Acidification of European croplands by nitrogen fertilization: Consequences for carbonate losses, and soil health.

Soil acidification is an ongoing problem in intensively cultivated croplands due to inefficient and excessive nitrogen (N) fertilization. We collected high-resolution data comprising 19,969 topsoil (0-20 cm) samples from the Land Use and Coverage Area frame Survey (LUCAS) of the European commission in 2009 to assess the impact of N fertilization on buffering substances such as carbonates and base cations. We have only considered the impacts of mineral fertilizers from the total added N, and a N use efficiency of 60 %. Nitrogen fertilization adds annually 6.1 × 107 kmol H+ to European croplands, leading to annual loss of 6.1 × 109 kg CaCO3. Assuming similar acidification during the next 50 years, soil carbonates will be completely removed from 3.4 × 106 ha of European croplands. In carbonate-free soils, annual loss of 2.1 × 107 kmol of basic cations will lead to strong acidification of at least 2.6 million ha of European croplands within the next 50 years. Inorganic carbon and basic cation losses at such rapid scale tremendously drop the nutrient status and production potential of croplands. Soil liming to ameliorate acidity increases pH only temporarily and with additional financial and environmental costs. Only the direct loss of soil carbonate stocks and compensation of carbonate-related CO2 correspond to about 1.5 % of the proposed budget of the European commission for 2023. Thus, controlling and decreasing soil acidification is crucial to avoid degradation of agricultural soils, which can be done by adopting best management practices and increasing nutrient use efficiency. Regular screening or monitoring of carbonate and base cations contents, especially for soils, where the carbonate stocks are at critical levels, are urgently necessary.

Size matters: Aerobic methane oxidation in sediments of shallow thermokarst lakes.

Shallow thermokarst lakes are important sources of greenhouse gases (GHGs) such as methane (CH4 ) and carbon dioxide (CO2 ) resulting from continuous permafrost thawing due to global warming. Concentrations of GHGs dissolved in water typically increase with decreasing lake size due to coastal abrasion and organic matter delivery. We hypothesized that (i) CH4 oxidation depends on the natural oxygenation gradient in the lake water and sediments and increases with lake size because of stronger wind-induced water mixing; (ii) CO2 production increases with decreasing lake size, following the dissolved organic matter gradient; and (iii) both processes are more intensive in the upper than deeper sediments due to the in situ gradients of oxygen (O2 ) and bioavailable carbon. We estimated aerobic CH4 oxidation potentials and CO2 production based on the injection of 13 C-labeled CH4 in the 0-10 cm and 10-20 cm sediment depths of small (~300 m2 ), medium (~3000 m2 ), and large (~106 m2 ) shallow thermokarst lakes in the West Siberian Lowland. The CO2 production was 1.4-3.5 times stronger in the upper sediments than in the 10-20 cm depth and increased from large (158 ± 18 nmol CO2 g-1 sediment d.w. h-1 ) to medium and small (192 ± 17 nmol CO2 g-1 h-1 ) lakes. Methane oxidation in the upper sediments was similar in all lakes, while at depth, large lakes had 14- and 74-fold faster oxidation rates (5.1 ± 0.5 nmol CH4 -derived CO2 g-1 h-1 ) than small and medium lakes, respectively. This was attributed to the higher O2 concentration in large lakes due to the more intense wind-induced water turbulence and mixing than in smaller lakes. From a global perspective, the CH4 oxidation potential confirms the key role of thermokarst lakes as an important hotspot for GHG emissions, which increase with the decreasing lake size.

Efficacy and safety of the all-oral bedaquiline-containing regimen as treatment for pediatric multidrug/rifampicin-resistant tuberculosis: a multicenter, retrospective, cohort study.

