Mechanosynthesis of Pyrrole-2-carboxylic Acids via Copper-Catalyzed Spiroannulation/Ring-Opening Aromatization of 4-Arylidene Isoxazol-5-ones with Enamino Esters.

An efficient and practical tandem reaction of 4-arylidene isoxazol-5-ones with enamino esters catalyzed by an inexpensive copper salt has been established in a ball mill. This innovative approach yields a diverse array of structurally novel pyrrole-2-carboxylic acids, showing excellent tolerance toward different functional groups. By integrating spiroannulation and ring-opening aromatization processes, this protocol introduces a facile and cost-effective strategy for synthesizing highly functionalized pyrrole derivatives.

Global transboundary synergies and trade-offs among Sustainable Development Goals from an integrated sustainability perspective.

Domestic attempts to advance the Sustainable Development Goals (SDGs) in a country can have synergistic and/or trade-off effects on the advancement of SDGs in other countries. Transboundary SDG interactions can be delivered through various transmission channels (e.g., trade, river flow, ocean currents, and air flow). This study quantified the transboundary interactions through these channels between 768 pairs of SDG indicators. The results showed that although high income countries only comprised 14.18% of the global population, they contributed considerably to total SDG interactions worldwide (60.60%). Transboundary synergistic effects via international trade were 14.94% more pronounced with trade partners outside their immediate geographic vicinity than with neighbouring ones. Conversely, nature-caused flows (including river flow, ocean currents, and air flow) resulted in 39.29% stronger transboundary synergistic effects among neighboring countries compared to non-neighboring ones. To facilitate the achievement of SDGs worldwide, it is essential to enhance collaboration among countries and leverage transboundary synergies.

Low-carbon development pathways for resource-based cities in China under the carbon peaking and carbon neutrality goals.

Resource-based cities are important strategic bases for securing resources in China and have made great contributions to the country's economic development. Long-term extensive resource development has made resource-based cities an important region constraining China from achieving comprehensive low-carbon development. Therefore, it is of great significance to explore the low-carbon transition path of resource-based cities for their energy greening, industrial transformation, and high-quality economic development. This study compiled the CO2 emission inventory of resource-based cities in China from 2005 to 2017, explored the contribution to CO2 emissions from three perspectives (driver, industry, and city), and predicted the peak of CO2 emissions in resource-based cities. The results show that resource-based cities contribute 18.4% of the country's GDP and emit 44.4% of the country's CO2 and that economic growth and CO2 emissions have not yet been decoupled. The per capita CO2 emissions and emission intensity of resource-based cities are 1.8 times and 2.4 times higher than the national average, respectively. Economic growth and energy intensity are the biggest drivers and main inhibitors of CO2 emissions growth. Industrial restructuring has become the biggest inhibitor of CO2 emissions growth. Based on the different resource endowments, industrial structures, and socio-economic development levels of resource-based cities, we propose differentiated low-carbon transition pathways. This study can provide references for cities to develop differentiated low-carbon development paths under the "double carbon" target.

Interleukin-17A plays a key role in pulmonary fibrosis following Propionibacterium acnes-induced sarcoidosis-like inflammation.

Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis.

Microscopic insights to spin transport-driven ultrafast magnetization dynamics in a Gd/Fe bilayer.

Laser-induced spin transport is a key ingredient in ultrafast spin dynamics. However, it remains debated to what extent ultrafast magnetization dynamics generates spin currents and vice versa. We use time- and spin-resolved photoemission spectroscopy to study an antiferromagnetically coupled Gd/Fe bilayer, a prototype system for all-optical switching. Spin transport leads to an ultrafast drop of the spin polarization at the Gd surface, demonstrating angular-momentum transfer over several nanometers. Thereby, Fe acts as spin filter, absorbing spin majority but reflecting spin minority electrons. Spin transport from Gd to Fe was corroborated by an ultrafast increase of the Fe spin polarization in a reversed Fe/Gd bilayer. In contrast, for a pure Gd film, spin transport into the tungsten substrate can be neglected, as spin polarization stays constant. Our results suggest that ultrafast spin transport drives the magnetization dynamics in Gd/Fe and reveal microscopic insights into ultrafast spin dynamics.

