The response of microbial compositions and functions to chronic single and multiple antibiotic exposure by batch experiment.

Understanding the response of the microbial community to external disturbances such as micropollutants is vital for ecological risk evaluation. In this study, the effect of chronic antibiotic exposure on community compositions and functions was investigated by two batch experiments. The first experiment investigated the effect of chronic sulfamethoxazole (SMX) exposure, while the second investigated the combined effect of dissolved organic matter (DOM) sources and multi-antibiotic exposure. The results showed that the community responses to chronic antibiotic exposure depended on the dynamic balance among community resistance, adaptation, recovery, and selection, leading to nonlinear composition diversity variations. The disturbance strength of chronic SMX exposure increased with concentration (0.5-50 µg/L). However, complex sources and structures of coexisting organic matter might delay the disturbance by elevating metabolic activity and generating functional redundancy. Especially, when nutrient was a limiting factor, the disturbance strength by DOM source was greater than that by chronic antibiotic exposure. The resistance of abundant taxa to external distributions resulted in a low explanation of community diversity, while rare taxa played key roles in response to community variation and thereby affected community assembly. Long-term SMX exposure reduced the number of key species and favored the deterministic assembly process by 21%. However, elevated community adaptability might weaken the influence of antibiotic selection. Chronic SMX exposure elevated the relative abundance of sulfonamide resistance genes (sul1, sul2) by a factor of 1.2-4.3, while that of nitrogen-fixing genes (nifH, nifK) and the metabolic pathways related to the toluene, ethylbenzene, and dioxin degradation decreased. However, the combined influence of DOM sources and multi-antibiotic exposure barely caused the difference in the genes linking to element metabolism and drug resistance of microbial communities between blank and exposed groups. This study suggested that more concern should be given to the chronic environmental effect of organic micropollutants.

Intravascular imaging during percutaneous coronary intervention: temporal trends and clinical outcomes in the USA.

AIMS: Prior trials have demonstrated that intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) results in less frequent target lesion revascularization and major adverse cardiovascular events (MACEs) compared with standard angiographic guidance. The uptake and associated outcomes of IVI-guided PCI in contemporary clinical practice in the USA remain unclear. Accordingly, temporal trends and comparative outcomes of IVI-guided PCI relative to PCI with angiographic guidance alone were examined in a broad, unselected population of Medicare beneficiaries. METHODS AND RESULTS: Retrospective cohort study of Medicare beneficiary data from 1 January 2013, through 31 December 2019 to evaluate temporal trends and comparative outcomes of IVI-guided PCI as compared with PCI with angiography guidance alone in both the inpatient and outpatient settings. The primary outcomes were 1 year mortality and MACE, defined as the composite of death, myocardial infarction (MI), repeat PCI, or coronary artery bypass graft surgery. Secondary outcomes were MI or repeat PCI at 1 year. Multivariable Cox regression was used to estimate the adjusted association between IVI guidance and outcomes. Falsification endpoints (hospitalized pneumonia and hip fracture) were used to assess for potential unmeasured confounding. The study population included 1 189 470 patients undergoing PCI (38.0% female, 89.8% White, 65.1% with MI). Overall, IVI was used in 10.5% of the PCIs, increasing from 9.5% in 2013% to 15.4% in 2019. Operator IVI use was variable, with the median operator use of IVI 3.92% (interquartile range 0.36%-12.82%). IVI use during PCI was associated with lower adjusted rates of 1 year mortality [adjusted hazard ratio (aHR) 0.96, 95% confidence interval (CI) 0.94-0.98], MI (aHR 0.97, 95% CI 0.95-0.99), repeat PCI (aHR 0.74, 95% CI 0.73-0.75), and MACE (aHR 0.85, 95% CI 0.84-0.86). There was no association with the falsification endpoint of hospitalized pneumonia (aHR 1.02, 95% CI 0.99-1.04) or hip fracture (aHR 1.02, 95% CI 0.94-1.10). CONCLUSION: Among Medicare beneficiaries undergoing PCI, use of IVI has increased over the previous decade but remains relatively infrequent. IVI-guided PCI was associated with lower risk-adjusted mortality, acute MI, repeat PCI, and MACE.

