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In arid regions, the optimal utilization of river channels to collect rainwater resources can effectively alleviate the problem of water scarcity. This paper employs visual MODFLOW software to simulate the infiltration volume of rainwater under different schemes, with the objective of identifying the optimal infiltration volume. The results indicate that the infiltration volume of rainwater is 0.6, 79.7, 36.5, 62, and 10,000 m3 under different design schemes. COMSOL software is employed to simulate the infiltration situation of rainwater under different schemes, and the scheme with the most favourable infiltration effect is identified. The simulation results indicate that scenarios 2, 4, and 5 demonstrate superior early-stage infiltration performance. Ultimately, the optimal infiltration scheme is selected by integrating the infiltration volume, infiltration effect, construction, economic, and ecological factors to achieve the objective of enhancing rainwater harvesting and utilization. This study offers effective and reasonable measures for addressing the challenge of water resources management in arid regions. It provides suitable reference schemes for river channel rainwater storage projects and offers innovative approaches to rainwater resource utilization, thereby contributing to the alleviation of water scarcity in arid areas.

Abstract Background Green foxtail [Setaria viridis (L.)] is one of the most abundant and troublesome annual grass weeds in alfalfa fields in Northeast China. Synthetic auxin herbicide is widely used in agriculture, while how auxin herbicide affects tillering on perennial grass weeds is still unclear. A greenhouse experiment was conducted to examine the effects of auxin herbicide 2,4-D on green foxtail growth, especially on tillers. Results In the study, 2,4-D isooctyl ester was used. There was an inhibition of plant height and fresh weight on green foxtail after application. The photosynthetic rate of the leaves was dramatically reduced and there was an accumulation of malondialdehyde (MDA) content. Moreover, applying 2,4-D isooctyl ester significantly reduced the tillering buds at rates between 2100 and 8400 ga. i. /ha. Transcriptome results showed that applying 2,4-D isooctyl ester on leaves affected the phytohormone signal transduction pathways in plant tillers. Among them, there were significant effects on auxin, cytokinin, abscisic acid (ABA), gibberellin (GA), and brassinosteroid signaling. Indeed, external ABA and GA on leaves also limited tillering in green foxtail. Conclusions These data will be helpful to further understand the responses of green foxtail to 2, 4-D isooctyl ester, which may provide a unique perspective for the development and identification of new target compounds that are effective against this weed species.

Tuberculosis (TB) is caused by infection with the bacterial pathogen Mycobacterium tuberculosis (M.tb) in the respiratory tract. There was an estimated 10.6 million people newly diagnosed with TB, and there were approximately 1.3 million deaths caused by TB in 2022. Although the global prevalence of TB has remained high for decades and is an annual leading cause of death attributed to infectious diseases, only one vaccine, Bacillus Calmette–Guérin (BCG), has been approved so far to prevent/attenuate TB disease. Correlates of protection or immunological mechanisms that are needed to control M.tb remain unknown. The protective role of antibodies after BCG vaccination has also remained largely unclear; however, recent studies have provided evidence for their involvement in protection against disease, as biomarkers for the state of infection, and as potential predictors of outcomes. Interestingly, the antibodies generated post-vaccination with BCG are linked to the activation of innate immune cascades, providing further evidence that antibody effector functions are critical for protection against respiratory pathogens such as M.tb. In this review, we aim to provide current knowledge of antibody application in TB diagnosis, prevention, and treatment. Particularly, this review will focus on 1) The role of antibodies in preventing M.tb infections through preventing Mtb adherence to epithelium, antibody-mediated phagocytosis, and antibody-mediated cellular cytotoxicity; 2) The M.tb-directed antibody response generated after vaccination and how humoral profiles with different glycosylation patterns of these antibodies are linked with protection against the disease state; and 3) How antibody-mediated immunity against M.tb can be further explored as early diagnosis biomarkers and different detection methods to combat the global M.tb burden. Broadening the paradigm of differentiated antibody profiling and antibody-based detection during TB disease progression offers new directions for diagnosis, treatment, and preventative strategies. This approach involves linking the aforementioned humoral responses with the disease state, progression, and clearance.

