1,070 research outputs found

    A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context

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    Summary: Background: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus’s impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. Methods: In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. Findings: Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1+ macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor–ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFβ signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. Interpretation: Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFβ signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19. Funding: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501)

    A Randomized, Double-Blind, Placebo-Controlled, Bridging Study to Evaluate the Efficacy and Safety of Vibegron in Treating Korean Patients With Overactive Bladder

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    Purpose Vibegron, a novel, potent β3 agonist, has been approved for clinical use in overactive bladder (OAB) treatment in Japan and the Unites States. We performed a bridging study to investigate the efficacy and safety of a daily 50-mg vibegron (code name JLP-2002) dose in Korean patients with OAB. Methods A multicenter, randomized, double-blind, placebo-controlled study was conducted from September 2020 to August 2021. Adult patients with OAB with a symptom duration of more than 6 months entered a 2-week placebo run-in phase. Eligibility was assessed at the end of this phase and selected patients entered a double-blind treatment phase after 1:1 randomization to either the placebo or vibegron (50 mg) group. The study drug was administered once daily for 12 weeks and follow-up visits were scheduled at weeks 4, 8, and 12. The primary endpoint was the change in mean daily micturition at the end of treatment. The secondary endpoints included changes in OAB symptoms (daily micturition, nocturia, urgency, urgency incontinence, and incontinence episodes, and mean voided volume per micturition) and safety. A constrained longitudinal data model was used for statistical analysis. Results Patients who took daily vibegron had significant improvements over the placebo group in both primary and secondary endpoints, except for daily nocturia episodes. The proportions of patients with normalized micturition and resolution of urgency incontinence and incontinence episodes were significantly higher in vibegron group than in the placebo. Vibegron also improved the patients’ quality of life with higher satisfaction rates. The incidence of adverse events in the vibegron and placebo groups was similar with no serious, unexpected adverse drug reactions. No abnormality in electrocardiographs was observed as well as no significant increase in postvoid residual volume. Conclusions Once daily vibegron (50 mg) for 12 weeks was effective, safe, and well-tolerated in Korean patients with OAB

    Influence of an abnormal ankle-brachial index on ischemic and bleeding events in patients undergoing percutaneous coronary intervention

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    Background/Aims Bleeding events after percutaneous coronary intervention (PCI) have important prognostic implications. Data on the influence of an abnormal ankle-brachial index (ABI) on both ischemic and bleeding events in patients undergoing PCI are limited. Methods We included patients who underwent PCI with available ABI data (abnormal ABI, ≤ 0.9 or > 1.4). The primary endpoint was the composite of all-cause death, myocardial infarction (MI), stroke, and major bleeding. Results Among 4,747 patients, an abnormal ABI was observed in 610 patients (12.9%). During follow-up (median, 31 months), the 5-year cumulative incidence of adverse clinical events was higher in the abnormal ABI group than in the normal ABI group: primary endpoint (36.0% vs. 14.5%, log-rank test, p < 0.001); all-cause death (19.4% vs. 5.1%, log-rank test, p < 0.001); MI (6.3% vs. 4.1%, log-rank test, p = 0.013); stroke (6.2% vs. 2.7%, log-rank test, p = 0.001); and major bleeding (8.9% vs. 3.7%, log-rank test, p < 0.001). An abnormal ABI was an independent risk factor for all-cause death (hazard ratio [HR], 3.05; p < 0.001), stroke (HR, 1.79; p = 0.042), and major bleeding (HR, 1.61; p = 0.034). Conclusions An abnormal ABI is a risk factor for both ischemic and bleeding events after PCI. Our study findings may be helpful in determining the optimal method for secondary prevention after PCI

    Mechanical integrity and erosion resistance of 3D sand printing materials

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    3D sand printing, a binder jetting-based additive manufacturing process, can directly produce sand molds with complex geometries for high-quality and lightweight metal parts. However, there is still a lack of information on how to degrade and erode the mechanical integrity of 3D sand molds. Here, correlations have been investigated between 3D printing materials and various properties of 3D-printed molds: microstructure, flexural strength, reliability, and erosion resistance. As a result, given the mechanical strength and the formation of the binder necks, the most appropriate flexural strength of 4.2 MPa, reliability of 7.8, and high erosion resistance of 86% are achieved from the 3D-printed sand molds prepared with a binder of 2 wt% and an activator of 0.25 wt%. The exhaust manifold casted using a 3D-printed sand mold with optimum conditions, it shows the same or better performance than the genuine part

    Partial Purification and Biochemical Evaluation of Protease Fraction (MA-1) from <i>Mycoleptodonoides aitchisonii</i> and Its Fibrinolytic Effect

