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Background The aim of this study was to gain further investigation of non-small cell lung cancer (NSCLC) tumorigenesis and identify biomarkers for clinical management of patients through comprehensive bioinformatics analysis. Methods miRNA and mRNA microarray datasets were downloaded from GEO (Gene Expression Omnibus) database under the accession number GSE102286 and GSE101929, respectively. Genes and miRNAs with differential expression were identified in NSCLC samples compared with controls, respectively. The interaction between differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) was predicted, followed by functional enrichment analysis, and construction of miRNA-gene regulatory network, protein-protein interaction (PPI) network, and competing endogenous RNA (ceRNA) network. Through comprehensive bioinformatics analysis, we anticipate to find novel therapeutic targets and biomarkers for NSCLC. Results A total of 123 DEmiRs (5 up- and 118 down-regulated miRNAs) and 924 DEGs (309 up- and 615 down-regulated genes) were identified. These genes and miRNAs were significantly involved in different pathways including adherens junction, relaxin signaling pathway, and axon guidance. Furthermore, hsa-miR-9-5p, has-miR-196a-5p and hsa-miR-31-5p, as well as hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p were shown to have higher degree in the miRNA-gene regulatory network and ceRNA network, respectively. Furthermore, BIRC5 and FGF2 , as well as RTKN2 and SLIT3 were hubs in the PPI network and ceRNA network, respectively. Conclusion Several pathways (adherens junction, relaxin signaling pathway, and axon guidance) miRNAs (hsa-miR-9-5p, has-miR-196a-5p, hsa-miR-31-5p, hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p) and genes ( BIRC5 , FGF2 , RTKN2 and SLIT3 ) may play important roles in the pathogenesis of NSCLC.

Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice; they also inhibited junctional protein degradation and translocation to reduce paracellular permeability in human brain microvascular endothelial cells (ECs) exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with α3β1 integrin on ECs, inhibiting Src activation-dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization. Notably, localization of VE-cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. All together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus’ regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice.

In this work, a novel GaN MIS‐HEMT (metal‐insulator‐semiconductor high electron mobility transistors) featuring a floating clamp (FC) electrode is proposed for suppressing the short‐channel effect. By inserting the FC electrode near to the drain‐side gate edge, the transverse potential at the gate edge can be clamped to less than 2 V, thereby the short‐channel effect can be suppressed. Compared to the conventional short‐channel GaN MIS‐HEMT, the proposed device exhibits much decreased off‐state electron density at the drain voltage of 10 V, which leads to the off‐state leakage current decreasing from 10–1 to 10–7 A/mm, without an obvious sacrifice of the on‐state current. Meanwhile, the proposed GaN MIS‐HEMT also delivers a much lower reverse gate‐to‐drain capacitor. The excellent characteristics of the proposed GaN MIS‐HEMT show that the device is promising for the future power applications.

Kidney disease (KD) is a life-threatening disease characterized by high morbidity and mortality in clinical settings, which can be caused by many reasons, and the incidence increases with age. However, supportive therapy and kidney transplantation still have limitations in alleviating KD progression. Recently, mesenchymal stem cells (MSCs) have shown great potential in repairing injury through their multidirectional differentiation and self-renewal ability. Of note, MSCs serve as a safe and effective therapeutic strategy for treating KD in preclinical and clinical trials. Functionally, MSCs ameliorate KD progression by regulating the immune response, renal tubular cell apoptosis, tubular epithelial–mesenchymal transition, oxidative stress, angiogenesis, and so on. In addition, MSCs exhibit remarkable efficacy in both acute kidney injury (AKI) and chronic kidney disease (CKD) through paracrine mechanisms. In this review, we outline the biological characteristics of MSCs, discuss the efficacy and mechanisms of MSCs-based therapy for KD, summarize the completed and ongoing clinical trials, as well as analyze limitations and new strategies, aiming to provide new ideas and approaches for the preclinical experiments and clinical trials of MSCs transplantation for KD.