Incidence, Treatment, and Outcomes of Symptomatic Device Lead-Related Venous Obstruction.

BACKGROUND: The incidence and clinical impact of lead-related venous obstruction (LRVO) among patients with cardiovascular implantable electronic devices (CIEDs) is poorly defined. OBJECTIVES: The objectives of this study were to determine the incidence of symptomatic LRVO after CIED implant; describe patterns in CIED extraction and revascularization; and quantify LRVO-related health care utilization based on each type of intervention. METHODS: LRVO status was defined among Medicare beneficiaries after CIED implant from October 1, 2015, to December 31, 2020. Cumulative incidence functions of LRVO were estimated by Fine-Gray methods. LRVO predictors were identified using Cox regression. Incidence rates for LRVO-related health care visits were calculated with Poisson models. RESULTS: Among 649,524 patients who underwent CIED implant, 28,214 developed LRVO, with 5.0% cumulative incidence at maximum follow-up of 5.2 years. Independent predictors of LRVO included CIEDs with >1 lead (HR: 1.09; 95% CI: 1.07-1.15), chronic kidney disease (HR: 1.17; 95% CI: 1.14-1.20), and malignancies (HR: 1.23; 95% CI: 1.20-1.27). Most patients with LRVO (85.2%) were managed conservatively. Among 4,186 (14.8%) patients undergoing intervention, 74.0% underwent CIED extraction and 26.0% percutaneous revascularization. Notably, 90% of the patients did not receive another CIED after extraction, with low use (2.2%) of leadless pacemakers. In adjusted models, extraction was associated with significant reductions in LRVO-related health care utilization (adjusted rate ratio: 0.58; 95% CI: 0.52-0.66) compared with conservative management. CONCLUSIONS: In a large nationwide sample, the incidence of LRVO was substantial, affecting 1 of every 20 patients with CIEDs. Device extraction was the most common intervention and was associated with long-term reduction in recurrent health care utilization.

Immunotherapy combined with rh-endostatin improved clinical outcomes over immunotherapy plus chemotherapy for second-line treatment of advanced NSCLC.

Background: Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy. Methods: We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators of this study were progression-free survival (PFS), safety profile, objective response rate (ORR), disease control rate (DCR), and 1-year overall survival (OS). Results: The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group (P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group (P = 0.049). The 1-year OS rate for the IE group was 69.4%, which was higher than the 61.4% of the IC group. Conclusion: Our study showed that ICI therapy combined with endostatin therapy exhibits high efficacy and safety, suggesting that such a combination might be a viable treatment option for patients with pre-treated NSCLC in the future.

Meningioma resection and venous thromboembolism incidence, management, and outcomes.

Background: Meningioma resection is associated with the risk of venous thromboembolism (VTE). Objectives: To determine the incidence and risk factors for VTE following meningioma resection and VTE outcomes based on the type and timing of anticoagulation. Methods: From 2011 to 2019, 901 consecutive patients underwent meningioma resection. We retrospectively evaluated the postoperative incidence of VTE and bleeding. For VTE, we determined the treatment strategy and rate of VTE complications and bleeding. Results: Pharmacologic prophylaxis was administered to 665 (73.8%) patients. The cumulative incidence for total postoperative VTE was 8.7% (95% CI: 6.9%-10.6%), and for symptomatic VTE was 6.0% (95% CI: 4.6%-7.7%). A multivariable model identified the following independent predictors of symptomatic VTE: history of VTE, obesity, and lack of pharmacologic prophylaxis. Following postoperative VTE, 58 (74.3%) patients received therapeutic anticoagulation either initially (33.3%) or after a median delay of 23.5 days (41.0%). Symptomatic recurrent VTE occurred in 13 (16.6%) patients. Following VTE, the use of subtherapeutic anticoagulation was associated with a lower rate of total VTE extension than no anticoagulation (17.5% vs 42.9%, OR 0.28, 95% CI: 0.09-0.93). In total, 14 patients (1.6%) experienced clinically relevant bleeding: 4 received therapeutic anticoagulants, 8 received prophylactic anticoagulation, and 2 received no anticoagulation. Among patients with VTE, 4 (5.1%) experienced bleeding. Conclusion: Recognition of risk factors for VTE following meningioma resection may help improve approaches to thromboprophylaxis. The management of postoperative VTE is highly variable, but most VTE patients are ultimately treated with therapeutic anticoagulants.

Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer.

Aim: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5 months; p < 0.001) and objective response rate (67.2 vs 42.9%; p = 0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.

This study retrospectively analyzed the effectiveness and safety of PD-1 inhibitors combined with recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. Among them, 58 patients received a PD-1 inhibitor combined with Rh-endostatin and chemotherapy (treatment group), and 42 patients received Rh-endostatin combined with chemotherapy (control group). Patients in the treatment group had a significantly improved objective response rate (67.2 vs 42.9%; p = 0.015) and prolonged survival without their disease getting worse (10.2 vs 6.5 months; p < 0.001). No significant differences were found in the adverse events between the two groups.

A female in vivo haploid-induction system via mutagenesis of egg cell-specific peptidases.

Crop breeding schemes can be significantly accelerated by using (doubled) haploid plants. In vivo haploid induction has been applied in plant breeding for decades but is still not available for all crops and genotypes, and haploidization rates are generally very low. Therefore, methodological improvements to and new concepts for haploidization are required. Here, we report a novel system for the induction of haploid plants by mutating genes encoding egg cell-specific aspartic endopeptidases (ECSs). We show that after successful sperm-egg cell fusion, ECSs play a critical role to ensure male and female nucleus fusion after fertilization. The ecs1 ecs2 double mutant can induce haploids by both selfing and hybridization in Arabidopsis and ECS mutation is also capable of producing haploids in rice. In summary, our study develops a novel approach for maternal haploidization and provides new insights into the molecular basis of fertilization.

microRNA-149-5p mediates the PM2.5-induced inflammatory response by targeting TAB2 via MAPK and NF-κB signaling pathways in vivo and in vitro.

Epidemiological evidence has shown that fine particulate matter (PM2.5)-triggered inflammatory cascades are pivotal causes of chronic obstructive pulmonary disease (COPD). However, the specific molecular mechanism involved in PM2.5-induced COPD has not been clarified. Herein, we found that PM2.5 significantly downregulated miR-149-5p and activated the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways and generated the inflammatory response in COPD mice and in human bronchial epithelial (BEAS-2B) cells. We determined that increased expression of interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) induced by PM2.5 was associated with decreased expression of miR-149-5p. The loss- and gain-of-function approach further confirmed that miR-149-5p could inhibit PM2.5-induced cell inflammation in BEAS-2B cells. The double luciferase reporter assay showed that miR-149-5p directly targeted TGF-beta-activated kinase 1 binding protein 2 (TAB2), which regulates the MAPK and NF-κB signaling pathways. We showed that miR-149-5p mediated the inflammatory response by targeting the 3'-UTR sequence of TAB2 and that it subsequently weakened the TAB2 promotor effect via the MAPK and NF-κB signaling pathways in BEAS-2B cells exposed to PM2.5. Thus, miR-149-5p may be a key factor in PM2.5-induced COPD. This study improves our understanding of the molecular mechanism of COPD.

The biogeochemical responses of hyporheic groundwater to the long-run managed aquifer recharge: Linking microbial communities to hydrochemistry and micropollutants.

Interactions of surface water and groundwater (SW-GW) in hyporheic zones produce biogeochemical hotspots. However, response patterns of hyporheic groundwater to external influences remain unclear. In this study, three datasets (hydrochemistry, antibiotics, and microbiome) were collected over a hydrological year to explore the influence of a 12-year managed aquifer recharge (MAR) project. We observed that the long-term MAR practice elevated nutrient and antibiotic levels while reduced redox potential in hyporheic groundwater, and these impacts depended on decreasing SW-GW interaction intensity with aquifer depth. In contrast, the long-term MAR practice increased community dissimilarity of 30-m groundwater but had little impact on 50-m or 80-m groundwater. Moreover, hyporheic community assembly was dominated by dispersal limitation, and thereby co-varied hydrochemistry and antibiotics only attributed to small community variability. The long-term MAR practice decreased species-interaction intensity and changed the abundance of metabolic functions in hyporheic groundwater. Furthermore, predicted community functions involving carbon, nitrogen, sulfur, and manganese cycles for 30-m groundwater showed higher abundances than those for 50- and 80-m groundwater. Collectively, we showed that hyporheic groundwater was sensitive to the SW-GW interaction and human activities, with the interactions of hydrochemistry, contaminants, and microbiome linking to hyporheic groundwater quality and ecosystem functioning.

