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Abstract C-to-G base editors have been successfully constructed recently, but limited work has been done on concurrent C-to-G and A-to-G base editing. In addition, there is also limited data on how chromatin-associated factors affect the base editing. Here, we test a series of chromatin-associated factors, and chromosomal protein HMGN1 was found to enhance the efficiency of both C-to-G and A-to-G base editing. By fusing HMGN1, GBE and ABE to Cas9, we develop a CRISPR-based dual-function A-to-G and C-to-G base editor (GGBE) which is capable of converting simultaneous A and C to G conversion with substantial editing efficiency. Accordingly, the HMGN1 role shown in this work and the resulting GGBE tool further broaden the genome manipulation capacity of CRISPR-directed base editors.

Highlights 1. This review focuses on NETs formation and the role of NETs in PF and presents research progress. 2. We describe specific mechanisms by which NETs induce PF in fibroblasts while revealing the transduction mechanisms that remain to be investigated. 3. We explore the possible consequences of NETs action on lung epithelial cells, including NETs-induced lung epithelial damage and NETs-driven epithelial mesenchymal transition. 4. We introduce recent key findings about the role of NETs-mediated chronic inflammation in PF and the effect of autophagy-driven production of NETs in fibrosis.

BackgroundRapidly progressive interstitial lung disease (RP-ILD) is the most serious complication of anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM). This study was performed to assess the prognostic factors of patients with anti-MDA5+ DM and the clinical characteristics and predictors of anti-MDA5+ DM in combination with RP-ILD.MethodsIn total, 73 MDA5+ DM patients were enrolled in this study from March 2017 to December 2021. They were divided into survival and non-survival subgroups and non-RP-ILD and RP-ILD subgroups.ResultsThe lactate dehydrogenase (LDH) concentration and prognostic nutritional index (PNI) were independent prognostic factors in patients with anti-MDA5+ DM: the elevated LDH was associated with increased mortality (p = 0.01), whereas the elevated PNI was associated with reduced mortality (p < 0.001). The elevated LDH was independent risk prognostic factor for patients with anti-MDA5+ DM (HR 2.42, 95% CI: 1.02–4.83, p = 0.039), and the elevated PNI was independent protective prognostic factor (HR, 0.27; 95% CI, 0.08 - 0.94; p = 0.039). Patients who had anti-MDA5+ DM with RP-ILD had a significantly higher white blood cell count and LDH concentration than those without RP-ILD (p = 0.007 and p = 0.019, respectively). In contrast, PNI was significantly lower in patients with RP-ILD than those without RP-ILD (p < 0.001). The white blood cell count and elevated LDH were independent and significant risk factors for RP-ILD (OR 1.54, 95% CI: 1.12 - 2.13, p = 0.009 and OR 8.68, 95% CI: 1.28 - 58.83, p = 0.027, respectively), whereas the lymphocyte was an independent protective factor (OR, 0.11; 95% CI, 0.01 - 0.81; p = 0.03).ConclusionThe elevated LDH and elevated PNI were independent prognostic factors for patients with anti-MDA5+ DM. The elevated LDH was independent risk factor for RP-ILD. Patients with anti-MDA5+ DM could benefit from the measurement of LDH and PNI, which are inexpensive and simple parameters that could be used for diagnosis as well as prediction of the extent of lung involvement and prognosis.

ObjectiveSeveral studies have demonstrated that anti-carbamylation protein antibodies (Anti-CarPA) are persistent in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), primary Sjögren’s syndrome (pSS), and interstitial lung disease associated with RA (RA-ILD). However, the relationship between anti-CarPA and other rheumatic diseases (RDs) and non-RA-ILD is not known till now. This study sought to examine the presence of anti-CarPA in Chinese Han patients with RDs and its clinical significance.MethodsThe study included 90 healthy controls (HCs) and 300 patients with RDs, including RA, SLE, polymyositis/dermatomyositis (PM/DM), pSS, SSC, spondyloarthritis (SpA), anti-neutrophil cytoplasmic autoantibodies associated with vasculitis (AAV), undifferentiated connective tissue disease (UCTD), and Behcet’s disease (BD). Antibodies against carbamylated human serum albumin were detected using commercial enzyme-linked immunosorbent assay kits. Correlations between clinical and laboratory parameters were analyzed.ResultSerum levels of anti-CarPA in RA (34.43 ± 33.34 ng/ml), SLE (21.12 ± 22.23 ng/ml), pSS (16.32 ± 13.54 ng/ml), PM/DM (30.85 ± 17.34 ng/ml), SSC (23.53 ± 10.70 ng/ml), and UCTD (28.35 ± 21.91 ng/ml) were higher than those of anti-CarPA in the HCs (7.30 ± 5.05 ng/ml). The concentration of serum anti-CarPA was higher in patients with rheumatic disease-related interstitial lung disease (RD-ILD), especially RA-ILD, PM/DM-ILD, and pSS-ILD. Patients with RD-ILD who tested positive for anti-CarPA were more likely to have a more severe radiographic classification (grades II, p = 0.045; grades III, p = 0.003). Binary logistic regression analysis suggested that anti-CarPA had an association with ILD in RA (p = 0.033), PM/DM (p = 0.039), and pSS (p = 0.048). Based on receiver operating characteristics (ROC) analysis, anti-CarPA cutoffs best discriminated ILD in RA (>32.59 ng/ml, p = 0.050), PM/DM (>23.46 ng/ml, p = 0.038), and pSS (>37.08 ng/ml, p = 0.040). Moreover, serum levels of anti-CarPA were correlated with antibodies against transcription intermediary factor 1 complex (anti-TIF1) (R = –0.28, p = 0.044), antibodies against glycyl-transfer ribonucleic acid synthetase (anti-EJ) (R = 0.30, p = 0.031), and antibodies against melanoma differentiation-associated gene 5 (anti-MDA5) (R = 0.35, p = 0.011).ConclusionSerum anti-CarPA could be detected in patients with RA, PM/DM, pSS, SSC, and UCTD among the Chinese Han population. And it may also assist in identifying ILD in patients with RA, PM/DM, and pSS, which emphasized attention to the lung involvement in anti-CarPA-positive patients.