Tropospheric ozone pollution poses a major environmental challenge in China. As its primary natural source, Stratosphere-to-Troposphere Transport (STT) has been recognized as a significant contributor to tropospheric ozone in western, northeastern, and eastern China. However, the extent of STT’s influence on southeastern China has been less studied due to data limitations. Using a recently available one-year dataset of ozonesonde observations from a regional background station, we find that STT contributes significantly to tropospheric and surface ozone elevation in southeastern China. Our results show that STT plays a more substantial role in shaping tropospheric ozone during spring than previously believed, accounting for over 30% of ozone concentrations above 4 km. Without the stratospheric contribution, the spring seasonal peak almost disappears. STT can also significantly influence ozone concentrations at the surface. For example, a distinct ozone profile was observed on 4 May 2022, with a notable increase in tropospheric ozone. This tropospheric ozone increase was caused by a STT event triggered by a robust horizontal trough and subsequent southward movement of subtropical jets in the upper troposphere. According to a stratospheric tracer derived from an atmospheric chemistry model, this STT event contributed to 25%–30% of the surface ozone increase. Overall, this study highlights the important role of STT in driving tropospheric ozone variations, even in regions with comparatively lower ozone levels in southeastern China.

A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary hyperparathyroidism (SHPT) is caused by excessive PTH production and release, as well as parathyroid enlargement. At present, the mechanism of cell proliferation in secondary hyperparathyroidism (SHPT) is not completely clear. Decreased expression of the vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), and 1,25(OH)2D3 insufficiency all lead to a decrease in cell proliferation suppression, and activation of multiple pathways is also involved in cell proliferation in renal hyperparathyroidism. The interaction between the parathormone (PTH) and parathyroid hyperplasia and 1,25(OH)2D3 has received considerable attention. 1,25(OH)2D3 is commonly applied in the therapy of renal hyperparathyroidism. It regulates the production of parathormone (PTH) and parathyroid cell proliferation through transcription and post-transcription mechanisms. This article reviews the role of 1,25(OH)2D3 in parathyroid cells in secondary hyperparathyroidism and its current understanding and potential molecular mechanism.

Background NLRP3 inflammasome has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The activation of NLRP3 inflammasome results in the production of IL-1β and the subsequent inflammation. Anti-dsDNA antibodies (anti-dsDNA Abs) play critical roles in the development and progression of SLE. However, the mechanism of NLRP3 inflammasome activation in SLE is still not known. This study investigated the activation of NLRP3 inflammasome stimulated by anti-dsDNA Abs in monocytes/macrophages from SLE patients. Methods Monocytes/macrophages from SLE patients or healthy controls were stimulated with anti-dsDNA Ab-positive serum or purified anti-dsDNA Abs. Activation of inflammasome was measured by flow cytometry or Western blot. Anti-dsDNA Abs isolated from active SLE patients were injected into female (NZB × NZW) F1 mice and the activation of NLRP3 inflammasome and the frequencies of Th17 and Treg were examined. Results The activity of caspase-1 was significantly increased in active SLE patients and was correlated with serum levels of anti-dsDNA Abs and disease activities. The concentrations of IL-1β and IL-17A were also significantly higher in SLE patients compared to healthy controls. Anti-dsDNA Ab-positive serum rather than healthy serum or RF (rheumatoid factor)-positive serum stimulated the activation of caspase-1 in monocytes. Anti-dsDNA Abs bound to TLR4 on macrophages and induced the production of ROS. Mitochondria-targeting antioxidant Mito-TEMPO, IκB kinase inhibitor peptide or TLR4 siRNA inhibited the activation of NLRP3 inflammasome and the secretion of IL-1β induced by anti-dsDNA Abs. Injection of anti-dsDNA Abs into (NZB × NZW) F1 mice resulted in increased caspase-1 activation and production of IL-1β and IL-17A. The Th17/Treg cell ratio also significantly increased following anti-dsDNA Ab injection. Conclusions Anti-dsDNA Abs activated NLRP3 inflammasome in monocytes/macrophages from SLE patients by binding to TLR4 and inducing the production of mitochondrial ROS.