Snail-mediated partial epithelial mesenchymal transition augments the differentiation of local lung myofibroblast.

The pathogenesis of pulmonary fibrosis diseases is considered to be related with environmental exposures, but the exact mechanism is unclear and there are no effective treatments. The contribution of epithelial-mesenchymal transition (EMT) to lung fibrosis has been controversial. It was found that partial EMT might play a vital role in renal fibrosis. We also found that partial EMT might be involved in fibrosis diseases. In this study, we used a silicosis animal model of pulmonary fibrosis to observe whether partial EMT existed in pulmonary fibrosis disease and a co-culture system culturing fibroblasts and alveolar epithelial cells stimulated by TGF-ß1 to evaluate the probable effects of partial EMT, thus determined the probable role of partial EMT in pulmonary fibrosis diseases. In vivo, the results revealed that partial EMT might exist in silica-induced lung fibrosis model and Snail which is a potent EMT inducer was involved during the process. In vitro, a co-culture system was used to evaluate the effects of EMT in murine alveolar epithelial type II (ATII) cells on the activation of underlying murine lung fibroblasts into myofibroblasts. The results showed that epithelial cells undergoing EMT promoted the differentiation of lung myofibroblast and this epithelial-mesenchymal crosstalk was mainly controlled by Snail. Following Snail silencing the EMT and the activation of NIH-3T3 into myofibroblast were obviously inhibited. It indicated that targeting this novel Snail might be a viable strategy for the treatment of lung fibrosis diseases.

Estimated Prevalence of Masked Asleep Hypertension in US Adults.

Importance: High blood pressure (BP) during sleep (asleep blood pressure) is associated with an increased risk of cardiovascular disease, but a national prevalence estimate of masked asleep hypertension (high BP while sleeping but without high BP measured in the clinic [clinic BP]) for the United States is lacking. Objectives: To estimate the prevalence of masked asleep hypertension among US adults by using BP thresholds from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) and the 2017 American College of Cardiology-American Heart Association (ACC-AHA) BP guidelines. Design, Setting, and Participants: This cohort analysis pooled data from 3000 participants in 4 US population-based studies that conducted 24-hour ambulatory BP monitoring (ABPM) and 17 969 participants in the 2011-2016 National Health and Nutrition Examination Survey (NHANES) without ABPM. Masked asleep hypertension status in NHANES was imputed using a 2-stage multiple imputation process. Data were collected from 2000 to 2016 and analyzed from March 4, 2019, to June 29, 2020. Main Outcomes and Measures: High clinic BP was defined as clinic systolic BP (SBP)/diastolic BP (DBP) of at least 140/90 mm Hg using JNC7 and at least 130/80 mm Hg using 2017 ACC-AHA guidelines. High asleep BP was defined as mean asleep SBP/DBP of at least 120/70 mm Hg for JNC7 and at least 110/65 mm Hg for the 2017 ACC-AHA guidelines. Masked asleep hypertension was defined as high asleep BP without high clinic BP. Results: For the 3000 pooled cohort participants, the mean (SD) age was 52.0 (12.0) years, and 62.6% were women. For the 17 969 NHANES participants, the mean (SD) age was 46.7 (17.5) years, and 51.8% (weighted) were women. The estimated prevalence of masked asleep hypertension among US adults was 18.8% (95% CI, 16.7%-20.8%; 44.4 million US adults) using the JNC7 guideline and 22.7% (95% CI, 20.6%-24.8%; 53.7 million US adults) using the 2017 ACC-AHA guideline criteria. The prevalence of masked asleep hypertension was higher among older adults (aged ≥65 years, 24.4% [95% CI, 20.7%-28.0%]), men (27.0% [95% CI, 24.1%-29.9%]), non-Hispanic Black individuals (28.7% [95% CI, 25.4%-32.0%]), those who were taking antihypertensives (24.4% [95% CI, 21.1%-27.8%]), those who had masked daytime hypertension (44.7% [95% CI, 40.1%-49.3%]), and those with diabetes (27.6% [95% CI, 23.5%-31.8%]), obesity (24.3% [95% CI, 21.8%-26.9%]), or chronic kidney disease (21.5% [95% CI, 17.3%-25.6%]) using the 2017 ACC-AHA guideline. An estimated 11.9% of US adults (28.2 million) had isolated masked asleep hypertension (masked asleep hypertension but without high awake BP) using JNC7 guideline criteria, as did an estimated 13.3% (31.5 million) using 2017 ACC-AHA guideline criteria. Conclusions and Relevance: These findings suggest that the prevalence of masked asleep hypertension is high among US adults. Data are needed on the cardiovascular risk reduction benefits of treating asleep hypertension.