Summary: Antibodies represent a primary mediator of protection against respiratory viruses. Serum neutralizing antibodies (NAbs) are often considered a primary correlate of protection. However, detailed antibody profiles including characterization of antibody functions in different anatomic compartments are poorly understood. Here we show that antibody correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge are different in systemic versus mucosal compartments in rhesus macaques. In serum, NAbs were the strongest correlate of protection and linked to spike-specific binding antibodies and other extra-NAb functions that create a larger protective network. In bronchiolar lavage (BAL), antibody-dependent cellular phagocytosis (ADCP) proved the strongest correlate of protection rather than NAbs. Within BAL, ADCP was linked to mucosal spike-specific immunoglobulin (Ig)G, IgA/secretory IgA, and Fcγ-receptor binding antibodies. Our results support a model in which antibodies with different functions mediate protection at different anatomic sites.

Objective: To evaluate the anti-fatigue effects of different extracts from Cistanche tubulosa (Schenk) Wight (C. tubulosa, Rou Cong Rong), focusing on central and exercise-induced fatigue in mice. This study investigated the pharmacological effects of the total oligosaccharides, polysaccharides, and phenylethanoid glycosides (CPhGs) extracted from C. tubulosa. Methods: Models of sleep deprivation and forced swimming fatigue were established to simulate central and exercise-induced fatigue. The mice were treated with different extracts of C. tubulosa, and their effects were assessed using behavioral tests to measure exercise capacity, learning, and memory function. Biochemical analyses were performed to evaluate the changes in serum and brain neurotransmitter levels, liver and muscle glycogen storage, and various fatigue-related biomarkers. Results: This study found that treatment with C. tubulosa extract improved exercise capacity, learning, and memory in mice. Total oligosaccharides from C. tubulosa enhanced adrenocorticotropic hormone, cholinesterase, and thyroid-stimulating hormone levels, reduced cortisol levels in central fatigue models, and ameliorated biochemical markers of exercise-induced fatigue, including lowering lactic acid, blood urea nitrogen, and malondialdehyde levels. Among the tested extracts, the total oligosaccharides showed the most comprehensive anti-fatigue effects. Conclusion: The anti-fatigue effects of C. tubulosa, particularly those of its total oligosaccharides, are pronounced in both central and exercise-induced fatigue. These effects are mediated by the regulation of neurotransmitter levels, enhancement of glycogen storage, and improvement of antioxidant enzyme activity, suggesting potential therapeutic benefits in fatigue-related conditions.

In this narrative review, we highlight the challenges of comparing emissions from different tobacco products under controlled laboratory settings (using smoking/ vaping machines). We focus on tobacco products that generate inhalable smoke or aerosol, such as cigarettes, cigars, hookah, electronic cigarettes, and heated tobacco products. We discuss challenges associated with sample generation including variability of smoking/vaping machines, lack of standardized adaptors that connect smoking/vaping machines to different tobacco products, puffing protocols that are not representative of actual use, and sample generation session length (minutes or number of puffs) that depends on product characteristics. We also discuss the challenges of physically characterizing and trapping emissions from products with different aerosol characteristics. Challenges to analytical method development are also covered, highlighting matrix effects, order of magnitude differences in analyte levels, and the necessity of tailored quality control/quality assurance measures. The review highlights two approaches in selecting emissions to monitor across products, one focusing on toxicants that were detected and quantified with optimized methods for combustible cigarettes, and the other looking for productspecific toxicants using non-targeted analysis. The challenges of data reporting and statistical analysis that allow meaningful comparison across products are also discussed. We end the review by highlighting that even if the technical challenges are overcome, emission comparison may obscure the absolute exposure from novel products if we only focus on relative exposure compared to combustible products.

Abstract Objective To determine the pharmacodynamic mechanism underlying Cordyceps sinensis relief in a murine model of non-small cell lung cancer (NSCLC). Methods We created a murine model of NSCLC and studied the potential molecular mechanism by which C. sinensis relieved NSCLC using a combination of transcriptomics, proteomics, and experimental validation. Results C. sinensis markedly suppressed the fluorescence values in mice with NSCLC, improved the pathologic morphology of lung tissue, ameliorated inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and the oxidative stress indicators superoxide dismutase, malondialdehyde, and glutathione peroxidase). Transcriptomics results showed that the therapeutic effect of C. sinensis was primarily involved in the differentiation and activation of T cells. Based on the proteomic results, C. sinensis likely exerted a protective effect by recruiting immune cells and suppressing tumor cell proliferation via the MAPK pathway. Finally, the experimental validation results indicated that C. sinensis significantly decreased the VEGF and Ki67 expression, downregulated RhoA, Raf-1, and c-fos expression, which are related to cell migration and invasion, increased the serum concentration of hematopoietic factors (EPO and GM-CSF), and improved the percentage of immune cells (natural killer cells, dendritic cells, and CD4+ and CD8+ lymphocytes), which enhanced immune function. Conclusions Based on our preclinical study, C. sinensis was shown to exert a protective effect on NSCLC, primarily by inhibiting the MAPK pathway.