OBJECTIVE: The study aimed to observe the efficacy and safety of an all-oral bedaquiline (BDQ)-containing regimen for pediatric multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) through a multicenter, retrospective study in China. METHODS: In the study, pediatric patients receiving all-oral BDQ-containing regimen (BDQ group) with clinical matched control group were included, the control group received an injection-containing regimen. The treatment outcomes and the incidence of adverse events (AEs) were compared and analyzed. RESULTS: 79 pediatric patients were enrolled, including 37 cases in BDQ group and 42 cases in the control group, the median age was 12 {8-16} and 11 {9-15} in both groups respectively. Favorable treatment outcome and cure rate in BDQ group were significantly higher than those in control group (100%vs 83.3%, p 0.03; 94.6%vs 63.3%, p 0.00). Median time of sputum culture conversion in BDQ group was significantly shorter than that in the control group (4 weeks vs 8 weeks, p 0.00). The incidence of AEs in the BDQ group was significantly less than that in the control group (48.6% vs 71.4%, p 0.03). No AEs leading to treatment discontinuation of BDQ occurred. CONCLUSIONS: The all-oral BDQ-containing regimens may be effective and safe in the Chinese pediatric population.

Analysis of Drug-Resistant Tuberculosis in Children in Shenyang, China, 2017-2021.

Objective: Drug-resistant tuberculosis (DR-TB) in children seriously threatens TB control. Information on the epidemiology and characteristics of DR-TB in children in China is limited. We studied data in Shenyang Tenth People's Hospital to understand the DR-TB epidemiology in children in Shenyang. Design or Methods: We retrospectively analyzed drug resistance testing data of pediatric TB patients between 2017 and 2021, and included 2976 clinically-diagnosed pediatric TB patients. We described the epidemiology of DR-TB and analyzed the trends of DR-TB incidence. The Kappa value was calculated to assess the agreement between MGIT 960 DST and Xpert MTB/RIF for detecting rifampicin resistance. Multivariate logistic regression was used to identify the risk factors for DR-TB in pediatric patients. Results: Of the 2976 TB patients, 1076 were confirmed by MGIT 960 culture and/or Xpert MTB/RIF. Among the 806 patients identified by MGIT 960 culture, 232 cases (28.78%) were DR-TB. Resistance to the six drugs was in the following order: streptomycin (21.09%), isoniazid (9.35%), rifampin (15.01%), levofloxacin (6.20%), ethambutol (4.22%), and amikacin (3.23%). Alarmingly, 12.90% were MDR-TB (104/806), including 28 (3.47%) pre-XDR-TB. Of the 1076 pediatric TB patients, 295 (27.4%) developed DR-TB to any one drug (including 69 rifampicin-resistant cases identified by Xpert MTB/RIF only). No difference was found in the incidence of pediatric DR-TB between 2017 and 2021. Among 376 patients who were positive for both methods, using the MGIT 960 DST results as the gold standard, Xpert MTB/RIF's sensitivity for detecting rifampicin resistance was 91.38% and its specificity was 94.65%. Conclusion: Between 2017 and 2021, the DR-TB incidence in children remained unchanged in Shenyang. RR-TB, MDR-TB, and even Pre-XDR-TB require attention in children with drug-resistant TB. Xpert MTB/RIF helped to detect more rifampicin-resistant pediatric patients; thus Xpert MTB/RIF should be widely used as an important complementary tool to detect rifampicin-resistant TB in children.

Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD.

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

The spatial distribution of rhizosphere microbial activities under drought: water availability is more important than root-hair-controlled exudation.

Root hairs and soil water content are crucial in controlling the release and diffusion of root exudates and shaping profiles of biochemical properties in the rhizosphere. But whether root hairs can offset the negative impacts of drought on microbial activity remains unknown. Soil zymography, 14 C imaging and neutron radiography were combined to identify how root hairs and soil moisture affect rhizosphere biochemical properties. To achieve this, we cultivated two maize genotypes (wild-type and root-hair-defective rth3 mutant) under ambient and drought conditions. Root hairs and optimal soil moisture increased hotspot area, rhizosphere extent and kinetic parameters (Vmax and Km ) of ß-glucosidase activities. Drought enlarged the rhizosphere extent of root exudates and water content. Colocalization analysis showed that enzymatic hotspots were more colocalized with root exudate hotspots under optimal moisture, whereas they showed higher dependency on water hotspots when soil water and carbon were scarce. We conclude that root hairs are essential in adapting rhizosphere properties under drought to maintain plant nutrition when a continuous mass flow of water transporting nutrients to the root is interrupted. In the rhizosphere, soil water was more important than root exudates for hydrolytic enzyme activities under water and carbon colimitation.