Objective：Macrophages are the main source of inflammatory mediators and play important roles in the pathogenesis of rheumatoid arthritis (RA). Interleukin-21 (IL-21) regulates both innate and adaptive immune responses and exerts major effects on inflammatory responses that promote the development of RA. However, its effect on macrophage polarisation remains unclear. Methods：CD14+ monocytes of the peripheral blood of Human healthy donors (HD) and RA, and macrophages of RA synovial fluid (RA-SF MΦs) were isolated. IL-21 receptor (IL-21R) was detected by flow cytometry. Cytokine production by MΦs from different sources pre-treated with IL-21 and/or LPS was measured by real-time polymerase chain reaction (RT-PCR) and ELISA. CD14+ monocytes were differentiated into M1-like and M2-like macrophages via stimulation with GM-CSF, interferon-γ (IFN-γ), and LPS or M-CSF, IL-4, and IL-13, respectively. To determine the effect of IL-21 on macrophage polarisation, macrophage phenotypes, gene expression, and cytokine secretion were detected by flow cytometry, RT-PCR, and ELISA. TLR4 and ERK1/2 were determined by western blotting. Results：IL-21 exerted different effects on LPS-mediated inflammatory responses in various derived MΦs, and inhibited macrophages polarisation to M1-like macrophages and promote their polarisation to M2-like macrophages in HD and RA. Moreover, IL-21 inhibited LPS-mediated secretion of inflammatory cytokines, probably by downregulating the ERK1/2, in RA-SF MΦs. Conclusion：For the first time, we indicated that IL-21 inhibits LPS-mediated cytokine production in RA-SF MΦs, and impairs pro-inflammatory activity of M1-like macrophages, hereby exerting anti-inflammatory effects on RA. Thus, IL-21 might not be an appropriate therapeutic target for RA.

Polyacrylamide (PAM) is a water-soluble polymer with strong cohesiveness and a strong water absorption capacity, and it has been widely used to modify soil structural stability. However, little information is available on the impact of PAM application on the aggregate-breaking process of purple soils in hilly areas of southwestern China. Therefore, the current study aimed to examine the influence of PAM application on the aggregate stability of purple soil in terms of different breakdown mechanisms at different hillslope locations. Three disruptive tests employing the Le Bissonnais method (FW, fast-wetting sieving; SW, slow-wetting sieving; and WS, wet-stirring sieving) were used to determine the mean weight diameter (MWD), geometric mean diameter (GMD), and mass fractal dimension (D) of the soil aggregates, and soil erodibility factor (K) was calculated as an index of soil anti-erodibility. Overall, the major aggregate-breaking mechanism for purple soils was the following: SW (differential swelling) > WS (mechanical breakdown) > FW (slaking). The content of water-stable aggregates (>0.25 mm) obviously rose after PAM application, with the most significant influences shown under FW. A significant difference in MWD was observed between PAM application and without polyacrylamide application (CK) under WS (p < 0.05). However, there was a significant difference in GMD between PAM and CK (p < 0.05) under FW and SW. In comparison with CK, D value in PAM under FW and SW was significantly reduced, mainly at the slope locations of 0 and 20 m. A descending order of FW, WS, and SW was found on the basis of K value at different slope locations. These findings contribute to improved understanding of proper application of soil amendments to control soil and water loss in purple soils.