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    The antioxidative proteolytic fraction, MA-1, was partially purified from Mycoleptodonoides aitchisonii. MA-1 was purified to homogeneity using a two-step procedure, which resulted in an 89-fold increase in specific activity and 42.5% recovery. SDS-PAGE revealed two proteins with a molecular weight of 48 kDa. The zymography results revealed proteolytic activity based on the MA-1 band. MA-1 was found to be stable in the presence of Na+, Ca2+, Fe3+, K+, and Mg2+. MA-1 was also stable in methanol, ethanol, and acetone, and its enzyme activity increased by 15% in SDS. MA-1 was inhibited by ethylenediaminetetra-acetic acid or ethylene glycol tetraacetic acid and exerted the highest specificity for the substrate, MeO-Suc-Arg-Pro-Tyr-pNA, for chymotrypsin. Accordingly, MA-1 belongs to the family of chymotrypsin-like metalloproteins. The optimum temperature was 40 °C and stability was stable in the range of 20 to 35 °C. The optimum pH and stability were pH 5.5 and pH 4–11. MA-1 exhibited stronger fibrinolytic activity than plasmin. MA-1 hydrolyzed the Aα, Bβ, and γ chains of fibrinogen within 2 h. MA-1 exhibited an antithrombotic effect in animal models. MA-1 was devoid of hemorrhagic activity at a dose of 80,000 U/kg. Overall, our results show that M. aitchisonii produces an acid-tolerant and antioxidative chymotrypsin-like fibrinolytic enzyme, and M. aitchisonii containing MA-1 could be a beneficial functional material for the prevention of cardiovascular diseases and possible complications

    Phase-Controlled Multi-Dimensional-Structure SnS/SnS<sub>2</sub>/CdS Nanocomposite for Development of Solar-Driven Hydrogen Evolution Photocatalyst

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    The quest for water-splitting photocatalysts to generate hydrogen as a clean energy source from two-dimensional (2D) materials has enormous implications for sustainable energy solutions. Photocatalytic water splitting, a major field of interest, is focused on the efficient production of hydrogen from renewable resources such as water using 2D materials. Tin sulfide and tin disulfide, collectively known as SnS and SnS2, respectively, are metal sulfide compounds that have gained attention for their photocatalytic properties. Their unique electronic structures and morphological characteristics make them promising candidates for harnessing solar energy for environmental and energy-related purposes. CdS/SnS/SnS2 photocatalysts with two Sn phases (II and IV) were synthesized using a solvothermal method in this study. CdS was successfully placed on a broad SnS/SnS2 plane after a series of characterizations. We found that it is composited in the same way as a core-shell shape. When the SnS/SnS2 phase ratio was dominated by SnS and the structure was composited with CdS, the degradation efficiency was optimal. This material demonstrated high photocatalytic hydrogenation efficiency as well as efficient photocatalytic removal of Cr(VI) over 120 min. Because of the broad light absorption of CdS, the specific surface area, which is the reaction site, became very large. Second, it served as a transport medium for electron transfer from the conduction band (CB) of the SnS to the CB of the SnS2. Because of the composite, these electrons flowed into the CB of CdS, improving the separation efficiency of the photogenerated carriers even further. This material, which was easily composited, also effectively prevented mineral corrosion, which is a major issue with CdS

    Synergistic bactericidal effects of carvone and β-lactams against Xanthomonas campestris pv. vesicatoria

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    Abstract Xanthomonas campestris pv. vesicatoria (Xcv) causes brown spots on the leaves, stems, and fruits of plants, called bacterial leaf scorch (BLS). For the control of pathogens, antibiotics have been used frequently, and they can develop the resistance. In this study, the bactericidal and synergistic effects of caraway oil and its main components against the pathogen (Xcv) were investigated. The tested caraway oil consisted of 58.4% of carvone and 31.1% of limonene. The minimum inhibitory concentration (MIC) of caraway oil and carvone was the same as 125 μg mL−1, and the minimum bactericidal concentration (MBC) was 1000 μg mL−1 for caraway oil and 500 μg mL−1 for carvone, while limonene showed no inhibition below 1000 μg ml−1. In the growth of Xcv, carvone treatment over 31.3 μg mL−1 inhibited dose-dependently, and the bactericidal effect showed after 18 h more than 250 μg mL−1; It was agreed with the release of intracellular components over 250 μg mL−1, especially. Furthermore, carvone damaged the plasmid DNA of Xcv, and it would be the reason for the bactericidal activity. The synergistic effect of carvone was found with β-lactams selectively; the fractional inhibitory concentration (FIC) indexes of carvone with ampicillin or amoxicillin were below 0.5, and the mixture of carvone (125 μg mL−1) and ampicillin (500 μg mL−1) showed the bactericidal activity as well