Diversity in rhizospheric microbial communities in tea varieties at different locations and tapping potential beneficial microorganisms.

Soil microenvironments and plant varieties could largely affect rhizosphere microbial community structure and functions. However, their specific effects on the tea rhizosphere microbial community are yet not clear. Beneficial microorganisms are important groups of microbial communities that hold ecological functionalities by playing critical roles in plant disease resistance, and environmental stress tolerance. Longjing43 and Zhongcha108 are two widely planted tea varieties in China. Although Zhongcha108 shows higher disease resistance than Longjing43, the potential role of beneficial tea rhizosphere microbes in disease resistance is largely unknown. In this study, the structure and function of rhizosphere microbial communities of these two tea varieties were compared by using the Illumina MiSeq sequencing (16S rRNA gene and ITS) technologies. Rhizosphere soil was collected from four independent tea gardens distributed at two locations in Hangzhou and Shengzhou cities in eastern China, Longjing43 and Zhongcha108 are planted at both locations in separate gardens. Significant differences in soil physicochemical properties as demonstrated by ANOVA and PCA, and distinct rhizosphere microbial communities by multiple-biotech analyses (PCoA, LEfSe, Co-occurrence network analyses) between both locations and tea varieties (p < 0.01) were found. Functions of bacteria were annotated by the FAPROTAX database, and a higher abundance of Nitrososphaeraceae relating to soil ecological function was found in rhizosphere soil in Hangzhou. LDA effect size showed that the abundance of arbuscular mycorrhizal fungi (AMF) was higher in Zhongcha108 than that in Longjing43. Field experiments further confirmed that the colonization rate of AMF was higher in Zhongcha108. This finding testified that AMF could be the major beneficial tea rhizosphere microbes that potentially function in enhanced disease resistance. Overall, our results confirmed that locations affected the microbial community greater than that of tea varieties, and fungi might be more sensitive to the change in microenvironments. Furthermore, we found several beneficial microorganisms, which are of great significance in improving the ecological environment of tea gardens and the disease resistance of tea plants. These beneficial microbial communities may also help to further reveal the mechanism of disease resistance in tea and potentially be useful for mitigating climate change-associated challenges to tea gardens in the future.

Advantages and challenges of metagenomic sequencing for the diagnosis of pulmonary infectious diseases.

OBJECTIVE: We aim to familiarize the application status of metagenomic sequencing in diagnosing pulmonary infections, to compare metagenomic sequencing with traditional diagnostic methods, to conclude the advantages and limitations of metagenomic sequencing, and to provide some advice for clinical practice and some inspiration for associated researches. DATA SOURCES: The data were obtained from peer-reviewed literature, white papers, and meeting reports. RESULTS: This review focused on the applications of untargeted metagenomic sequencing in lungs infected by bacteria, viruses, fungi, chlamydia pneumoniae, Mycoplasma pneumoniae, parasites, and other pathogens. Compared with conventional diagnostic methods, metagenomic sequencing is better in detecting novel, rare, and unexpected pathogens and being applied in co-infections. Meanwhile, it can also provide more comprehensive information about pathogens. However, metagenomic sequencing still has limitations. Also, the situations that should be applied in and how the results should be interpreted are discussed in this review. CONCLUSION: Metagenomic sequencing improves efficiency to identify pathogens compared with traditional diagnostic methods and can be applied in clinical diagnosis. However, the technology of metagenomic sequencing still needs to be improved. Also, clinicians should learn more about when to use metagenomic sequencing and how to interpret its results.

Visualization and quantification of carbon "rusty sink" by rice root iron plaque: Mechanisms, functions, and global implications.