Abstract Background: Interleukin‐21 (IL‐21) has a regulatory effect on various immune cells. Its effect on macrophage function remains unclear. Aims: This study aimed to investigate the effect of IL‐21 on the macrophages‐mediated inflammatory response and explore its mechanism. Materials & Methods: Phorbol myristate acetate was used to induce THP‐1‐derived macrophages. Then, cells were stimulated with IL‐21 and/or lipopolysaccharide (LPS). To determine the effect of IL‐21 on the production of inflammatory factors in THP‐1‐derived macrophages, the messenger RNA (mRNA) and protein levels of IL‐6, tumor necrosis factor‐α (TNF‐α), IL‐8, and IL‐10 were detected by real‐time polymerase chain reaction (RT‐PCR) and enzyme‐linked immunosorbent assay (ELISA), respectively. Meanwhile, to explore the effect of IL‐21 on macrophage polarization, macrophage phenotype, gene expression, and cytokine secretion mediated by THP‐1‐derived macrophage were detected by flow cytometry, RT‐PCR, and ELISA. Results: First, we found that the IL‐21 receptor was expressed in THP‐1‐derived macrophages. IL‐21 enhanced LPS‐mediated TNF‐α, IL‐6, and IL‐10 production in THP‐1‐derived macrophages. During the polarization of THP‐1‐derived macrophages to M1‐like macrophages, IL‐21 induced the expression of macrophage surface markers CD86 and CD80, and related genes, such as TNF‐α, IL‐6, IL‐1β, and DC‐SIGN mRNA, inhibited Dectin‐1 mRNA expression and promoted the secretion of TNF‐α. During the polarization of THP‐1‐derived macrophages to M2‐like macrophages, IL‐21 enhanced the expression of macrophage surface markers CD86 and CD163, and related genes, such as TNF‐α, IL‐1β, IL‐10, Dectin‐1, and DC‐SIGN mRNA, and promoted the secretion of IL‐10. Conclusion: IL‐21 promotes LPS‐mediated production of inflammatory cytokines by THP‐1‐derived macrophages; IL‐21 plays a two‐way regulatory role in THP‐1‐derived macrophage polarization.

An exploitable amount of groundwater in arid regions is related to changes in water resource utilization patterns, and the traditional water resource allocation model assumes a constant exploitable amount of groundwater. In this study, a water resource allocation model consisting of a water resource optimal allocation module, an exploitable amount analysis module, and a mutual feedback iterative module connecting the abovementioned two modules is established based on the dynamic exploitable amount of groundwater. The proposed model is applied to Jinghe County, Xinjiang, which is one of the most arid regions in the world. The results show that the actual exploitable amount of groundwater in 2035 will be 181.54 million m³ when changes in the exploitable amount of groundwater in response to changes in the water resources utilization patterns are considered, which is 43.99 million m³ lower than the current amount, and the groundwater supply will be 167.82 million m³. However, the groundwater supply based on the current exploitable amount of groundwater (225.53 million m3) will be 188.29 million m3, which is 6.75 million m3 higher than the actual exploitable amount of groundwater and thus may lead to groundwater overdraft. This is mainly attributed to the reduction in the exploitable amount of groundwater with the reduction in farmland, and it is estimated that the exploitable amount of groundwater would be decreased by about 110,000 m3 with the reduction of 1 km2 farmland. The results of this study underline the need to consider changes in the exploitable amount of groundwater in the allocation and management of water resources in arid regions, and the model developed in this study can provide an effective tool for rational allocation of water resources in arid regions.

Abstract Base editing events in eukaryote require a compatible chromatin environment, but there is little research on how chromatin factors contribute to the editing efficiency or window. By engineering BEs (base editors) fused with various pioneer factors, the authors found that SOX2 substantially increased the editing efficiency for GBE and CBE. While SoxN‐GBE (SOX2‐NH3‐GBE) improved the editing efficiency at overall cytosines of the protospacer, SoxM‐GBE/CBE (SOX2‐Middle‐GBE/CBE) enabled the higher base editing at PAM‐proximal cytosines. By separating functional domains of SOX2, the SadN‐GBE (SOX2 activation domain‐NH3‐GBE) is constructed for higher editing efficiency and SadM‐CBE for broader editing window to date. With the DNase I assay, it is also proved the increased editing efficiency is most likely associated with the induction of chromatin accessibility by SAD. Finally, SadM‐CBE is employed to introduce a stop codon in the proto‐oncogene MYC, at a locus rarely edited by previous editors with high efficiency. In this work, a new class of pioneer‐BEs is constructed by fusion of pioneer factor or its functional domains, which exhibits higher editing efficiency or broader editing window in eukaryote.

Abstract Background Opioid receptors are implicated in cell proliferation and cancer migration. However, the effects and underlying mechanisms of opioid receptor κ (OPRK1) in breast cancer remain unknown. Methods Small interfering RNA (siRNAs) was used to knockdown the expression of OPRK1. Western blot was used to determine the protein expression and reverse transcription-quantitative PCR (RT-qPCR) determined the genes transcription. Cell viability was detected by MTT assay and cell death rates were determined by Annexin V/PI and flow cytometry. Cell migration and invasion were detected by wound healing analysis and transwell assay, respectively. Results Our research demonstrated that OPRK1 was overexpressed in breast cancer cells compared with the normal human mammary epithelial cells. OPRK1 knockdown could inhibited cell viability and migration in cancer cells, accompanied with the decreased proteins and genes expression of N-cadherin, Snail, MMP2 and Vimentin, while the E-cadherin expression was increased. Additionally, OPRK1 knockdown also promoted PI3K/AKT signaling inactivation. Activation of AKT reversed the OPRK1 knockdown-induced cell viability inhibition and migration suppression, while inhibition of AKT reduced cell viability and promoted cell death. Conclusions Our findings illustrated the role of OPRK1 played on promoting migration in vitro, and we also provided the therapeutic research of OPRK1 knockdown combined with AKT inhibition.