Response of ammonia oxidation activities to water-level fluctuations in riparian zones in a column experiment.

Biogeochemical hotspots of nitrogen cycling such as ammonia oxidation commonly occur in riparian ecosystems. However, the responses of ammonia-oxidizing archaea (AOA) and bacteria (AOB) to water-level fluctuations (WLF) in riparian zones remain unclear. In this study, two patterns of WLF (gradual waterlogging and drying) were investigated in a 9-month column experiment, and the abundances and activities of AOA and AOB were investigated. The recovery evaluation revealed AOB abundance had not returned to the initial level at the end of the experiment, while AOA abundance had recovered nearly completely. AOA outnumbered AOB at almost all depths, and AOA showed higher resistance and adaptation to WLF than AOB. However, higher microbial abundance was not always linked to the larger contribution to nitrification. Changes in environmental parameters such as moisture and dissolved oxygen caused by WLF instead of ammonia-oxidizing microorganism (AOM) abundance might play a key role in regulating the expression of amoA gene and thus the activity of ammonia oxidizers. In addition, the community structure of AOM evolved over the incubation period. The composition of AOA species in sediment changed in the same way as that in soil, and the Nitrosopumilus cluster showed strong resistance to WLF. Conversely, waterlogging changed the community structure of AOB in soil while drying had no significant effect on the AOB community structure in sediment. This study suggests that the ammonia oxidizers will respond to WLF and eventually affect N fate in riparian ecosystems considering the coupling with other N transformation processes.

Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model.

BACKGROUND: Silicosis is an occupational respiratory disease caused by long-term excessive silica inhalation, which is most commonly encountered in industrial settings. Unfortunately, there is no effective therapy to delay and cure the progress of silicosis. In the recent years, stem cell therapy has emerged as an attractive tool against pulmonary fibrosis (PF) owing to its unique biological characteristics. However, the direct use of stem cells remains limitation by many risk factors for therapeutic purposes. The exclusive utility of exosomes secreted from stem cells, rather than cells, has been considered a promising alternative to overcome the limitations of cell-based therapy while maintaining its advantages. METHODS AND RESULTS: In this study, we first employed a three-dimensional (3D) dynamic system to culture human umbilical cord mesenchymal stem cell (hucMSC) spheroids in a microcarrier suspension to yield exosomes from serum-free media. Experimental silicosis was induced in C57BL/6J mice by intratracheal instillation of a silica suspension, with/without exosomes derived from hucMSC (hucMSC-Exos), injection via the tail vein afterwards. The results showed that the gene expression of collagen I (COL1A1) and fibronectin (FN) was upregulated in the silica group as compared to that in the control group; however, this change decreased with hucMSC-Exo treatment. The value of FEV0.1 decreased in the silica group as compared to that in the control group, and this change diminished with hucMSC-Exo treatment. These findings suggested that hucMSC-Exos could inhibit silica-induced PF and regulate pulmonary function. We also performed in vitro experiments to confirm these findings; the results revealed that hucMSC-Exos decreased collagen deposition in NIH-3T3 cells exposed to silica. CONCLUSIONS: Taken together, these studies support a potential role for hucMSC-Exos in ameliorating pulmonary fibrosis and provide new evidence for improving clinical treatment induced by silica.