Paddies contain 78% higher organic carbon (C) stocks than adjacent upland soils, and iron (Fe) plaque formation on rice roots is one of the mechanisms that traps C. The process sequence, extent and global relevance of this C stabilization mechanism under oxic/anoxic conditions remains unclear. We quantified and localized the contribution of Fe plaque to organic matter stabilization in a microoxic area (rice rhizosphere) and evaluated roles of this C trap for global C sequestration in paddy soils. Visualization and localization of pH by imaging with planar optodes, enzyme activities by zymography, and root exudation by 14 C imaging, as well as upscale modeling enabled linkage of three groups of rhizosphere processes that are responsible for C stabilization from the micro- (root) to the macro- (ecosystem) levels. The 14 C activity in soil (reflecting stabilization of rhizodeposits) with Fe2+ addition was 1.4-1.5 times higher than that in the control and phosphate addition soils. Perfect co-localization of the hotspots of ß-glucosidase activity (by zymography) with root exudation (14 C) showed that labile C and high enzyme activities were localized within Fe plaques. Fe2+ addition to soil and its microbial oxidation to Fe3+ by radial oxygen release from rice roots increased Fe plaque (Fe3+ ) formation by 1.7-2.5 times. The C amounts trapped by Fe plaque increased by 1.1 times after Fe2+ addition. Therefore, Fe plaque formed from amorphous and complex Fe (oxyhydr)oxides on the root surface act as a "rusty sink" for organic matter. Considering the area of coverage of paddy soils globally, upscaling by model revealed the radial oxygen loss from roots and bacterial Fe oxidation may trap up to 130 Mg C in Fe plaques per rice season. This represents an important annual surplus of new and stable C to the existing C pool under long-term rice cropping.

Variations in Soil Nutrient Dynamics and Bacterial Communities After the Conversion of Forests to Long-Term Tea Monoculture Systems.

The soil microbial community is a key indicator to evaluate the soil health and productivities in agricultural ecosystems. Monoculture and conversions of forests to tea plantations have been widely applied in tea plantation globally, but long-term monoculture of tea plantation could lead to soil degradation and yield decline. Understanding how long-term monoculture systems influence the soil health and ecosystem functions in tea plantation is of great importance for soil environment management. In this study, through the comparison of three independent tea plantations across eastern China composed of varying stand ages (from 3 to 90 years after conversion from forest), we found that long-term tea monoculture led to significant increases in soil total organic carbon (TOC) and microbial nitrogen (MBN). Additionally, the structure, function, and co-occurrence network of soil bacterial communities were investigated by pyrosequencing 16S rRNA genes. The pyrosequencing analysis revealed that the structures and functions of soil bacterial communities were significantly affected by different stand ages, but sampling sites and land-use conversion (from forest to tea plantation) had stronger effects than stand age on the diversity and structure of soil bacterial communities. Soil bacterial diversity can be improved with increasing stand ages in tea plantation. Further RDA analysis revealed that the C and N availability improvement in tea plantation soils led to the variation of structure and function in soil bacterial communities. Moreover, co-occurrence network analysis of soil bacterial communities also demonstrated that interactions among soil bacteria taxa were strengthened with increasing stand age. Our findings suggest that long-term monoculture with proper managements could be beneficial to soil ecosystems by increasing the C and N content and strengthening bacterial associations in tea plantations. Overall, this study provides a comprehensive understanding of the impact of land-use change and long-term monoculture stand age on soil environments in tea plantation.

Performance of TB-LAMP in the Diagnosis of Tuberculous Empyema Using Samples Obtained From Pleural Decortication.

Purpose: To evaluate the performance of TB-LAMP in the diagnosis of TB empyema using pleural tissue specimens obtained during pleural decortication. Methods: Using the clinical records and the different diagnostic test results of patients who underwent pleural decortication in a TB-designated hospital over 3.5 years, we calculated the sensitivity, specificity positive predictive, and negative predictive values of the pathology, MGIT 960 culture, and TB-LAMP obtained by using pleural tissue specimens against the etiologic diagnosis and composite clinical reference standard (CCRS) as the reference standards. Result: A total of 304 patients' records were extracted. All these patients had gone through pleural decortication. When the etiologic diagnosis was used as the reference, the sensitivity of TB-LAMP in identifying TB empyema was 77.8% (compared to 10.6% of MGIT 960 P < 0.05). The sensitivity of MGIT 960, pathology, and TB-LAMP was 8.2%, 77.7%, and 67.2% against CCRS as the reference; and the specificity of the three was 100.0, 100.0, and 96.2% against the same standard. A combination of pathology and TB-LAMP would increase the sensitivity and specificity to 84.7 and 96.0%. Using TB-LAMP to diagnose TB empyema using pleural tissue samples obtained from pleural decortication was faster with satisfactory performance. Conclusion: TB-LAMP has great potential in faster and more accurate diagnosis of TB empyema. Our findings provide insights for optimizing diagnostic algorithms for TB empyema.