USP13 Deficiency Impairs Autophagy and Facilitates Age-related Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an age-related disease. Failure of the proteostasis network with age, including insufficient autophagy, contributes to the pathology of IPF. Mechanisms underlying autophagy disruption in IPF are unclear and may involve regulation of USP (ubiquitin-specific protease) by post-translational modifications. To expand our previous observation of low USP13 expression in IPF, this study evaluated the role of USP13 in age-related lung fibrosis. Here, we demonstrated that Usp13-deficient aged mice exhibited impaired autophagic activity and increased vulnerability to bleomycin-induced fibrosis. Mechanistically, USP13 interacted with and deubiquitinated Beclin 1, and Beclin 1 overexpression abolished the effects of USP13 disruption. In addition, Beclin 1 inhibition resulted in insufficient autophagy and more severe lung fibrosis after bleomycin injury, consistent with the phenotype of aged Usp13-deficient mice. Collectively, we show a protective role of USP13 in age-related pulmonary fibrosis. Aging-mediated USP13 loss impairs autophagic activity and facilitates lung fibrosis through Beclin 1 deubiquitination. Our findings support the notion that age-dependent dysregulation of autophagic regulators enhances vulnerability to lung fibrosis.

A male germ-cell-specific ribosome controls male fertility.

Ribosomes are highly sophisticated translation machines that have been demonstrated to be heterogeneous in the regulation of protein synthesis1,2. Male germ cell development involves complex translational regulation during sperm formation3. However, it remains unclear whether translation during sperm formation is performed by a specific ribosome. Here we report a ribosome with a specialized nascent polypeptide exit tunnel, RibosomeST, that is assembled with the male germ-cell-specific protein RPL39L, the paralogue of core ribosome (RibosomeCore) protein RPL39. Deletion of RibosomeST in mice causes defective sperm formation, resulting in substantially reduced fertility. Our comparison of single-particle cryo-electron microscopy structures of ribosomes from mouse kidneys and testes indicates that RibosomeST features a ribosomal polypeptide exit tunnel of distinct size and charge states compared with RibosomeCore. RibosomeST predominantly cotranslationally regulates the folding of a subset of male germ-cell-specific proteins that are essential for the formation of sperm. Moreover, we found that specialized functions of RibosomeST were not replaceable by RibosomeCore. Taken together, identification of this sperm-specific ribosome should greatly expand our understanding of ribosome function and tissue-specific regulation of protein expression pattern in mammals.

IL-17A promotes lung fibrosis through impairing mitochondrial homeostasis in type II alveolar epithelial cells.

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)-17A has been demonstrated to have a pro-fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL-17 receptor A (IL-17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)-induced PF murine model. We found that IL-17A knockout (IL-17A-/- ) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL-17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN-induced putative kinase 1 (PINK1)/Parkin signal-mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL-17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL-17A exerts its pro-fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1-mediated mitophagy, thereby leading to apoptosis of AECIIs.

Navigating Chinese cities to achieve sustainable development goals by 2030.

Achieving the 17 United Nations sustainable development goals (SDGs) in China largely depends on the transition of cities toward sustainable development. However, significant knowledge gaps exist in evaluating the SDG index at the city scale and in understanding how to simulate pathways to achieve the 17 SDGs for Chinese cities by 2030. This study aimed to quantify the SDG index of 285 Chinese cities and developed a forecasting model to simulate the performance of each SDG in each city until 2030 using varied scenarios. The results indicated that although the SDG index in Chinese cities increased by 33.97% during 2005-2016, Chinese cities, which continued their past paths, achieved an average of only five SDGs by 2030. To promote the joint achievement of all SDGs, we designed different paths for all SDGs of each of the 285 cities and simulated their SDG index until 2030. Under the scenarios, 216 Chinese cities (75.79%) could achieve 9-13 more SDGs in 2030 and the overall SDG index can improve from 74.57 in 2030 to 97.49 (target score 100) by adopting more intensive path adjustment. We lastly determined a cost-effective path for each SDG of each city to promote joint achievement of all SDGs by 2030. The proposed simulation model and cost-effective path serve as a foundation for other countries to simulate SDG progress and develop pathways for achieving SDGs in the future.