Sodium tanshinone IIA sulfonate attenuates silica-induced pulmonary fibrosis in rats via activation of the Nrf2 and thioredoxin system.

Silicosis is characterized by pulmonary fibrosis due to long-term inhalation of silica particles. Although the cause of this serious disease is known, its pathogenesis remains unclear and there are currently no specific treatments. Recent studies have shown that the anti-oxidant transcription factor Nrf2 is expressed at reduced levels in fibrotic foci, which may be related to disease progression. However, the molecular mechanisms by which this might occur have yet to be elucidated. Sodium tanshinone IIA sulfonate (STS), an extract of Salvia miltiorrhiza, is used in traditional Chinese medicine in the treatment of coronary heart disease. STS has been shown to play a strong anti-oxidative role in various organs. Here, we employed a rat model to explore the effects of STS on oxidative stress and the progression of fibrosis in silicosis. STS significantly reduced collagen deposition in the lungs, thereby antagonising silicosis. Immunohistochemical and immunofluorescence staining showed that Nrf2 was differentially expressed in lung cells during silica induced fibrosis, and chromatin immunoprecipitation-sequencing experiments demonstrated that Nrf2 promoted the expression of the antioxidant proteins thioredoxin and thioredoxin reductase. Our results suggest that the anti-fibrotic effects of STS may be related to upregulation of Nrf2 nuclear expression, especially in fibrotic lesions, and the promotion of thioredoxin and thioredoxin reductase expression. Our findings may open up new avenues for the development of STS as a treatment for silicosis.

Ammonia oxidizers in river sediments of the Qinghai-Tibet Plateau and their adaptations to high-elevation conditions.

Ammonia-oxidizing bacteria (AOB) and archaea (AOA) as well as complete ammonia oxidizers (comammox) aerobically catalyze ammonia oxidation which plays essential roles in riverine nitrogen cycle. However, performances of these ammonia oxidizers in high-elevation river sediments have rarely been documented. This study investigated the abundance, community, and activity of ammonia oxidizers in five high-elevation rivers of the Qinghai-Tibet Plateau (QTP). Comammox were dominant ammonia oxidizers in 23% of studied samples and the clade B was principal comammox type. amoA gene abundances of AOA and AOB in these high-elevation rivers were comparable to those in low-elevation rivers. However, in contrast to most studied low-elevation rivers, AOB amoA gene abundance outnumbered AOA in 92% samples, which might be caused by the lower temperature and more intense solar radiation of the QTP. Potential nitrification rates (PNRs) ranged from 0.02 to 2.95 nmol-N h-1 g-1 dry sediment. Ammonia concentration was the limiting factor to PNRs at some sites, and when ammonia was not limiting, the PNR: ammonia ratio was greater at higher temperatures. There was no apparent variation in ammonia oxidizer community compositions along the elevation gradient due to the high elevation (2687 to 4223 m) of our entire study area. However, compared with low-elevation rivers, the lower temperature, huge diurnal temperature change, and lower nutrient conditions in the QTP rivers shaped distinctive communities for ammonia oxidizers; the unique community characteristics were significantly correlated to PNRs. These results suggest that ammonia oxidizers in the five high-elevation rivers have adapted to high-elevation conditions; more research should be conducted to study their adaptation mechanisms and their roles in riverine nitrogen cycle.

Integrative characterization of fine particulate matter-induced chronic obstructive pulmonary disease in mice.