A Comprehensive Evaluation of a Loop-Mediated Isothermal Amplification Assay for the Diagnosis of Pulmonary Tuberculosis in Children Using Bronchoalveolar Lavage Fluid.

Objective: Using TB-LAMP for diagnosing pediatric PTB, however, still requires systematic evaluation. Here, we evaluated TB-LAMP performance alone and in combination with conventional assays for diagnosing PTB in Chinese children, using mycobacterial culture or CCRS (the composite clinical reference standard) as references. Design or Methods: BALF samples were collected at Shenyang Tenth People's Hospital from 251 children susceptible to TB infection with indications for fiberoptic bronchoscopy. Results: When mycobacterial culture was the reference, TB-LAMP used alongside smear microscopy doubled sensitivity for detecting pediatric PTB compared with smear microscopy alone (82.5% vs 40.0%). When CCRS was the reference, AFB microscopy, MTB culture, and TB-LAMP had sensitivities of 16.5%, 30.1%, and 51.1%, respectively, and specificities of 98.2%, 100.0%, and 99.1%. Combining MTB culture with TB-LAMP gave a sensitivity of 61.1% and specificity of 96.6%. TB-LAMP identified 39.3% and 43.2% of cases with negative MTB culture or AFB microscopy results. Conclusion: TB-LAMP using BALF samples provided faster results, allowing early and accurate PTB diagnosis. Our findings provide insights for optimizing diagnostic algorithms for pediatric PTB.

Temperature sensitivity of anaerobic methane oxidation versus methanogenesis in paddy soil: Implications for the CH4 balance under global warming.

The global methane (CH4 ) budget is based on a sensitive balance between methanogenesis and CH4 oxidation (aerobic and anaerobic). The response of these processes to climate warming, however, is not quantified. This largely reflects our lack of knowledge about the temperature sensitivity (Q10 ) of the anaerobic oxidation of CH4 (AOM)-a ubiquitous process in soils. Based on a 13 CH4 labeling experiment, we determined the rate, Q10 and activation energy of AOM and of methanogenesis in a paddy soil at three temperatures (5, 20, 35°C). The rates of AOM and of methanogenesis increased exponentially with temperature, whereby the AOM rate was significantly lower than methanogenesis. Both the activation energy and Q10 of AOM dropped significantly from 5-20 to 20-35°C, indicating that AOM is a highly temperature-dependent microbial process. Nonetheless, the Q10 of AOM and of methanogenesis were similar at 5-35°C, implying a comparable temperature dependence of AOM and methanogenesis in paddy soil. The continuous increase of AOM Q10 over the 28-day experiment reflects the successive utilization of electron acceptors according to their thermodynamic efficiency. The basic constant for Q10 of AOM was calculated to be 0.1 units for each 3.2 kJ mol-1 increase of activation energy. We estimate the AOM in paddy soils to consume 2.2~5.5 Tg CH4 per year on a global scale. Considering these results in conjunction with literature data, the terrestrial AOM in total consumes ~30% of overall CH4 production. Our data corroborate a similar Q10 of AOM and methanogenesis. As the rate of AOM in paddy soils is lower than methanogenesis, however, it will not fully compensate for an increased methane production under climate warming.

A novel belowground in-situ gas labeling approach: CH4 oxidation in deep peat using passive diffusion chambers and 13C excess.