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization.

Silicosis is one of the potentially fatal occupational diseases characterized by respiratory dysfunction, chronic interstitial inflammation, and fibrosis, for which treatment options are limited. Previous studies showed that a novel N-arylpyridone compound named AKEX0011 exhibited anti-inflammatory and anti-fibrotic effects in bleomycin-induced pulmonary fibrosis; however, it is unknown whether it could also be effective against silicosis. Therefore, we sought to investigate the preventive and therapeutic roles of AKEX0011 in a silicosis rodent model and in a silica-stimulated macrophage cell line. In vivo, our results showed that AKEX0011 ameliorated silica-induced imaging lung damages, respiratory dysfunction, reduced the secretion of inflammatory and fibrotic factors (TNF-α, IL-1ß, IL-6, TGF-ß, IL-4, and IL-10), and the deposition of fibrosis-related proteins (collagen I, fibronectin, and α-SMA), regardless of early or advanced therapy. Specifically, we found that AKEX0011 attenuated silicosis by inhibiting apoptosis, blocking the ASK1-p38 MAPK signaling pathway, and regulating polarization of macrophages. In vitro, AKEX0011 inhibited macrophages from secreting inflammatory cytokines and inhibited apoptosis of macrophages in pre-treated and post-treated models, concurrent with blocking the ASK1-p38 pathway and inhibiting M1 polarization. Collectively, AKEX0011, as a novel N-arylpyridone compound, exerted protective effects for silica-induced pulmonary inflammation and fibrosis both in vivo and in vitro, and hence, it could be a strong drug candidate for the treatment of silicosis.

Krebs von den Lungen-6 levels in untreated idiopathic pulmonary fibrosis.

BACKGROUND: Serum Krebs von den Lungen-6 (KL-6) has been reported to be elevated in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The aim of this study was to evaluate the diagnostic value of KL-6 and whether the expression value of KL-6 could indicate the severity of the disease in IPF patients. To address this question, it is necessary to see whether the patients' physical characteristics and other clinical conditions could affect the baseline KL-6 level. DESIGN: We conducted a study of 100 patients who were diagnosed with IPF. Lung function, computed tomography (CT), and serological lab tests data were analyzed. RESULTS: The tests showed that there is a significant elevation of KL-6 in IPF patients compared with other interstitial lung disease (ILD) and healthy controls. It was noted that serum KL-6 is a stable biomarker not affected by lung infection and smoking, though IPF patients with antinuclear antibody (ANA) showed higher KL-6 levels. KL-6, in conjunction with poor pulmonary function and higher radiological fibrosis scores, indicates the severity of the disease but not poor survival. CONCLUSIONS: It is identified that serum KL-6 is a useful noninvasive biomarker to help improve the certainty of IPF diagnosis from other interstitial lung disease and assist evaluation of disease severity and prognosis.

Global and regional burden of interstitial lung disease and pulmonary sarcoidosis from 1990 to 2019: results from the Global Burden of Disease study 2019.