Abstract Environmental tobacco smoke (ETS) is known to cause lung inflammatory and injurious responses. Smoke exposure is associated with the pathobiology related to lung fibrosis, whereas the mechanism that ETS exposure augments pulmonary fibrogenesis is unclear. We hypothesized that ETS exposure could exacerbate fibrotic responses via collagen dynamic dysregulation and complement activation. C57BL/6J and p16-3MR mice were exposed to ETS followed by bleomycin administration. ETS exposure exacerbated bleomycin-induced collagen and lysyl oxidase overexpression in the fibrotic lesion. ETS exposure also led to augmented bleomycin-induced upregulation of C3 and C3AR, which are pro-fibrotic markers. Moreover, overexpressed collagens and C3 levels were highly significant in males than females. The old mice (17 months old) were exposed to ETS and treated with bleomycin to induce fibrogenesis which is considered as an aging-associated disease. Fewer gene and protein dysregulations trends were identified between ETS exposure with the bleomycin group and the bleomycin alone group in old mice. Based on our findings, we suggested that ETS exposure increases the risk of developing severe lung fibrotic responses via collagen overexpression and lysyl oxidase-mediated collagen stabilization in the fibrotic lesion, and potentially affected the complement system activation induced by bleomycin. Further, male mice were more susceptible than females during fibrogenesis exacerbation. Thus ETS and bleomycin induced lung fibrotic changes via collagen-lysyl oxidase in an age-dependent mechanism.

Abstract Background Electronic cigarette (e-cig) vaping has increased in the past decade in the US, and e-cig use is misleadingly marketed as a safe cessation for quitting smoking. The main constituents in e-liquid are humectants, such as propylene glycol (PG) and vegetable glycerine (VG), but different flavoring chemicals are also used. However, the toxicology profile of flavored e-cigs in the pulmonary tract is lacking. We hypothesized that menthol and tobacco-flavored e-cig (nicotine-free) exposure results in inflammatory responses and dysregulated repair in lung fibroblast and epithelium. Method We exposed lung fibroblast (HFL-1) and epithelium (BEAS-2B) to Air, PG/VG, menthol flavored, or tobacco-flavored e-cig, and determined the cytotoxicity, inflammation, and wound healing ability in 2D cells and 3D microtissue chip models. Results After exposure, HFL-1 showed decreased cell number with increased IL-8 levels in the tobacco flavor group compared to air. BEAS-2B also showed increased IL-8 secretion after PG/VG and tobacco flavor exposure, while menthol flavor exposure showed no change. Both menthol and tobacco-flavored e-cig exposure showed decreased protein abundance of type 1 collagen α 1 (COL1A1), α-smooth-muscle actin (αSMA), and fibronectin as well as decreased gene expression level of αSMA (Acta2) in HFL-1. After tobacco flavor e-cig exposure, HFL-1 mediated wound healing and tissue contractility were inhibited. Furthermore, BEAS-2B exposed to menthol flavor showed significantly decreased tight junction gene expressions, such as CDH1, OCLN, and TJP1. Conclusion Overall, tobacco-flavored e-cig exposure induces inflammation in both epithelium and fibroblasts, and tobacco-flavored e-cig inhibits wound healing ability in fibroblasts.