The impacts of ambient fine particulate matter (PM2.5) on public health are a worldwide concern. Epidemiological evidence has shown that PM2.5-triggered inflammatory cascades and lung tissue damage are important causes of chronic obstructive pulmonary disease (COPD). However, most laboratory studies of COPD have focused on animal models of cigarette smoke exposure or combined exposure to cigarette smoke and PM2.5. Furthermore, a single method is used to evaluate the development of COPD without integrality. In this study, we investigated pulmonary pathophysiological alterations using integrated functional, morphological, and biochemical techniques and a mouse model exposed to PM2.5 alone for 3 months. Emphysema in this model was confirmed by reconstructed three-dimensional micro-CT images. Typical histopathological signs were neutrophil/macrophage infiltration and accumulation at 2 months after exposure and emphysema/atelectasis at 3 months. Respiratory mechanical parameters confirmed that PM2.5 caused a decline in respiratory function. PM2.5 also triggered complex cytokine profile changes in the lungs with characteristic inflammation-related tissue destruction. This study showed that chronic PM2.5 exposure impaired lung function, triggered emphysematous lesions, and induced pulmonary inflammation and airway wall remodeling. Most importantly, prolonged exposure to PM2.5 alone caused COPD in mice. These results improve the understanding of the mechanisms and mediators underlying PM2.5-induced COPD.

Ammonia Oxidizers in High-Elevation Rivers of the Qinghai-Tibet Plateau Display Distinctive Distribution Patterns.

Ammonia-oxidizing bacteria (AOB) and archaea (AOA) as well as comammox catalyze ammonia oxidation. The distribution and biogeography of these ammonia oxidizers might be distinctive in high-elevation rivers, which are generally characterized by low temperature and low ammonium concentration but strong solar radiation; however, these characteristics have rarely been documented. This study explored the abundance, community, and activity of ammonia oxidizers in the overlying water of five rivers in the Qinghai-Tibet Plateau (QTP). Potential nitrification rates in these rivers ranged from 5.4 to 38.4 nmol N liter-1 h-1, and they were significantly correlated with ammonium concentration rather than temperature. Comammox were found in 25 of the total 28 samples, and they outnumbered AOA in three samples. Contrary to most studied low-elevation rivers, average AOB amoA gene abundance was significantly higher than that of AOA, and AOB/AOA ratios increased with decreasing water temperature. The Simpson index of the AOA community increased with elevation (P < 0.05), and AOA and AOB communities exhibited high dissimilarities with low-elevation rivers. Cold-adapted (Nitrosospira amoA cluster 1, 33.6%) and oligotrophic (Nitrosomonas amoA cluster 6a, 31.7%) groups accounted for large proportions in the AOB community. Suspended sediment concentration exerted significant effects on ammonia oxidizer abundance (r > 0.56), and owing to their elevational variations in source and concentration, suspended sediments facilitated distance-decay patterns for AOA and AOB community similarities. This study demonstrates distinctive biogeography and distribution patterns for ammonia oxidizers in high-elevation rivers of the QTP. Extensive research should be conducted to explore the role of these microbes in the nitrogen cycle of this zone.IMPORTANCE Ammonia-oxidizing archaea (AOA) and bacteria (AOB) as well as comammox contribute to ammonia oxidation, which plays significant roles in riverine nitrogen cycle and N2O production. Source regions of numerous rivers in the world lie in high-elevation zones, but the abundance, community, and activity of ammonia oxidizers in rivers in high-elevation regions have rarely been investigated. This study revealed distinctive distribution patterns and community structures for ammonia oxidizers in five high-elevation rivers of the Qinghai-Tibet Plateau, and the individual and combined effects of low temperature, low nutrients, and strong solar radiation on ammonia oxidizers were elucidated. The findings of this study are helpful to broaden our knowledge on the biogeography and distribution pattern of ammonia oxidizers in river systems. Moreover, this study provides some implications to predict the performance of ammonia oxidizers in high-elevation rivers and its variations under global climate warming.

Triple oxygen isotopic evidence for atmospheric nitrate and its application in source identification for river systems in the Qinghai-Tibetan Plateau.

