups, the XGBoost, LASSO regression and Get With the Guidelines-Heart Failure (GWTG-HF) risk score models showed acceptable discrimination. The XGBoost and LASSO regression models also showed good calibration. In pairwise comparison, the prediction effectiveness was higher with the XGBoost and LASSO regression models than with the GWTG-HF risk score model (p

Developing novel drug formulations and progressing them to the clinical environment relies on preclinical in vitro studies and animal tests to evaluate efficacy and toxicity. However, these current techniques have failed to accurately predict the clinical success of new therapies with a high degree of certainty. The main reason for this failure is that conventional in vitro tissue models lack numerous physiological characteristics of human organs, such as biomechanical forces and biofluid flow. Moreover, animal models often fail to recapitulate the physiology, anatomy, and mechanisms of disease development in human. These shortfalls often lead to failure in drug development, with substantial time and money spent. To tackle this issue, organ-on-chip technology offers realistic in vitro human organ models that mimic the physiology of tissues, including biomechanical forces, stress, strain, cellular heterogeneity, and the interaction between multiple tissues and their simultaneous responses to a therapy. For the latter, complex networks of multiple-organ models are constructed together, known as multiple-organs-on-chip. Numerous studies have demonstrated successful application of organ-on-chips for drug testing, with results comparable to clinical outcomes. This review will summarize and critically evaluate these studies, with a focus on kidney, liver, and respiratory system-on-chip models, and will discuss their progress in their application as a preclinical drug-testing platform to determine in vitro drug toxicology, metabolism, and transport. Further, the advances in the design of these models for improving preclinical drug testing as well as the opportunities for future work will be discussed.

For the past 50 years, the route of inhalation has been utilized to administer therapies to treat a variety of respiratory and pulmonary diseases. When compared with other drug administration routes, inhalation offers a targeted, non-invasive approach to deliver rapid onset of drug action to the lung, minimizing systemic drug exposure and subsequent side effects. However, despite advances in inhaled therapies, there is still a need to improve the preclinical screening and the efficacy of inhaled therapeutics. Innovative in vitro models of respiratory physiology to determine therapeutic efficacy of inhaled compounds have included the use of organoids, micro-engineered lung-on-chip systems and sophisticated bench-top platforms to enable a better understanding of pulmonary mechanisms at the molecular level, rapidly progressing inhaled therapeutic candidates to the clinic. Furthermore, the integration of complementary ex vivo models, such as precision-cut lung slices (PCLS) and isolated perfused lung platforms have further advanced preclinical drug screening approaches by providing in vivo relevance. In this review, we address the challenges and advances of in vitro models and discuss the implementation of ex vivo inhaled drug screening models. Specifically, we address the importance of understanding human in vivo pulmonary mechanisms in assessing strategies of the preclinical screening of drug efficacy, toxicity and delivery of inhaled therapeutics.

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

Background: Lifestyle involving uncontrolled alcohol consumption coupled regularly with red meat and other iron sources has detrimental effects on the liver, which in the long term, results in Alcoholic Liver Disease (ALD). Procyanidin has lately garnered increasing attention and has become the focus of research owing to its antioxidant properties. This study explores the anti-inflammatory effects of procyanidins, in preventing ALD, by analyzing the biological activities of the compound on liver injury caused by excessive alcohol and iron. Method: Male SPF Wistar rats were placed in 4 groups; the control Group A (basic diet); the model Group B (excess alcohol 8–12 mL/kg/d and iron 1000 mg/kg diet); the low dose procyanidin Group C (model group diet plus 60 mg/kg/d of procyanidin); and the high dose procyanidin Group D (model group diet plus 120 mg/kg/d of procyanidin). Serum biochemical markers for liver damage were measured spectrophotometrically. The NFκB and IκB mRNA expression levels were determined using RT-PCR; the NFκB p65 and IκB protein expression levels were assessed via western blotting, while ELISA was used to detect serum inflammatory factors. Results: The pathological score of the model Group B, low and high dose procyanidin Groups C and D were 6.58 ± 0.90,4.69 ± 0.70 and 2.00 ± 0.73, respectively (P < 0.05). The results showed that high alcohol and iron contents in the model group led to significant damage of liver structure, increased low-density lipoproteins (LDLs), steatosis, and increased levels of inflammatory cytokines. High amounts of procyanidins led to the preservation of the liver structure, production of high-density lipoproteins, and reduction in serum inflammatory cytokines while also significantly decreasing the expression levels of NFκB p65. Conclusion: The results prove that procyanidins have hepatoprotective potential and could be effective in reversing histopathology, possibly by alleviating inflammation and improving lipid metabolism.