Abstract Background Disulfidptosis and the disulfidptosis-related gene SLC7A11 have recently attracted significant attention for their role in tumorigenesis and tumour management. However, its association with adrenocortical carcinoma (ACC) is rarely discussed. Methods Differential analysis, Cox regression analysis, and survival analysis were used to screen for the hub gene SLC7A11 in the TCGA and GTEx databases and disulfidptosis-related gene sets. Then, we performed an association analysis between SLC7A11 and clinically relevant factors in ACC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic value of SLC7A11 and clinically relevant factors. Weighted gene coexpression analysis was used to find genes associated with SLC7A11. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and the LinkedOmics database were used to analyse the functions of SLC7A11-associated genes. The CIBERSORT and Xcell algorithms were used to analyse the relationship between SLC7A11 and immune cell infiltration in ACC. The TISIDB database was applied to search for the correlation between SLC7A11 expression and immune chemokines. In addition, we performed a correlation analysis for SLC7A11 expression and tumour mutational burden and immune checkpoint-related genes and assessed drug sensitivity based on SLC7A11 expression. Immunohistochemistry and RT‒qPCR were used to validate the upregulation of SLC7A11 in the ACC. Results SLC7A11 is highly expressed in multiple urological tumours, including ACC. SLC7A11 expression is strongly associated with clinically relevant factors (M-stage and MYL6 expression) in ACC. SLC7A11 and the constructed nomogram can accurately predict ACC patient outcomes. The functions of SLC7A11 and its closely related genes are tightly associated with the occurrence of disulfidptosis in ACC. SLC7A11 expression was tightly associated with various immune cell infiltration disorders in the ACC tumour microenvironment (TME). It was positively correlated with the expression of immune chemokines (CXCL8, CXCL3, and CCL20) and negatively correlated with the expression of immune chemokines (CXCL17 and CCL14). SLC7A11 expression was positively associated with the expression of immune checkpoint genes (NRP1, TNFSF4, TNFRSF9, and CD276) and tumour mutation burden. The expression level of SLC7A11 in ACC patients is closely associated withcthe drug sensitivity. Conclusion In ACC, high expression of SLC7A11 is associated with migration, invasion, drug sensitivity, immune infiltration disorders, and poor prognosis, and its induction of disulfidptosis is a promising target for the treatment of ACC.

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA.

The increasing incorporation of new energy sources into power grids introduces significant variability, complicating traditional load frequency control (LFC) methods. This variability can cause frequent load disturbances and severe frequency fluctuations in island city microgrids, leading to increased generation costs. To tackle these challenges, this paper introduces a novel Data knowledge-driven load frequency control (DKD-LFC) method, aimed at optimizing the balance between generation cost and frequency stability in isolated microgrids with high renewable energy integration. The DKD-LFC replaces conventional controllers with agent-based systems, utilizing reinforcement learning for adaptive frequency control in complex environments. A new policy generation algorithm, based on generative adversarial-proximal policy optimization (DAC-PPO), is proposed. This algorithm extends the traditional Actor-Critic framework of the Proximal Policy Optimization (PPO) by incorporating a Discriminator network. This network evaluates whether the input state-action pairs align with current or expert policies, guiding policy updates toward expert policies during training. Such an approach enhances the algorithm’s generalization capability, crucial for effective LFC application in diverse operational contexts. The efficacy of the DKD-LFC method is validated using the isolated island city microgrid LFC model of the China Southern Grid (CSG), demonstrating its potential in managing the complexities of modern power grids.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

Abstract Quick Access Recorders (QARs) provide an important data source for Flight Operation Quality Assurance (FOQA) and flight safety. It is generally characterized by large volume, high-dimensionality and high frequency, and these features result in extreme complexities and uncertainties in its usage and comprehension. In this study, we proposed a Time-Feature Attention (TFA)-based Convolutional Auto-Encoder (TFA-CAE) network model to extract essential flight features from QAR data. As a case study, we used the QAR data landing at the Kunming Changshui International Airport and Lhasa Gonggar International Airport as the experimental data. The results show that (1) the TFA-CAE model performs the best in extracting representative flight features in comparison to some traditional or similar approaches, such as Principal Component Analysis (PCA), Convolutional Auto-Encoder (CAE), Self-Attention-based CAE (SA-CAE), Gate Recurrent Unit based Auto-Encoder (GRU-AE) and TFA-GRU-AE models; (2) flight patterns corresponding to different runways can be recognized; and (3) anomalous flights can effectively deviate from many observations. Overall, the TFA-CAE model provides a well-established technique for further usage of QAR data, such as flight risk detection or FOQA.

Tripterygium glycosides tablet (TGT), the classical commercial drug of Tripterygium wilfordii Hook. F. has been effectively used in the treatment of rheumatoid arthritis, nephrotic syndrome, leprosy, Behcet's syndrome, leprosy reaction and autoimmune hepatitis. However, due to its narrow and limited treatment window, TGT-induced organ toxicity (among which liver injury accounts for about 40% of clinical reports) has gained increasing attention. The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing (scRNA-seq) technology. The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Using the mouse model, we identified 15 specific subtypes of cells in the liver tissue, including endothelial cells, hepatocytes, cholangiocytes, and hepatic stellate cells. Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations; led to marked inflammatory response, apoptosis and fatty acid metabolism dysfunction in hepatocytes; activated hepatic stellate cells; brought about the activation, inflammation, and phagocytosis of liver capsular macrophages cells; resulted in immune dysfunction of liver lymphocytes; disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways. Thus, these findings elaborate the mechanism underlying TGT-induced acute liver injury, provide new insights into the safe and rational applications in the clinic, and complement the identification of new biomarkers and therapeutic targets for liver protection.