Nitrate source identification in river systems is important for water quality management. Recently, the oxygen isotopic anomaly of nitrate in atmospheric deposition (Δ17Oatm) is used to identify unprocessed atmospheric nitrate in river systems to reduce the uncertainty caused by the wide range of δ18O. In high-elevation regions, such as the Qinghai-Tibetan Plateau (QTP) featured with lower temperature and pressure as well as strong radiation, the Δ17Oatm might be different from that in low-elevation regions, but no relevant studies have been reported. In this work, Δ17Oatm in the QTP was studied, and the fingerprints of nitrate isotopes in synthetic fertilizer, livestock manure, domestic sewage, and soil organic nitrogen (SON) were identified and used to quantify various source contributions to riverine nitrate in the Yellow River and Changjiang River source regions located in the QTP during 2016-2017. The results showed that the average of Δ17Oatm in the QTP was 16.4‰, lower than the range (19-30‰) reported for the low-elevation regions. The possible mechanism is decreased O3 as well as increased hydroxyl and peroxy radical levels in the troposphere caused by the climate condition and ozone valley in the QTP will affect the production pathways of atmospheric nitrate. By combining the sewage discharge data with the output results of the SIAR (stable isotope analysis in R) model based on the stable isotope data, manure was determined to be one of the major sources to riverine nitrate for both rivers. The contributions of various sources to riverine nitrate were 47 ±â€¯10% for manure, 30 ±â€¯5% for SON, 10 ±â€¯4% for atmospheric precipitation, 9 ±â€¯2% for synthetic fertilizer, and 4 ±â€¯0% for sewage in the Yellow River source region. This study indicates that the unique atmospheric conditions in the QTP have led to a lower Δ17Oatm value, and atmospheric source makes a considerable contribution to riverine nitrate in the QTP.

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model.

Lung epithelial-mesenchymal transition (EMT) plays an important role in silicosis fibrosis. The reverse process of EMT is mesenchymal-epithelial transition (MET), which is viewed as an anti-EMT therapy and is a good target toward fibrosis. MicroRNAs (miRNAs) have emerged as potent regulators of EMT and MET programs, and, hence, we tested the miRNA expression using microarray assay and investigated their roles in silica-induced EMT in lung epithelial cells. We found that miRNA-29b (miR-29b) was dynamically downregulated by silica and influenced the promotion of MET in RLE-6TN cells. Furthermore, delivery of miR-29b to mice significantly inhibited silica-induced EMT, prevented lung fibrosis, and improved lung function. Together, our results clearly demonstrated that miR-29b acted as a novel negative regulator of silicosis fibrosis-inhibited lung fibrosis, probably by promoting MET and by suppressing EMT in the lung. These findings may represent a new potential therapeutic target for treating silicosis fibrosis.

Inhibition of nuclear thioredoxin aggregation attenuates PM2.5-induced NF-κB activation and pro-inflammatory responses.

Exposure to fine particulate matter (PM2.5) can induce oxidative stress and proinflammatory cytokine production, which are central for the induction of PM2.5-mediated adverse effects on public health. Nuclear factor kappa B (NF-κB) signaling is essential for inflammation. The subcellular distribution of thioredoxin (Trx) is related to the activation of NF-κB, but the mechanism involved is unclear. In the current study, we focused on the relationship between the antioxidant Trx and NF-κB in human bronchial epithelial cells (BEAS-2B) after PM2.5 exposure. We inhibited the nuclear translocation of Trx by cHCEU (4-cyclohexyl-[3-(2-chloroethyl)ureido]benzene) and subsequently increased the transcriptional activity of Nrf2 to upregulate the expression of Trx by t-BHQ. Our data suggest that PM2.5 exposure induces the activation of NF-κB and the expression of the downstream proinflammatory cytokines IL-1, IL-6, IL-8 and TNF-α in BEAS-2B cells. CHCEU alleviates inflammatory cytokines by blocking Trx nuclear translocation and inhibits the DNA binding activity of NF-κB. T-BHQ could promote the transcriptional activity of Nrf2 but failed to alleviate the production of inflammatory cytokines. Furthermore, the synergistic effect of t-BHQ and cHCEU on alleviating PM2.5-induced inflammation is more effective than the use of cHCEU alone. Our findings characterize the underlying molecular mechanisms of proinflammatory responses induced by PM2.5 and show that the nuclear translocation and accumulation of Trx in nuclei play important roles in PM2.5-induced NF-κB activation and proinflammatory responses.