BACKGROUND: Interstitial lung disease (ILD) and pulmonary sarcoidosis are common respiratory diseases with a heterogeneous distribution worldwide. The global burden and temporal trends of ILD and sarcoidosis are rarely explored. METHODS: Using the classification 'ILD and pulmonary sarcoidosis' from the Global Burden of Disease 2019 dataset, we described the age-standardised rates of incidence, mortality, disability-adjusted life-years (DALYs), and their average annual percentage change from 1990 to 2019 by sex, Sociodemographic Index (SDI) and region. RESULTS: In 2019, the global incidence and mortality of ILD and pulmonary sarcoidosis were 24.2 million and 169 833 cases, respectively. From 1990 to 2019, the global incidence, deaths and DALYs due to ILD and pulmonary sarcoidosis increased by 118.6%, 166.63% and 122.87% respectively. The global incidence of ILD and pulmonary sarcoidosis was higher in men and was mainly concentrated among persons aged 70‒79 of both sexes. Significant regional differences could be seen in the disease burden of ILD and pulmonary sarcoidosis: since 2006, high-SDI regions had higher age-standardised incidence rates but lower age-standardised death rates compared with the low-SDI regions. CONCLUSIONS: Our study suggests the incidence, mortality and DALYs from ILD and pulmonary sarcoidosis are increasing globally. To reduce the ongoing burden of this condition, early diagnosis and treatment are vital, and more targeted and specific strategies should be established in high-burden regions. Differences in incidence and mortality across regions may reflect the influence of genetic, environmental, diagnostic, pharmacotherapeutic, and health system factors.

Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis.

BACKGROUND & AIMS: The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, stratified by sex, underlying liver disease etiology, and severity of hepatic dysfunction. METHODS: PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with an additional manual search of bibliographies of relevant articles. Cohort studies of ≥100 patients with cirrhosis and ≥12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included. RESULTS: Twenty-two studies involving 6,965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), and was higher in male patients, those with alcohol-associated liver disease, those with Child-Pugh grade C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index). Sarcopenia was associated with an increased risk of mortality in patients with cirrhosis (adjusted hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in a sensitivity analysis of patients with cirrhosis without hepatocellular carcinoma (aHR 2.35, 95% CI 1.95-2.83) and in subgroups stratified by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the association between sarcopenia and poor prognosis (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in any of our analyses. CONCLUSIONS: Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis. LAY SUMMARY: The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% of patients with alcohol-related liver disease or Child-Pugh class C cirrhosis. Sarcopenia was independently associated with an ∼2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer durations of sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.

Corrigendum: A novel N-arylpyridone compound alleviates the inflammatory and fibrotic reaction of silicosis by inhibiting the ASK1-p38 pathway and regulating macrophage polarization.

[This corrects the article DOI: 10.3389/fphar.2022.848435.].

Erratum: Addendum: A novel N-Arylpyridone compound alleviates the inflammatory and fibrotic reaction of silicosis by inhibiting the ASK1-p38 pathway and regulating macrophage polarization.

[This corrects the article DOI: 10.3389/fphar.2022.848435.].

Prosthodontic Rehabilitation of a Patient with Hypophosphatasia Using Dental Implants: A Case Report with Seven Years Follow-Up.

Hypophosphatasia is a rare metabolic inherited dento-osseous disorder. Although there is some available literature on various dental characteristics of hypophosphatasia patients, few reports focus on the effects of hypophosphatasia on the permanent dentition and prosthodontic rehabilitation, particularly in relation to the use of dental implants. This paper reports a case with hypophosphatasia and prosthodontic rehabilitation using dental implants with 7-year follow-up.

CO2 emission accounts of Russia's constituent entities 2005-2019.

Constituent entities which make up Russia have wide-ranging powers and are considered as important policymakers and implementers of climate change mitigation. Formulation of CO2 emission inventories for Russia's constituent entities is the priority step in achieving emission reduction. Russia is the world's largest exporter of oil and gas combined and the fourth biggest CO2 emitter, so it's efforts in mitigating CO2 emissions are globally significant in curbing climate change. However, the existing emission inventories only present national CO2 emissions; the subnational emission details are missing. In addition, the emission factors are not country-specific and energy activity data by fossil energy types and sectors are not sufficiently detailed. In this study, the CO2 emission inventories of Russia and its 82 constituent entities from 2005 to 2019 are constructed. The emission inventories include energy-related emissions with 89 socio-economic sectors and 17 energy types and process-related emissions. The uniformly formatted emission inventories can be a reference for in-depth analysis of emission characteristics and emission-related studies of Russia.

Value of Visceral Fat Area and Resting Energy Expenditure in Assessment of Metabolic Characteristics in Obese and Lean Nonalcoholic Fatty Liver Disease.