ObjectiveAlthough Traditional Chinese Yijinjing Qigong Exercise (YJJQE) as mind–body intervention is popularly used among adults to ameliorate depressive symptoms in China, no randomized controlled trials (RCTs) are available to evaluate the effects of YJJQE in patients with poststroke depression (PSD). This study aims to explore the clinical efficacy and the neurological and psychiatric mechanism in brain network functional connectivity underlying electroencephalography (EEG).Materials and methodsA total of 60 patients, diagnosed with mild PSD, were randomly (1:1) assigned to YJJQE group (n = 30) and control group of routine segmental rehabilitation training group (n = 30) for a 60-min exercise session once a day for 3 weeks. All outcome measures were collected at baseline and 3-weeks ending intervention. The primary outcome was the 24-item Hamilton Depression Scale (HAMD-24) score, evaluation at more time points for 1 month of follow-up. The secondary outcomes were EEG data in four frequency domains (δ, θ, α, and β), global efficiency (GE), local efficiency (LE), GE/LE curve [areas under the curve (AUC)], Phase Lag Index (PLI), (HAMD-24) Score and EEG correlation analysis.ResultsAll patients showed no significant differences in baseline data. After 3 weeks and 1 month of follow-up, the YJJQE group demonstrated significant decreasing changes compared to the control group on the HAMD-24 scores (p < 0.001). Furthermore, the YJJQE group also showed a significant reduction in θ wave, and an increase in both GE and LE. Compared to the control group, the YJJQE Qigong group showed significantly greater functional connectivity in the δ, θ, and β frequency bands in the brain network of the degree of phase synchronization (p < 0.001). HAMD-24 Score and EEG correlation analysis negative correlation in the Qigong group θ wave (p < 0.001).ConclusionOur findings demonstrated that YJJQE is estimated to effectively alleviate the depressed mood of patients with PSD by promoting the efficiency in information transmission of network functional connectivity and its integration ability in different brain regions. Therefore, the YJJQE would be useful as a non-pharmacological treatment to prevent PSD.Clinical trial registration[http://www.chictr.org.cn/showproj.aspx?proj=55789], identifier [ChiCTR2000035588].

Many studies have focused on the impacts of rainfall duration and intensity, while overlooking the role of rainfall patterns on intensive tillage erosion in hilly agricultural landscapes. The objective of this study was to determine the combined effects of rainfall patterns and tillage erosion on surface runoff and soil loss on sloping farmland in the purple soil area of China. Five simulated rainfall patterns (constant, rising, falling, rising–falling, and falling–rising) with the same total precipitation were designed, and the intensive tillage treatment (IT) and no-tillage treatment (NT) were subjected to simulated rainfall using rectangular steel tanks (2 m × 5 m) with a slope of 15°. To analyse the differences in the hydrological characteristics induced by tillage erosion, we calculated the flow velocity (V), Reynolds number (Re), Froude number (Fr), and Darcy–Weisbach resistance coefficient (f). The results indicate that significant differences in surface runoff and sediment yield were found among different rainfall patterns and rainfall stages (p < 0.05). The falling pattern and falling–rising pattern had a shorter time gap between the rainfall initiation and runoff occurrence as well as a larger sediment yield than those of the other rainfall patterns. The value of f varied from 0.30 to 9.05 for the IT and 0.48 to 11.57 for the NT and exhibited an approximately inverse trend to V and Fr over the course of the rainfall events. Compared with the NT, the mean sediment yield rates from the IT increased the dynamic range of 8.34–16.21% among the different rainfall patterns. The net contributions of the IT ranged from 2.77% to 46.39% in terms of surface runoff and 10.14–78.95% in terms of sediment yield on sloping farmland. The surface runoff and sediment yield were positively correlated with rainfall intensity, V, and Fr, but negatively correlated with f irrespective of tillage operation (p < 0.05). The results showed that the tillage erosion effects on soil and water loss were closely related to rainfall patterns in hilly agricultural landscapes. Our study not only sheds light on the mechanism of tillage erosion and rainfall erosion but also provides useful insights for developing tillage water erosion prediction models to evaluate soil and water loss on cultivated hillslopes.

Background and Objective: Knee osteoarthritis (KOA) is a chronic degenerative disease characterized by pain, morning stiffness and swelling in the knee joints. And KOA is common in the elderly and seriously affects the exercise function and physical health of patients. This study aimed to explore the curative effects of patellar inward pushing method (PIPM) on KOA. Methods: In this study, we established rabbit animal models of KOA for the research by using the New Zealand white rabbits. A total of n=30 rabbits were divided into 5 groups by random number table method: blank group, model group, glucosamine hydrochloride (GH) group, PIPM group and PIPM combined with GH group. The rabbits were then modeled. Results: After 9-weeks cultured in groups, 5 ml blood was collected from the heart, and cytokines were detected. The result suggested that iNOS, NO and TNF-α were the pathogenic inflammatory factor of KOA, and aggravated cartilage damage and degeneration. Besides, this study indicated that PIPM combined with GH treatment significantly reduced the activity of inflammatory cytokines in serum and joint fluid of KOA models in rabbits. In addition, PIPM combined with GH therapy exhibited the best therapeutic effect among these treatments, which was working on KOA better than PIPM treatment alone or GH treatment alone. Conclusion: PIPM could effectively treat KOA via regulating cytokines, and the PIPM combined with GH therapy could be a novel therapeutic strategy for KOA.