Rheumatoid arthritis (RA) is an autoimmune disease with features of synovial inflammation, cartilage erosion, bone destruction, and pain and is currently lacking a satisfactory treatment strategy. Dihydroartemisinin (DHA), the active metabolite of artemisinin, has exhibited outstanding suppressive effects on RA without obvious side effects. However, the underlying mechanisms remain unclear, which limits its further clinical application. The purpose of this study is to reveal the pharmacodynamic mechanism of DHA against RA by means of a combination of single-cell RNA sequencing (RNA-seq), proteomics, as well as transcriptomics both in vivo and in vitro. In our results, DHA effectively reduced the degree of redness, swelling, and pain in RA rats and dramatically changed the synovial tissue microenvironment under the pathological state. Within this microenvironment, fibroblasts, macrophages, B cells, and endothelial cells were the major affected cell types, primarily through DHA targeting the extracellular matrix (ECM) structural constituent signaling pathway. In addition, we confirmed that DHA regulated the ECM by modulating matrix metalloproteinase 2 (MMP2) and MMP3 in the synovial tissue of RA rats. Moreover, DHA induced apoptosis in MH7A cells, further validating the bioinformatics data. In conclusion, DHA effectively reduced the inflammatory response and improved the immune microenvironment in synovial tissue by inhibiting MMP2 and MMP3. Our findings provide a basis for the application of DHA in the treatment of RA.

The molecular clock REV-ERBα regulates lung injury during fibrosis, but the role of REV-ERBα in fibrogenesis remains unknown. Here, the authors show that REV-ERBα interacts with the lysyl oxidase-collagen axis during fibrogenesis and demonstrate the therapeutic potential of Rev-erbα agonist against lung fibrosis.

Anemoside B4 (AB4), as an important ingredient of Chinese herb Pulsatilla Chinensis, has been used in Chinese ancient medicine for thousands of years with exact therapeutic effects of anti-inflammation and anti-tumor. Due to its high potency and low toxicity, AB4 has caused more and more attention of researchers. In this paper, our article reviews the research progress on pharmacological actions and molecular mechanisms of AB4 in order to provide references for its development and utilization.

Until the Mw 6.6 Luding earthquake ruptured the Moxi section of the Xianshuihe fault (XSHF) on 5 September 2022, the region had not experienced an Mw >6 earthquake since instrumental records began. We used Global Positioning System (GPS) and Sentinel-1 interferometric synthetic aperture radar (InSAR) observations to image the coseismic deformation and constrain the location and geometry of the seismogenic fault using a Bayesian method We then present a distributed slip model of the 2022 Mw6.6 Luding earthquake, a left-lateral strike-slip earthquake that occurred on the Moxi section of the Xianshuihe fault in the southwest Sichuan basin, China. Two tracks (T26 and T135) of the InSAR data captured a part of the coseismic surface deformation with the line-of-sight displacements range from ∼−0.16 m to ~0.14 m in the ascending track and from ~−0.12 m to ~0.10 m in the descending track. The inverted best-fitting fault model shows a pure sinistral strike-slip motion on a west-dipping fault plane with a strike of 164.3°. We adopt a variational Bayesian approach and account for the uncertainties in the fault geometry to retrieve the distributed slip model. The inverted result shows that the maximum slip of ~1.82 m occurred at a depth of 5.3 km, with the major slip concentrated within depths ranging from 0.9–11 km. The InSAR-determined moment is 1.3 × 1019 Nm, with a shear modulus of 30 GPa, equivalent to Mw 6.7. The published coseismic slip models of the 2022 Luding earthquake show apparent differences despite the use of similar geodetic or seismic observations. These variations underscore the uncertainty associated with routinely performed source inversions and their interpretations for the underlying fault model.

Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

Based on the theories and methods of complex network, crude oil trade flows between countries along the Belt and Road (B&R, hereafter) are inserted into the Geo-space of B&R and form a spatial interaction network which takes the countries as nodes and takes the trade relations as edges. The networked mining and evolution analysis can provide important references for the research on trade relations among the B&R countries and the formulation of trade policy. This paper researches and discusses the construction, statistical analysis, top networks and stability of the crude oil trade network between the B&R countries from 2001 to 2020 from the perspectives of Geo-Computation for Social Sciences (GCSS) and spatial interaction. Firstly, evolutions of out-degree, in-degree, out-strength and in-strength of the top 10 countries in the crude oil trade network are computed and analyzed. Secondly, the top network method is used to explore the evolution characteristics of hierarchical structures. And finally, the sequential evolution characteristics of the crude oil trade network stability are analyzed utilizing the network stability measure method based on the trade relationship autocorrelation function. The analysis results show that Russia has the largest out-degree and out-strength, and China has the largest in-degree and in-strength. The crude oil trade volume of the top 10 import and export networks between 2001—2020 accounts for over 90% of the total trade volume of the crude oil trade network, and the proportion remains relatively stable. However, the stability of the network showed strong fluctuations in 2009, 2012 and 2014, which may be closely related to major international events in these years, which could furtherly be used to build a correlation model between network volatility and major events. This paper explores how to construct and analyze the spatial interaction network of crude oil trade and can provide references for trade relations research and trade policy formulation of B&R countries.

This paper presents a set of nonparametric methods for selecting credit evaluation indicators under the condition of unknown index distribution, and applies the data of four power companies as samples for application analysis. The results show that through the first round of credit feature screening based on nonparametric Bayes discrimination and the second round of nonparametric clustering, this paper finally constructs a credit feature screening model based on non parametric Bayesian discriminant and clustering analysis, and carries out application analysis. Finally, 18 credit characteristics which can be used in power market credit evaluation are screened out, and the evaluation accuracy has been significantly improved from 73.64% to 77.02%.

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.

In this paper, a hybrid Mach-Zehnder optical modulator is proposed based on silicon nitride/organic polymer waveguides, which is expected to break through the performance bottleneck of the silicon-based optical modulator by exploiting the low-loss optical transmission property of silicon nitride waveguides and the excellent modulation performance of organic polymers. For reduction of the optical loss and ease of photonic packaging, perfectly vertical silicon nitride bidirectional grating couplers are utilized for both input/output optical coupling and power splitting/combining. Thus, a Mach-Zehnder interferometer can be constructed with a back-to-back configuration of such grating couplers. With grating apodization, the coupler can achieve a simulated coupling efficiency of 70%. To bridge the silicon nitride waveguides and the polymer waveguides, a longitudinal adiabatic mode-spot converter with a transmission efficiency of 99.2% was designed. In this paper, high-β donor-π bridge-accepter molecule YLD-124 combined with HD-BB-OH as the host polymer is utilized for a design example. The polymer waveguides with inverted ridge structure can be realized through the processes of silica cladding etching, spin coating or microfluidic trench filling of polymer. Following this design, we numerically demonstrate a hybrid silicon nitride-polymer Mach-Zehnder modulator with modulation efficiency of 1.57 Vcm and Electric-Optical bandwidth of 174 GHz. The total insertion loss is less than 5.74 dB, including two grating coupler losses of about 3.08 dB.

PurposeIn this study, DOTA-IBA was radiolabeled with 68Ga and we determined the optimum labelling conditions and assessed the biological properties of 68Ga-DOTA-IBA. We investigated the biodistribution of 68Ga-DOTA-IBA in normal animals and undertook PET/CT imaging in humans. Finally, we explored the feasibility 68Ga-DOTA-IBA as a bone imaging agent and demonstrated its potential for the therapeutic release of 177Lu/225Ac-DOTA-IBA.MethodsThe controlled variables method was used to assess the impact of variables on the radiochemical purity of 68Ga-DOTA-IBA. The biological properties of 68Ga-DOTA-IBA were investigated.68Ga-DOTA-IBA micro-PET/CT imaging was performed on animals. Volunteers were recruited for 68Ga-DOTA-IBA imaging and data were compared to 99mTc-MDP imaging studies to calculate the target to non-target ratio (T/NT) of the lesions.ResultsThe prepared 68Ga-DOTA-IBA had a radiochemical purity of >97% and demonstrated good biological properties with a good safety profile in normal mice. PET/CT imaging of the animals showed rapid blood clearance with high contrast between the bone and stroma. Human imaging showed that 68Ga-DOTA-IBA could detect more lesions compared to 99mTc-MDP and had a higher targeted to untargeted ratio.Conclusions68Ga-DOTA-IBA is an osteophilic radiopharmaceutical that can be synthesized using a simple labelling method. 68Ga-DOTA-IBA has high radiochemical purity and is stable in vitro stability. It is rapidly cleared from the blood, has low toxicity and has strong targeting to the bone with long retention times. We also found that it is rapidly cleared in non-target tissues and has high contrast on whole-body bone imaging. 68Ga-DOTA-IBA PET/CT has potential as a novel bone imaging bone modality in patients with metastatic disease.