In the Global Navigation Satellite System, ionospheric delay is a significant source of error. The magnitude of the ionosphere total electron content (TEC) directly impacts the magnitude of the ionospheric delay. Correcting the ionospheric delay and improving the accuracy of satellite navigation positioning can both benefit from the accurate modeling and forecasting of ionospheric TEC. The majority of current ionospheric TEC forecasting research only considers the temporal or spatial dimensions, ignoring the ionospheric TEC’s spatial and temporal autocorrelation. Therefore, we constructed a spatiotemporal network model with two modules: (i) global spatiotemporal characteristics extraction via forwarding spatiotemporal characteristics transfer and (ii) regional spatiotemporal characteristics correction via reverse spatiotemporal characteristics transfer. This model can realize the complementarity of TEC global spatiotemporal characteristics and regional spatiotemporal characteristics. It also ensures that the global spatiotemporal characteristics of the global ionospheric TEC are transferred to each other in both temporal and spatial domains at the same time. The spatiotemporal network model thus achieves a spatiotemporal prediction of global ionospheric TEC. The Huber loss function is also used to suppress the gross error and noise in the ionospheric TEC data to improve the forecasting accuracy of global ionospheric TEC. We compare the results of the spatiotemporal network model with the Center for Orbit Determination in Europe (CODE), the convolutional Long Short-Term Memory (convLSTM) model and the Predictive Recurrent Neural Network (PredRNN) model for one-day forecasts of global ionospheric TEC under different conditions of time and solar activity, respectively. With internal data validation, the average root mean square error (RMSE) of our proposed algorithm increased by 21.19, 15.75, and 9.67%, respectively, during the maximum solar activity period. During the minimum solar activity period, the RMSE improved by 38.69, 38.02, and 13.54%, respectively. This algorithm can effectively be applied to ionospheric delay error correction and can improve the accuracy of satellite navigation and positioning.

The unique physicochemical properties of soda saline-alkali soils significantly reduce soil nitrogen availability and crop nitrogen use efficiency. While high-yield and high-efficiency cultivation practice offer a key strategy for the synergistic improvement of both crop productivity and resource use efficiency. However, the optimal nitrogen input rate for these practices remains to be determined. Hence, a three-year field study was implemented with nitrogen fertilizer application rates ranging from 0 to 325 kg ha (0, 125, 175, 225, 275, 325 kg ha ) to assess their effects on ionic balance, stress physiology, nitrogen use efficiency, and grain yield in rice grown under soda saline-alkali soil conditions. The findings indicate that additional nitrogen fertilizer, particularly at 275 kg ha within the high-yield and high-efficiency cultivation practice, significantly reduced the leaf Na /K ratio and levels of superoxide anion (O ) and malondialdehyde (MDA), while increasing K concentration and enhancing the levels of soluble proteins and proline, as well as the activities of peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX). Conversely, leaf Na concentration increased significantly with rising nitrogen application rates. Furthermore, supplementary nitrogen fertilizer significantly improved total nitrogen uptake, nitrogen use efficiency (NUE), and nitrogen agronomic efficiency (NAE) in rice, which can be attributed to markedly enhanced activities of key nitrogen metabolism enzymes. Consequently, grain yields under the N4 (275 kg ha ), N5 (325 kg ha ), N3 (225 kg ha ), N2 (175 kg ha ), and N1 (125 kg ha ) treatments exhibited significant increases of 94.34%, 62.40%, 56.15%, 37.78%, and 24.01%, respectively, relative to the N0 control. These results demonstrate that, within the high-yield and high-efficiency cultivation practice, nitrogen fertilization at a rate of 275 kg ha plays a crucial role in improving rice productivity and optimizing nitrogen use efficiency in soda saline-alkali paddy fields.