    Genetic variants in key necroptosis regulators predict prognosis of non‐small cell lung cancer after surgical resection

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    Abstract Background Necroptosis is a regulated inflammatory cell death which plays a significant role in cancer development and progression. In this study, we evaluated whether genetic variants in key regulators of necroptosis may affect survival outcome of non‐small cell lung cancer (NSCLC) patients after surgical resection. Methods A total of 674 patients who underwent curative surgery were included. Fifteen genetic variants in key regulators of necroptosis (RIPK1, RIPK3, and MLKL) were selected. The association of these variants with survival outcomes was evaluated. Results Two variants, RIPK1 rs17548629C > T and MLKL rs877375G > C, were associated with better overall survival and disease‐free survival in multivariate analyses. When the patients were divided according to histology, the associations were significant only in adenocarcinoma, but not in squamous cell carcinoma. RIPK1 rs17548629 C‐to‐T change was associated with significantly increased luciferase activity by modulating the binding of miR‐642a. Promoter assays showed a significantly increased promoter activity in MLKL rs877375C allele compared to G allele. Consistently, the mRNA expression level of RIPK1 and MLKL showed significant positive correlation with RIPK1 rs17548629C‐to‐T and MLKL rs877375G‐to‐C changes. Conclusion Two genetic variants in key regulators in necroptosis, RIPK1 rs17548629C > T and MLKL rs877375G > C, may be used as biomarkers to predict survival outcomes in surgically resected NSCLC patients

    The risk of colorectal cancer according to obesity status at four-year intervals: a nationwide population-based cohort study

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    Abstract Obesity is a risk factor for colorectal cancer. However, the effect of body weight change on colorectal cancer is uncertain. This study aimed to investigate the relationship between difference in body mass index and the risk of colorectal cancer. In this nationwide population-based cohort study, participants of the national cancer screening program in 2005 and 2009 were enrolled. Difference of body mass index was calculated from screening data from 2005 and 2009. Participants were divided into four groups according to direction of obesity status: non-obese/non-obese, non-obese/obese, obese/non-obese, and obese/obese. The effect of differences in body mass index on colorectal cancer was analyzed. Among 3,858,228 participants, 47,894 (1.24%) participants were newly diagnosed with colorectal cancer during the 9.2 years of follow-up. The incidence of colorectal cancer was higher in the obese/obese group than the non-obese/non-obese group (hazard ratio = 1.08 [1.06–1.11], P trend < 0.001). The men in the obese/obese group had a higher risk of colon cancer than women (hazard ratio = 1.13 [1.10–1.17] in men, and hazard ratio = 1.04 [1.01–1.18] in women, P = 0.001). Persistent obesity was associated with a higher risk of incidence of colorectal cancer

    Spectral analysis of a parsec-scale jet in M 87: Observational constraint on the magnetic field strengths in the jet

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    Context. Because of its proximity and the large size of its black hole, M 87 is one of the best targets for studying the launching mechanism of active galactic nucleus jets. Currently, magnetic fields are considered to be an essential factor in the launching and accelerating of the jet. However, current observational estimates of the magnetic field strength of the M 87 jet are limited to the innermost part of the jet (less than or similar to 100 r(s)) or to HST-1 (similar to 10(5) r(s)). No attempt has yet been made to measure the magnetic field strength in between. Aims. We aim to infer the magnetic field strength of the M 87 jet out to a distance of several thousand r(s) by tracking the distance-dependent changes in the synchrotron spectrum of the jet from high-resolution very long baseline interferometry observations. Methods. In order to obtain high-quality spectral index maps, quasi-simultaneous observations at 22 and 43 GHz were conducted using the KVN and VERA Array (KaVA) and the Very Long Baseline Array (VLBA). We compared the spectral index distributions obtained from the observations with a model and placed limits on the magnetic field strengths as a function of distance. Results. The overall spectral morphology is broadly consistent over the course of these observations. The observed synchrotron spectrum rapidly steepens from alpha(22 - 43 GHz) similar to -0.7 at similar to 2 mas to alpha(22 - 43 GHz) similar to -2.5 at similar to 6 mas. In the KaVA observations, the spectral index remains unchanged until similar to 10 mas, but this trend is unclear in the VLBA observations. A spectral index model in which nonthermal electron injections inside the jet decrease with distance can adequately reproduce the observed trend. This suggests the magnetic field strength of the jet at a distance of 2-10 mas (similar to 900 r(s) - similar to 4500 r(s) in the deprojected distance) has a range of B = (0.3-1.0 G)(z/2mas)(-0.73). Extrapolating to the Event Horizon Telescope scale yields consistent results, suggesting that the majority of the magnetic flux of the jet near the black hole is preserved out to similar to 4500 r(s) without significant dissipation