In-vitro incubation of environmental samples is a common approach to estimate CH4 oxidation potential. Here we developed and verified an in-situ method utilizing passive diffusion chambers (PDC, silicone tubes) to deliver 13C-labeled CH4 into peat for the determination of the CH4 oxidation potential based on 13C excess of CO2. To target CH4 oxidation under semi-aerobic and anaerobic conditions, we installed 20 PDCs (30 ml volume) below the water table in profiles from 35-cm to 2-m depths of a peatland in north-eastern Sweden in July 2017 using a peat auger. 13C-labeled CH4 was injected into PDCs through tubing twice during 12 days (day 0 and 6) and samples were collected at days 1, 3, 6, 8 and 11. Background (non-labeled) δ13C of CO2 ranged from -7.3 (35 cm) to +5.7‰ (200 cm) with depth. These δ13C values rose to +110 and + 204‰ after the CH4 injection. The estimated CH4-derived C in CO2 was the lowest at the bottom of the profile (0.3 µmol L-1), whereas the maximum was at 100 cm (6.1 µmol L-1) at five days after the second labeling. This corresponded to 1.5-7.2% of the total CH4 pool to be oxidized, depending on depth. This novel approach with belowground in-situ 13C labeling of gases demonstrated the suitability of tracing the transformations of these gases in soil depth by PDCs and for the first time verified the in-situ occurrence of a deep-peat CH4 oxidation.

Twenty-four-week interim outcomes of bedaquiline-containing regimens in treatment of adolescents with rifampicin-resistant tuberculosis: A retrospective cohort study in China.

AIM: To evaluate the 24-week interim outcomes of bedaquiline-containing regimens in the treatment of adolescents with rifampicin-resistant tuberculosis (RR-TB) in China. METHODS: Adolescents with RR-TB from two hospitals were included in this retrospective study. All patients received the longer regimen containing bedaquiline. Sputum culture, chest computed tomography, blood tests and electrocardiography were performed regularly, and the outcomes after 24 weeks of treatment were reported. RESULTS: Four male and six female adolescents aged 11 to 17 years old were included. Among them, four (40.0%), four (40.0%) and two (20.0%) were confirmed to have RR-TB, multidrug-resistant TB and extensively drug-resistant TB, respectively. The most common companion drugs included linezolid (100.0%), cycloserine (90.0%), pyrazinamide (80.0%), moxifloxacin (50.0%) and levofloxacin (40.0%). Culture conversion rates of 80.0%, 100.0% and 100.0% were observed at weeks 2, 4 and 24, respectively. The mean maximum drug concentration of bedaquiline at weeks 2, 12 and 24 was 3.29 ± 0.66, 1.78 ± 0.81 and 1.93 ± 0.74 µg/mL, respectively. Six adverse events including leukopenia (50.0%), Fridericia-corrected QT (QTcF) interval prolongation (16.7%), anaemia (16.7%) and peripheral neuropathy (16.7%) were observed in five (50.0%) patients. No patient discontinued bedaquiline owing to QTcF interval prolongation. Meanwhile, no deaths, reversions or serious adverse events were reported during 24 weeks of treatment. CONCLUSION: A longer regimen containing bedaquiline was effective and well tolerated in Chinese adolescents with RR-TB. The combination of bedaquiline and linezolid may be a favourable choice for this population.

Anti-IL-23 exerted protective effects on cerebral ischemia-reperfusion injury through JAK2/STAT3 signaling pathway.