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

To examine the mechanism of ocular axial elongation in myopia, guinea pigs (age: 2–3 weeks) which either underwent unilateral or bilateral lens-induced myopization (group 1) or which were primarily myopic at baseline (group 2) received unilateral intraocular injections of amphiregulin antibody (doses: 5, 10, or 15 μg) three times in intervals of 9 days. A third group of emmetropic guinea pigs got intraocular unilateral injections of amphiregulin (doses: 0.25, 0.50 or 1.00 ng, respectively). In each group, the contralateral eyes received intraocular injections of Ringer's solution. In intra-animal inter-eye comparison and intra-eye follow-up comparison in groups 1 and 2, the study eyes as compared to the contralateral eyes showed a dose-dependent reduction in axial elongation. In group 3, study eyes and control eyes did not differ significantly in axial elongation. Immunohistochemistry revealed amphiregulin labelling at the retinal pigment epithelium in eyes with lens-induced myopization and Ringer's solution injection, but not in eyes with amphiregulin antibody injection. Intraocular injections of amphiregulin-antibody led to a reduction of lens-induced axial myopic elongation and of the physiological eye enlargement in young guinea pigs. In contrast, intraocularly injected amphiregulin in a dose of ≤1 ng did not show a significant effect. Amphiregulin may be one of several essential molecular factors for axial elongation.

Objective: Abnormal proliferation or migration of vascular smooth muscle cells (VSMCs) can lead to vessel lesions, resulting in atherosclerosis and in stent-restenosis (IRS). The purpose of our study was to establish the role of miR-378a-5p and its targets in regulating VSMCs function and IRS.Methods: EdU assays and Cell Counting Kit-8 (CCK-8) assays were applied to evaluate VSMCs proliferation, wound healing assays and transwell assays were applied to assess cells migration. Furthermore, quantitative reverse transcription–polymerase chain reaction (qRT-PCR) was performed to investigate the expression level of miR-378a-5p IRS patients and healthy individuals. Target genes were predicted using Target Scan and miRanda software, and biological functions of candidate genes were explored through bioinformatics analysis. Moreover, RNA-binding protein immunoprecipitation (RIP) was carried out to analyze the miRNAs interactions with proteins. We also used Immunofluorescence (IF) and fluorescence microscopy to determine the binding properties, localization and expression of miR-378a-5p with downstream target CDK1.Results: The expression of miR-378a-5p was increased in the group with stent restenosis compared with healthy people, as well as in the group which VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) compared with NCs. MiR-378a-5p over-expression had significantly promoted proliferative and migratory effects, while miR-378a-5p inhibitor suppressed VSMC proliferation and migration. CDK1 was proved to be the functional target of miR-378a-5p in VSMCs. Encouragingly, the expression of miR-378a-5p was increased in patients with stent restenosis compared with healthy people, as well as in PDGF-BB-stimulated VSMCs compared with control cells. Furthermore, co-transfection experiments demonstrated that miR-378a-5p over-expression promoted proliferation and migration of VSMCs specifically by reducing CDK1 gene expression levels.Conclusion: In this investigatory, we concluded that miR-378a-5p is a critical mediator in regulating VSMC proliferation and migration by targeting CDK1/p21 signaling pathway. Thereby, interventions aimed at miR-378a-5p may be of therapeutic application in the prevention and treatment of stent restenosis.

Ischemia/reperfusion (IR)‐induced acute kidney injury (AKI) is a common clinical syndrome. Stem/progenitor cell therapy is a promising option to foster the intrinsic capacity for kidney regeneration. However, there are still several challenges to be resolved, including the potential risks during cell culture, low retention rate after transplantation, and unclear effect on the progression of chronic kidney disease (CKD). Recently, nonexpanded adipose stromal vascular fraction (SVF) has been regarded as an attractive cell source for cell‐based therapy. Preconditioning with ischemia has been suggested as a useful method to promote the retention and survival of transplanted cells in vivo. In this study, freshly isolated autologous SVF was transplanted to the kidney of rats before ischemia, and then an IR‐induced AKI model was established. Postischemic administration of SVF to the kidney was performed after renal IR injury was induced. A higher cell retention rate was detected in the preischemic group. Preischemic administration of SVF showed stronger functional and morphologic protection from renal IR injury than postischemic administration, through enhancing tubular cell proliferation and reducing apoptosis. Progression of kidney fibrosis was also significantly delayed by preischemic administration of SVF, which exhibited stronger inhibition of transforming growth factor‐β1‐induced epithelia‐mesenchymal transition and microvascular rarefaction. In addition, in vitro study showed that prehypoxic administration of SVF could significantly promote the proliferation, migration, and survival of hypoxic renal tubular epithelial cells. In conclusion, our study demonstrated that preischemic administration of nonexpanded adipose SVF protected the kidney from both acute IR injury and long‐term risk of developing CKD. Significance Renal ischemia/reperfusion (IR) injury is a common clinical syndrome. Cell‐based therapy provides a promising option to promote renal repair after IR injury. However, several challenges still remain because of the potential risks during cell culture, low retention rate after transplantation, and unclear effect on the progression of chronic kidney disease. Stromal vascular fraction (SVF) is considered as an attractive cell source. This study demonstrated that preischemic administration of uncultured SVF could increase cell retention and then improve renal function and structure at both early and long‐term stage after IR, which may provide a novel therapeutic approach for IR injury.

[This corrects the article DOI: 10.1371/journal.pone.0170729.].