With the conspicuous contradiction between water use inside and outside rivers, ecological reservoir operation has become a feasible approach to coordinate the relationship between socio-economic water use and ecological water use in rivers. However, ecological water demand in rivers remains difficult to be satisfied in areas facing serious water shortages, resulting in an imbalance between ecological and socio-economic water use. To satisfy the instream ecological water demands in water shortage areas, efforts were made on seeking an optimal reservoir operation scheme to balance the water supply for ecology and socio-economy. This study applied the index of guarantee rate of ecological water (GREW) to ecological river management, improved the previous reservoir operation rules, and constructed an optimization model of ecological reservoir operation rules based on dual-control management indexes. The Dagu River in Qingdao City, China, was selected as a study area to apply this model. The results showed that both the recommended scheme and the scheme without considering ecology could meet the socio-economic water demands, but the satisfaction degree of ecological water demand of the recommended scheme was significantly higher than that of the scheme without considering ecology. The scheme without considering ecology cannot ensure the ecological water demand in the Dagu River, especially for the non-flood season. Comparisons between the recommended scheme and the operation results without considering ecology demonstrated that the optimization model of ecological reservoir operation rules could effectively balance the ecological and socio-economic water use. In conclusion, the optimization model of reservoir operation rules with GREW can solve the problem of competitive water use inside and outside rivers, providing an important scientific basis for water resources management.

Abstract Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

Background and Objective: Knee osteoarthritis (KOA) is a chronic degenerative disease characterized by pain, morning stiffness and swelling in the knee joints. And KOA is common in the elderly and seriously affects the exercise function and physical health of patients. This study aimed to explore the curative effects of patellar inward pushing method (PIPM) on KOA. Methods: In this study, we established rabbit animal models of KOA for the research by using the New Zealand white rabbits. A total of n=30 rabbits were divided into 5 groups by random number table method: blank group, model group, glucosamine hydrochloride (GH) group, PIPM group and PIPM combined with GH group. The rabbits were then modeled. Results: After 9-weeks cultured in groups, 5 ml blood was collected from the heart, and cytokines were detected. The result suggested that iNOS, NO and TNF-α were the pathogenic inflammatory factor of KOA, and aggravated cartilage damage and degeneration. Besides, this study indicated that PIPM combined with GH treatment significantly reduced the activity of inflammatory cytokines in serum and joint fluid of KOA models in rabbits. In addition, PIPM combined with GH therapy exhibited the best therapeutic effect among these treatments, which was working on KOA better than PIPM treatment alone or GH treatment alone. Conclusion: PIPM could effectively treat KOA via regulating cytokines, and the PIPM combined with GH therapy could be a novel therapeutic strategy for KOA.

Connective tissue disease (CTD) patients may suffer from pulmonary arterial hypertension (PAH), a serious complication, and anti-U1 ribonucleoprotein (RNP) antibodies can be used as a potential indicator for the development and prognosis of CTD-associated PAH (CTD-PAH). However, there are still some controversies; thus, a systematic review and meta-analysis were performed. We searched PubMed, Embase, Cochrane Library, and Scopus for eligible studies and assessed their quality using Newcastle–Ottawa scales or Agency for Healthcare Research and Quality indicators according to the type of research. Odds ratio (OR) was adopted as a measure of effect in risk factor analysis, and hazard ratio (HR) was adopted for prognostic factor analysis. Publication bias was evaluated using the Egger’s test. Thirteen studies were finally included. Anti-U1 RNP antibody was proved as a risk factor for PAH among CTD patients (OR = 5.30, 95%CI 2.96–9.48, p < 0.05) and a protective factor against mortality among CTD-PAH patients (HR = 0.55, 95%CI 0.36–0.83, p < 0.05). CTD patients with positive anti-U1 RNP antibodies are at high risk for PAH, so routine screening examinations, including echocardiography, are recommended. Additionally, anti-U1 RNP positivity has been linked to decreased mortality in patients with CTD-PAH.

Pseudomonas aeruginosa is an important opportunistic pathogen capable of causing variety of infections in humans. The type III secretion system (T3SS) is a critical virulence determinant of P. aeruginosa in the host infections. Expression of the T3SS is regulated by ExsA, a master regulator that activates the expression of all known T3SS genes. Expression of the exsA gene is controlled at both transcriptional and posttranscriptional levels. Here, we screened a P. aeruginosa transposon (Tn5) insertional mutant library and found rplI, a gene coding for the ribosomal large subunit protein L9, to be a repressor for the T3SS gene expression. Combining real-time quantitative PCR (qPCR), western blotting and lacZ fusion assays, we show that RplI controls the expression of exsA at the posttranscriptional level. Further genetic experiments demonstrated that RplI mediated control of the exsA translation involves 5’ untranslated region (5’ UTR). A ribosome immunoprecipitation assay and qPCR revealed higher amounts of a 24 nt fragment from exsA mRNA being associated with ribosomes in the ΔrplI mutant. An interaction between RplI and exsA mRNA harboring its 24 nt, but not 12 nt, 5’ UTR was confirmed by RNA Gel Mobility Shift and Microscale Thermophoresis assays. Overall, this study identifies the ribosomal large subunit protein L9 as a novel T3SS repressor that inhibits ExsA translation in P. aeruginosa. Author summary Ribosomes provide all living organisms the capacity to synthesize proteins. The production of many ribosomal proteins is often controlled by an autoregulatory feedback mechanism. P. aeruginosa is an opportunistic human pathogen and its type III secretion system (T3SS) is a critical virulence determinant in host infections. In this study, by screening a Tn5 mutant library, we identified rplI, encoding ribosomal large subunit protein L9, as a novel repressor for the T3SS. Further exploring the regulatory mechanism, we found that the RplI protein interacts with the 5’ UTR (5’ untranslated region) of exsA, a gene coding for transcriptional activator of the T3SS. Such an interaction likely blocks ribosome loading on the exsA 5’ UTR, inhibiting the initiation of exsA translation. The significance of this work is in the identification of a novel repressor for the T3SS and elucidation of its molecular mechanism. Furthermore, this work provides evidence for individual ribosomal protein regulating mRNA translation beyond its autogenous feedback control.