Ischemia-reperfusion frequently occurs in ischemic cerebral vascular disease, during which the inflammatory signaling plays essential roles. The aim of this study was to discover the efficacy of the antibody to a key immune cytokine IL-23 (anti-IL-23) for the therapy of cerebral ischemia-reperfusion injury. We established the cerebral ischemia-reperfusion injury model by middle cerebral artery occlusion (MCAO). Anti-IL-23 injection attenuated lesions indicated by histology study. RT-PCR and Western blot were employed to detect the mRNA and protein expression of JAK2 and STAT3 after anti-IL-23 treatment. ELISA was utilized to measure the levels of MDA (malondialdehyde) and superoxide dismutase (SOD). Moreover, curcumin and IL-6 were implicated in the endogenous intervention of IL-23 signaling in vivo. Our data demonstrated that the treatment of anti-IL-23 might transcriptionally activate the classic immune pathway in the brain. Anti-IL-23 augmented phosphorylation levels of both JAK2 and STAT3, suggesting the amplification signaling of JAK/STAT after exogenous IL-23 intervention. Anti-IL-23 reduced ROS molecules of STAT downstream in the serum and brain. It also alleviated the injury by bringing down levels of MDA and SOD in the serum. JAK2 inhibitor could abolish the effect of anti-IL-23 whereas JAK3 ameliorated the injury. The combination of anti-IL-23 and JAK3i could reduce infarct volume more effectively. In summary, this study indicated that anti-IL-23 had protective effects against cerebral ischemia-reperfusion injury by targeting the immune specific JAK2-STAT3 in JAK/STAT pathway.

Medical treatment of 55 patients with COVID-19 from seven cities in northeast China who fully recovered: A single-center, retrospective, observational study.

ABSTRACT: Coronavirus disease 2019 (COVID-19) is an emerging disease caused by severe acute respiratory syndrome coronavirus 2; no specific effective medication to treat the disease has been identified to date. We aimed to investigate the administered medications and intervention times for patients who completely recovered from COVID-19.This single-center, retrospective, observational study included 55 patients with COVID-19 who were transferred to Shenyang Sixth People's Hospital between January 20 and March 15, 2020. Data on demographics, symptoms, laboratory indicators, treatment processes, and clinical outcomes were collected. Administered drugs and intervention times were compared in 47 and 8 patients with mild and severe symptoms, respectively.All 55 patients recovered. Fifty-three patients (96.36%) received antiviral therapy, including 45 in the mild group (median treatment: 14 days; 17 received umifenovir) and all 8 severe-group patients (median treatment: 17.5 days; 4 received lopinavir/ritonavir). Twenty-nine patients (52.72%) were administered antibiotics, including 21 in the mild group (median treatment: 13.5 days; 15 received moxifloxacin) and all 8 in the severe group (median treatment: 9 days; 2 received linezolid). Moreover, 7 patients (12.72%) were treated with glucocorticoids and 9 (16.36%) with immunomodulators.Given the 100% recovery rate, early administration of antiviral drugs can be considered. Umifenovir may benefit patients with mild symptoms, while lopinavir/ritonavir may benefit those with severe symptoms. Prophylactic administration of common antibiotics may reduce the risk of co-infection. The use of glucocorticoids is usually not necessary. Randomized, double-blind, and controlled trials remain necessary for more accurate conclusions.

AG490 protects cerebral ischemia/reperfusion injury via inhibiting the JAK2/3 signaling pathway.

BACKGROUND: Cerebral ischemia/reperfusion injury is a severe problem in patients with brain ischemia. Brain injury caused by the immune response is important in the pathogenesis of cerebral ischemia/reperfusion injury and immune pathways. It is important to investigate potential targets for the treatment of cerebral ischemia/reperfusion injury. METHODS: In this experiment, we evaluated the effect of an exogenous JAK antagonist AG490 in the cerebral ischemia/reperfusion injury model, which was established by middle cerebral artery occlusion (MCAO). Histology study, TUNEL staining, Western blot, and RT-PCR were employed to examine the effects of AG490 in cerebral ischemia/reperfusion injury. RESULTS: In the brain tissue of MCAO mice, JAK2 was highly expressed. AG490 is an inhibitor of JAK2, which reduced the phosphorylation level of JAK2. AG490 downregulated the phosphorylated activation of JAK3 and their downstream STAT3. The antiapoptotic activity of AG490 on cerebral ischemia/reperfusion injury mice was consistent with in vitro data. It reduced the phosphorylation of JAK2/JAK3/STAT3 and the apoptosis rate in cultured neurons upon apoptosis induction. Besides, we also observed the neuroprotective effects of AG490 on cerebral ischemia/reperfusion injury. Administration of AG490 could further enhance the expression of neurotrophins including BNDF, NT3, and the neurotrophin receptor TrkB. CONCLUSION: Therefore, AG490 is pluripotent for cerebral ischemia/reperfusion injury through both antiapoptosis and neuroprotective activities. The antiapoptosis effect is dependent on its regulation of the JAK-STAT pathway.