As a typical underwater robot, the robotic fish has been a hot topic of research in terms of the swimming control method and the reduction of energy consumption. Body flexibility and passive designs have been proven to be effective approaches for improving the swimming performance of robotic fishes. However, the addition of passive structures or motions of these approaches makes it more difficult to control the movement of robotic fish. In this paper, we proposed a deep reinforcement learning-based method for online learning control of a robotic eel with multiple passive structures. First, we designed a robotic eel with two wire-driven segments and two complaint bodies made of elastic material. Second, a simulation model of the robotic eel was built and the validity of the model was tested. Following that, the neural network was trained in simulation and deployed directly on the robotic eel, which was controlled without an underlying control model or strategy and directly online by the neural network. Finally, extensive experiments verified the effectiveness of our control method, which offers a valuable and potential solution for robots difficult to model and control.

Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.

Abstract Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.

Strain partitioning and accommodation are fundamental constraints to evaluate tectonic models of orogenic plateaus. The uplift mechanism issue of the eastern Tibetan Plateau has remained a long-term focus since the last century, namely, the steep uplift of the Longmen Shan area. Several tectonic models have been proposed to describe the uplift process of the central Longmen Shan area along the eastern margin of the Tibetan Plateau. Such as upper crustal shortening, mid-crustal channel flow, and whole-crust shearing. However, these models are typically examined through vertical differences. Geophysical, geological, remote sensing and geochemistry observation data indicate that there occur not only vertical differences but also obvious horizontal differences along the Longmen Shan orogenic belt. Based on the finite element method, we employed two-dimensional profiles crossed northern and southern Longmen Shan fault to reconstruct the uplift process of the Longmen Shan orogenic belt. The mechanical properties of the lithosphere south of the Longmen Shan orogenic belt were slightly less favorable than those of the lithosphere north of the Longmen Shan orogenic belt. For the better fitting result in the southern part viscosity of lower crust is less than 1021 Pa∙s and in the northern part viscosity of lower crust is around 1022 Pa∙s. The uplift processes in the upper and lower crust of the Longmen Shan orogenic belt were partially decoupled. The deformation of lithosphere in the northern Longmen Shan orogenic belt is smaller than it in southern Longmen Shan orogenic belt. Due to that the rigid Ruoergai block maybe resists the formation of a weak layer or enters of weak materials to the northern Longmen Shan block, resulting in the observed difference in lithospheric properties between the northern and southern Longmen Shan blocks.

Automatic extraction of road from multisource remote sensing data has always been a challenging task. Factors such as shadow occlusion and multisource data alignment errors prevent current deep learning-based road extraction methods from acquiring road features with high complementarity, redundancy, and crossover. Unlike previous works that capture contexts by multiscale feature fusion, we propose a dual attention dilated-LinkNet (DAD-LinkNet) to adaptively integrate local road features with their global dependencies by joint using satellite image and floating vehicle trajectory data. First, a joint least-squares feature matching-based floating vehicle trajectory correction model is used to correct the floating vehicle trajectory; then a convolutional network model DAD-LinkNet based on a dual-attention mechanism is proposed, and road features are extracted from the channel domain and spatial domain of the target image in turn by constructing a dual-attention module in the dilated convolutional layer and adopting a cascade connection; a weighted hyperparameter loss function is used as the loss function of the model; finally, the road extraction is completed based on the proposed DAD-LinkNet model. Experiments on three datasets show that the proposed DAD-LinkNet model outperforms the state-of-the-art methods in terms of accuracy and connectivity.

Abstract Transnational power trading can promote the development of global energy Internet, which can enable various countries and regions to optimize the allocation of resources on a larger scale. However, transnational electricity trading still faces many challenges. First, the issues of trust, member management, and huge transaction volume hinder the development of transnational power trading. Second, the issues of considering the differences among countries and establishing a reasonable and efficient transnational power market trading mechanism are also particularly important. The emergence of a consortium‐blockchain technology provides a new idea of solving these problems. The distributed‐ledger technology and member‐management services of a consortium blockchain can solve the problems of trust in the transnational power transaction and access the review of market subjects. Simultaneously, the chain‐code technology can be used to improve the efficiency of transactions. Therefore, according to the actual needs of transnational power transactions, the applicability of the consortium‐blockchain technology was analysed. Then, a mathematical model of transnational power transactions that considered the transaction costs was designed, and simulation tests were conducted on Hyperledger Fabric. The calculation example shows that the proposed transaction model plays a positive role and significance in promoting transnational power transactions and stabilizing the market.