An uncertain multi-attribute decision-making (MADM) problem is studied based on cloud models. Cloud models, referring to fuzziness and randomness, are utilized to depict evaluation and pre-evaluation information which can reflect the future development performance of alternatives. Because of bounded rationality, decision maker's (DM) risk attitudes should be considered when facing uncertainty. Thus, a behavioral MADM (BMADM) method is proposed by considering DM's risk attitudes and pre-evaluation. First, a distance measure for normal cloud models is developed with consideration of both DM's risk preferences and random distribution, aiming at making full use of information. Second, as a basis of applying prospect theory, positive ideal reference point is set by considering both evaluation and pre-evaluation information from three aspects: risk-averse, risk-neutral, and risk-seeking preference coefficients, in which the sign of distance is not necessary to determine. The third element is the establishment of an optimization model for handling incomplete attribute weights, following which is to obtain the ranking of alternatives. The final phase is the application of the proposed method to one case, along with sensitivity and comparison analyses, as a means of illustrating the applicability and feasibility of the new method.

Therapy for Pseudomonas aeruginosa infections is hard due to its high natural and acquirable antibiotic resistance. After colonization in the hosts, P. aeruginosa commonly accumulates genomic mutations which confer them antibiotic resistance and better adaptations to the host environment. Deciphering the mechanisms of antibiotic resistance development in the clinical setting may provide critical insights into the design of effective combinatory antibiotic therapies to treat P. aeruginosa infections. In this work, we demonstrate a resistance mechanism to aztreonam of a clinical isolate (ARP36) in comparison with a sensitive one (CSP18). RNAseq and genomic DNA resequencing were carried out to compare the global transcriptional profiles and in the clinical setting genomic profiles between these two isolates. The results demonstrated that hyperexpression of an efflux pump MexAB-OprM caused by a R70Q substitution in MexR, contributed to the increased resistance to aztreonam in the isolate ARP36. Simulation of mexR of ARP36 by gene editing in CSP18 conferred CSP18 an ARP36-like susceptibility to the aztreonam. The R70Q substitution prevented MexR from binding to the intergenic region between mexR and mexAB-oprM operon, with no impact on its dimerization. The presented experimental results explain for the first time why the clinically relevant R70Q substitution in the MexR derepresses the expression of mexAB-oprM in P. aeruginosa.

Background and purposeNeuropathic pain is the typical symptom of brachial plexus root avulsion (BPRA), and no effective therapy is currently available. Electroacupuncture (EA), as a complementary and alternative therapy, plays a critical role in the management of pain-associated diseases. In the present study, we aimed to reveal the peripheral immunological mechanism of EA in relieving the pain of BPRA through the IL-17–CD4+ T lymphocyte–β-endorphin axis.MethodsAfter receiving repeated EA treatment, the pain of BPRA in rats along with the expressions of a range of neurotransmitters, the contents of inflammatory cytokines, and the population of lymphocytes associated were investigated. CD4+ T lymphocytes were either isolated or depleted with anti-CD4 monoclonal antibody. The titers of IL-17A, interferon-γ (IFN-γ), and β-endorphin were examined. The markers of T lymphocytes, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), macrophages, and natural killer (NK) cells were assessed. The activation of the nuclear transcription factor κB (NF-κB) signaling pathway was tested.ResultsThe pain of BPRA was significantly relieved, and the amount of CD4+ T lymphocytes was increased after EA treatment. The release of β-endorphin was up-regulated with the up-regulation of IL-17A in CD4+ T lymphocytes. The titer of IL-17A was enhanced, leading to an activated NF-κB signaling pathway. The release of β-endorphin and the analgesic effect were almost completely abolished when CD4+ T lymphocytes were depleted.ConclusionWe, for the first time, showed that the neuropathic pain caused by BPRA was effectively relieved by EA treatment via IL-17–CD4+ T lymphocyte–β-endorphin mediated peripheral analgesic effect, providing scientific support for EA clinical application.

Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host environment. Characterizing the evolutionary traits would provide important insights into the development of effective combinatory antibiotic therapies to cure P. aeruginosa infections. In this work, we performed a detailed analysis of the molecular mechanisms by which a clinical isolate (CSP18) yields a ciprofloxacin-resistant derivative (CRP42). Genomic DNA re-sequencing and RNAseq were carried out to compare the genomic mutational signature and transcriptional profiles between the two isolates. The results indicated that D87G mutation in GyrA, together with MexEF-OprN hyper-expression caused by F7S mutation in MexS, was responsible for the increased resistance to ciprofloxacin in the isolate CRP42. Further simulation of CRP42 by gene editing in CSP18 demonstrated that D87G mutation in GyrA rendered CSP18 a fourfold increase in minimum inhibitory concentration against ciprofloxacin, while F7S mutation in MexS conferred an additional eightfold increase. Our experimental results demonstrate for the first time that the clinically relevant F7S point mutation in MexS results in hyper-expression of the mexEF-oprN and thus confers P. aeruginosa resistance to ciprofloxacin.

In real life, multiple network public opinion emergencies may break out in a certain place at the same time. So, it is necessary to invite emergency decision experts in multiple fields for timely evaluating the comprehensive crisis of the online public opinion, and then limited emergency resources can be utilized to give priority to respond to the one with the highest crisis. Due to the complexity of network public opinion emergencies and the limited cognition of experts, most of the decision problems for evaluating the network public opinion emergencies are highly uncertain. Also, prior to the selection of the highest crisis, it is preferable that experts reach a high degree of consensus among their assessments or opinions. To address such problems, this paper presents a novel adaptive consensus reaching model for multiattribute group decision making (MAGDM) with probabilistic linguistic decision matrices (PLDMs). First, to quantify the difference between any two probabilistic linguistic term sets (PLTSs) accurately and efficiently, we define a novel distance measure between PLTSs based on the Wasserstein metric. Then, by integrating the defined PLTSs-based Wasserstein (PL-Wasserstein) distance measure into the classical CCSD method, we construct an optimization model for objectively determining attribute weights. Subsequently, we develop the individual cumulative consensus contribution (ICCC) measure and the group consensus measure, respectively, following which is to present an integrated consensus improving strategy that considers both weight-updating (i.e., dynamic weights of experts and attributes) and assessment-adjusting. Finally, the feasibility and the applicability of the proposed approach are illustrated via a real evaluation of network public opinion emergencies. Through comparing with existing probabilistic linguistic MAGDM approaches, the proposed approach offers the advantages in terms of the accurate measurement of information difference and the integrated improvement of consensus efficiency.

The monthly accumulated precipitation and monthly average temperature of 117 meteorological stations in Song-Liao River Basin (SLRB) were used to calculate the Standardized Precipitation Evapotranspiration Indices (SPEI) to analyze the drought characteristics, including long-term trends, drought affected area, climate abrupt change, intensive drought occurrence regions, and drought durations during 1964–2013 with the support of GIS. The Area Drought Severity (ADS), a comprehensive index, is proposed to assess both the variations of drought degree and the extent of the drought affected area. The results revealed that (1) the drought happening probability and degree are rising and the affected areas of all degrees of drought have an increasing trend during the last 50 years; (2) there is a climate abrupt change which occurred in around 1994, and the area with declining SPEI is larger than that with declining SPI, which could be due to the rising temperature after the climate abrupt change; (3) all degrees of drought occurrence probability increased, and the intensive drought occurrence regions altered from the northern SLRB to the southwestern SLRB after the climate abrupt change; (4) the drought duration increased from 1994, and the increased drought durations occurred in most parts of SLRB.

The rational allocation of water resources in the basin/region can be better assisted and performed using a suitable water resources allocation model. Rule-based and optimization-based simulation methods are utilized to solve medium- and long-term water resources allocation problems. Since rule-based allocation methods requires more experience from expert practice than optimization-based allocation methods, it may not be utilized by users that lack experience. Although the optimal solution can be obtained via the optimization-based allocation method, the highly skilled expert experience is not taken into account. To overcome this deficiency and employ the advantages of both rule-based and optimization-based simulation methods, this paper proposes the optimal allocation model of water resources where the highly skilled expert experience has been considered therein. The “prospect theory” is employed to analyze highly skilled expert behavior when decision-making events occur. The cumulative prospect theory value is employed to express the highly skilled expert experience. Then, the various elements of the cumulative prospect theory value can be taken as the variables or parameters in the allocation model. Moreover, the optimal water allocation model developed by the general algebraic modeling system (GAMS) has been improved by adding the decision reversal control point and defining the inverse objective function and other constraints. The case study was carried out in the Wuyur River Basin, northeast of China, and shows that the expert experience considered as the decision maker’s preference can be expressed in the improved optimal allocation model. Accordingly, the improved allocation model will contribute to improving the rationality of decision-making results and helping decision-makers better address the problem of water shortage.

Urban agglomeration polders (UAPs) are often used to control flooding in eastern China. The impacts of UAPs on individual flood events have been extensively examined, but how flood risks are influenced by UAPs is much less examined. This study aimed to explore a three-dimensional joint distribution of annual flood volume, peak flow and water level to examine UAPs’ impact on flood risks based on hydrological simulations. The dependence between pairwise hydrological characteristics are measured by rank correlation coefficients and graphs. An Archimedean Copula is applied to model the dependence structure. This approach is applied to the Qinhuai River Basin where UAPs are used proactively for flood control. The result shows that the Frank Copula can better represent the dependence structure in the Qinhuai River Basin. UAPs increase risks of individual flood characteristics and integrated risks. UAPs have a relatively greater impact on water level than the other two flood characteristics. It is noted that the impact on flood risk levels off for greater floods.