BACKGROUND: The high prevalence and incidence of non-alcoholic fatty liver disease (NAFLD) have become a global medical concern. Compared with obesity, metabolic abnormalities may be more critical. Currently, there is lack of relevant data for nutritional status and energy metabolic characteristics in patients with obese and lean NAFLD. METHODS: All the enrolled NAFLD patients were divided into 2 groups: the obese group (205 patients with body mass index (BMI) ≥ 25 kg/m2) and the lean group (73 patients with BMI < 25 kg/m2). Using a body composition analyzer, we analyzed their nutritional status including skeletal muscle, body fat, protein content, and visceral fat area (VFA). Energy metabolic characteristics including resting energy expenditure (REE), respiratory quotient, and oxidation rate of 3 major nutrients (carbohydrate, CHO%, fat, FAT%, and protein, PRO%) were analyzed by metabolic cart. RESULTS: The lean NAFLD patients' LDL-c and UA even increased significantly than the obese patients (P = .001 and .006, respectively). Compared with the control group, VFA and REE were significantly higher in the lean NAFLD group (P = .008, P < .001 respectively). CHO%, FAT%, and PRO% in the lean NAFLD group were 29.31 ± 7.07%, 55.59 ± 12.09%, and 15.10 ± 4.07%, respectively, and there was no significant difference compared to the control. However, compared to the obese NAFLD group, their CHO% increased, whereas FAT% decreased (both P < .001). CONCLUSION: NAFLD patients suffer from nutritional imbalances and energy metabolic abnormalities, regardless of whether they are associated with obesity. LDL, UA, VFA, and REE can be used as good evaluation indicators.

Metformin ameliorates bleomycin-induced pulmonary fibrosis in mice by suppressing IGF-1.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, which is characterized by the progressive deterioration in lung function. In the pathogenesis of IPF, insulin-like growth factor-1 (IGF-1) has been found to be heavily involved. Metformin, a commonly used oral antidiabetic agent, is known to inhibit IGF-1 by the reversal of hyperinsulinemia. In this study, we evaluated the effects of metformin in pulmonary fibrosis in C57/BL6J mice, and further understand the role of IGF-1 signaling pathway involving in this process. Pulmonary fibrosis was induced experimentally in these mice by the intratracheal injection of bleomycin (BLM). Metformin was given orally the day before or 14 days after bleomycin injection, while pirfenidone was used as the positive control. Our study showed that intratracheal injection of bleomycin induced pulmonary fibrosis in mice, with observed elevation in collagen, fibronectin and α-SMA level, characterized by the enhanced IGF-1 and PI3K expression. Metformin was able to inhibit these effects significantly, and its antifibrotic effect had no marked difference with pirfenidone. Our results show that metformin attenuates bleomycin-induced pulmonary fibrosis via IGF-1 pathway.

Water-Soluble C60 Protects Against Bleomycin-Induced Pulmonary Fibrosis in Mice.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia. And, oxidation/antioxidant imbalance plays an important role in the progress of IPF. Fullerene is considered to be a novel "structural" antioxidant. This study aimed to explore if water-soluble C60 (C60(OH)22) can exhibit antifibrotic activity in its antioxidant role. METHODS: Healthy C57BL/6J mice were randomly grouped and induced pulmonary fibrosis by intratracheal injection of bleomycin. RESULTS: The survival rate of mice was observed and found that 10mg/kg was the optimal dose of water-soluble C60 for pulmonary fibrosis. We observed that water-soluble C60 can alleviate the severity of pulmonary fibrosis by observing the chest computed tomography, pulmonary pathology, and content of collagen, alpha smooth muscle actin and fibronectin in lung. Compared with bleomycin group, ROS, the content of TNF-α in BALF, and the number of fibroblasts was significantly decreased and the number of type Ⅱ alveolar epithelial cells was increased after treatment with C60. CONCLUSION: Therefore, thanks to its powerful antioxidant action, water-soluble C60 can reduce the severity of pulmonary fibrosis induced by bleomycin in mice.