Corticosteroids alleviate lipopolysaccharide-induced inflammation and lung injury via inhibiting NLRP3-inflammasome activation.

The role of corticosteroids in acute lung injury (ALI) remains uncertain. This study aims to determine the underlying mechanisms of corticosteroid treatment for lipopolysaccharide (LPS)-induced inflammation and ALI. We used corticosteroid treatment for LPS-induced murine ALI model to investigate the effect of corticosteroid on ALI in vivo. Moreover, LPS-stimulated macrophages were used to explore the specific anti-inflammatory effects of corticosteroids on NLRP3-inflammasome in vitro. We found corticosteroids attenuated LPS-induced ALI, which manifested in reduction of the alveolar structure destruction, the infiltration of neutrophils and the inflammatory cytokines release of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in Lung. In vitro, when NLRP3-inflammasome was knocked out, inflammatory response of caspase-1 activation and IL-1ß secretion was obviously declined. Further exploration, our results showed that when corticosteroid preprocessed macrophages before LPS primed, it obviously inhibited the activation of caspase-1 and the maturation of IL-1ß, which depended on inhibiting the nuclear factor-κB (NF-κB) signal pathway activation. However, when corticosteroids intervened the LPS-primed macrophages, it also negatively regulated NLRP3-inflammasome activation through suppressing mitochondrial reactive oxygen species (mtROS) production. Our results revealed that corticosteroids played a protection role in LPS-induced inflammation and ALI by suppressing both NF-κB signal pathway and mtROS-dependent NLRP3 inflammasome activation.

GPRC5A reduction contributes to pollutant benzo[a]pyrene injury via aggravating murine fibrosis, leading to poor prognosis of IIP patients.

Air pollution exposure is recently reported to be one of the drivers of exacerbation in idiopathic pulmonary fibrosis (IPF). But there was a lack of direct evidence between pollution and lung fibrosis. Here, our data show effects of pollutant benzo[a]pyrene (BaP) and protein G-protein-coupled receptor family C group 5 type A (GPRC5A) on pulmonary fibrosis, which might help limit potential pollutant injury and disease progression. We cross-referenced epithelial differentially-expressed-genes (DEGs) from pollutant injury and published experimental fibrosis and IPF patients' data, top common-DEG (CO-DEG) GPRC5A was identified as a potential link between exposure-damage and fibrogenesis. The role of GPRC5A was evaluated under BaP exposure, in idiopathic interstitial pneumonia (IIP) tissue-array and via CRISPR/Cas9 knockout mice (Gprc5a-/-). BaP exposure enhanced bleomycin (BLM)-induced murine pulmonary fibrosis with increased Fibronectin and α-SMA expression in primary fibroblasts, thickened respiratory membrane and damaged alveolar type II cell, combined with Gprc5a decline in fibrotic mass. GPRC5A mRNA reduced after 10-14 days' BaP exposure in human epithelial cell A549. GPRC5A protein was further found to decrease in IIP epithelium, especially hyperplastic regions. A high epithelial GPRC5A expression score was positively associated with long survival time (R = 0.34) while negatively with high age (R = -0.4) and IIP type IPF (R = -0.5). Low GPRC5A expression predicts poor prognosis (HR = 4.5). Gprc5a depletion aggravated mortality rate (50%) with increased collagen deposition and myofibroblast activation under BLM treatment and exacerbated BaP injury in lung remodeling. Vitamin metabolic imbalance and Mitofusion2 (Mfn2) or Opa1-regulated mitochondrial dynamics were deduced to contribute to Gprc5a depletion and fibrogenesis. Pollutant BaP exposure worsens murine fibrosis and myofibroblast activation via GPRC5A reduction in the damaged epithelium. GPRC5A deficiency was first confirmed to contribute to both poor prognosis of IIP patients and fibrogenesis in murine model; thus, GPRC5A could serve as a novel therapeutic target in pollutant injury and pulmonary fibrosis.