In order to mitigate environmental and ecological impacts resulting from groundwater overexploitation, we developed a multiple-iterated dual control model consisting of four modules for groundwater exploitation and water level. First, a water resources allocation model integrating calculation module of groundwater allowable withdrawal was built to predict future groundwater recharge and discharge. Then, the results were input into groundwater numerical model to simulate water levels. Groundwater exploitation was continuously optimized using the critical groundwater level as the feedback, and a groundwater multiple-iterated technique was applied to the feedback process. The proposed model was successfully applied to a typical region in Shenyang in northeast China. Results showed the groundwater numerical model was verified in simulating water levels, with a mean absolute error of 0.44 m, an average relative error of 1.33%, and a root-mean-square error of 0.46 m. The groundwater exploitation reduced from 290.33 million m3 to 116.76 million m3 and the average water level recovered from 34.27 m to 34.72 m in planning year. Finally, we proposed the strategies for water resources management in which the water levels should be controlled within the critical groundwater level. The developed model provides a promising approach for water resources allocation and sustainable groundwater management, especially for those regions with overexploited groundwater.

In this paper, a multi-dimensional equilibrium allocation model of water resources was developed based on the groundwater multiple loop iteration technique. The proposed model is an integrated framework of three modules respectively corresponding to the input layer, operation layer, and feedback layer in the allocation process. Firstly, a prediction model integrating the genetic algorithm-back propagation (GA-BP) model, the general regression neural network (GRNN) model, and the support vector machine (SVM) model was built to predict the future reservoir runoff, and the results were entered into the database of an optimal allocation model. Furthermore, taking exploitable groundwater as the feedback factor, the water resource optimal allocation model was continuously optimized. Also, the groundwater multiple loop iteration technique was applied to the feedback process. The proposed model was successfully applied to a typical region in Jinan, Eastern China. The uncertainties of future reservoir runoff and exploitable groundwater were taken into account. The results revealed that groundwater represented 36.6% of water supply in the base year, indicating that it is the main water source in Jinan. However, the amount of groundwater mining was decreased after considering the exploitable groundwater. The developed framework provides a comprehensive approach towards optimal future allocation of water resources, especially for the regions with overexploited groundwater.

Objective: Several studies have demonstrated that anti-carbamylation protein antibodies (Anti-CarPA) are persistent in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), primary Sjögren's syndrome (pSS), and interstitial lung disease associated with RA (RA-ILD). However, the relationship between anti-CarPA and other rheumatic diseases (RDs) and non-RA-ILD is not known till now. This study sought to examine the presence of anti-CarPA in Chinese Han patients with RDs and its clinical significance. Methods: The study included 90 healthy controls (HCs) and 300 patients with RDs, including RA, SLE, polymyositis/dermatomyositis (PM/DM), pSS, SSC, spondyloarthritis (SpA), anti-neutrophil cytoplasmic autoantibodies associated with vasculitis (AAV), undifferentiated connective tissue disease (UCTD), and Behcet's disease (BD). Antibodies against carbamylated human serum albumin were detected using commercial enzyme-linked immunosorbent assay kits. Correlations between clinical and laboratory parameters were analyzed. Result: Serum levels of anti-CarPA in RA (34.43 ± 33.34 ng/ml), SLE (21.12 ± 22.23 ng/ml), pSS (16.32 ± 13.54 ng/ml), PM/DM (30.85 ± 17.34 ng/ml), SSC (23.53 ± 10.70 ng/ml), and UCTD (28.35 ± 21.91 ng/ml) were higher than those of anti-CarPA in the HCs (7.30 ± 5.05 ng/ml). The concentration of serum anti-CarPA was higher in patients with rheumatic disease-related interstitial lung disease (RD-ILD), especially RA-ILD, PM/DM-ILD, and pSS-ILD. Patients with RD-ILD who tested positive for anti-CarPA were more likely to have a more severe radiographic classification (grades II, p = 0.045; grades III, p = 0.003). Binary logistic regression analysis suggested that anti-CarPA had an association with ILD in RA (p = 0.033), PM/DM (p = 0.039), and pSS (p = 0.048). Based on receiver operating characteristics (ROC) analysis, anti-CarPA cutoffs best discriminated ILD in RA (>32.59 ng/ml, p = 0.050), PM/DM (>23.46 ng/ml, p = 0.038), and pSS (>37.08 ng/ml, p = 0.040). Moreover, serum levels of anti-CarPA were correlated with antibodies against transcription intermediary factor 1 complex (anti-TIF1) (R = -0.28, p = 0.044), antibodies against glycyl-transfer ribonucleic acid synthetase (anti-EJ) (R = 0.30, p = 0.031), and antibodies against melanoma differentiation-associated gene 5 (anti-MDA5) (R = 0.35, p = 0.011). Conclusion: Serum anti-CarPA could be detected in patients with RA, PM/DM, pSS, SSC, and UCTD among the Chinese Han population. And it may also assist in identifying ILD in patients with RA, PM/DM, and pSS, which emphasized attention to the lung involvement in anti-CarPA-positive patients. [ABSTRACT FROM AUTHOR]