Background: Glycyrrhizic acid (GA) has been reported to be liver protective; however, the characters and underlying mechanisms of GA against tripterygium glycoside tablet (TGT)-induced acute liver injury remain unelucidated.Hypothesis/Purpose: We assumed that GA could relieve TGT-induced acute liver injury by regulating liver function-related genes and lipid metabolites.Study Design: TGT-induced acute liver injury models were constructed in vivo and in vitro. Then the liver protective effect and mechanisms of GA were investigated by a combination of transcriptome, lipid metabolomics, and experimental validation.Methods: Intraperitoneal injection of GA was given in advance for six successive days. Then, the TGT-induced acute liver injury model was constructed by a single oral administration of TGT at 270 mg/kg, except for the normal group. All animals were sacrificed 18 h later. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) were quantified. Liver tissues were used to observe pathological changes through hematoxylin–eosin (HE) staining and selected for transcriptome and metabolome sequencing. The underlying mechanisms were analyzed and further validated both in vivo and in vitro.Results: Pre-administration of GA markedly decreased the serum concentrations of AST, ALT, ALP, and TBIL but increased those of SOD and GSH-Px, improving the liver morphology of mice with TGT-induced acute liver injury. In addition, GA significantly increased the gene levels of Cyp2b13, Cyp2c69, Cyp3a16, Cyp3a44, Fmo3, and Nipal1. Differentially accumulated metabolites were screened and classified as phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The in vitro results indicated that pre-administration of GA markedly alleviated the inhibitory effect of TGT on BRL-3A activity.Conclusion: This study combined transcriptome, lipid metabolomics, and experimental validation to offer convincing evidence that GA alleviates TGT-induced acute liver injury partially by regulating the activities of CYP and the metabolism of PC and PE.

Abstract Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.

Introduction: FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes. Materials and methods: Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo. A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination. Results: HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4–11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells. Conclusions: FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.

Abstract Background Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy. Method Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade. Results In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53 wt , Trp53 mut , and Trp53-deficient (Trp53 −/− ) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8+ T cells in Trp53 wt tumors and M1 macrophages in Trp53 mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53 wt and Trp53 mut tumors upon combination treatment. Conclusion Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53 mut tumors.

Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA’s impact on TGT-induced acute liver injury by regulating oxidative stress remain unelucidated. In this study, TGT-induced acute liver injury models were established in vitro and in vivo. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were quantified. The anti-apoptotic effect of GA was tested using flow cytometry. Potential target proteins of GA were profiled via activity-based protein profiling (ABPP) using a cysteine-specific (IAA-yne) probe. The results demonstrate that GA markedly decreased the concentrations of ALT, AST, AKP, MDA, LDH, TNF-α, IL-1β and IL-6, whereas those of SOD, GSH and CAT increased. GA could inhibit TGT-induced apoptosis in BRL-3A cells. GA bound directly to the cysteine residue of PKM2. The CETSA and enzyme activity results validate the specific targets identified. GA could mitigate TGT-induced acute liver injury by mediating PKM2, reducing oxidative stress and inflammation and reducing hepatocyte apoptosis.

Objectives: This study aimed to investigate the physiological distribution characteristics of 68Ga-DOTA-FAPI-04 in the ovary, and assess the feasibility of early diagnosis of primary ovarian disease with 68Ga-DOTA-FAPI-04 PET/CT.Methods: We retrospectively analyzed the data of patients who received 18F-FDG and 68Ga-DOTA-FAPI-04 PET/CT scanning in the Nuclear Medicine Department of our hospital within 3 days from September 2020 to January 2021. We selected the data in which ovaries showed abnormal FDG activity. Patients with abnormal ovarian FDG uptake with focus confirmed by pathological biopsy or clinical follow-up as pathological changes were excluded. The uptake of tracers (18F-FDG and 68Ga-FAPI) was semi-quantitatively analyzed.Results: This study included 14 patients (average age was 38.6). Physiological ovarian uptake was mostly unilateral, and there was no significant difference in SUVmax between the left and right sides (FDGt = 0.272, FAPIt = 0.592). The ovary SUVmax of FDG (4.89 ± 1.84) was statistically significantly higher than that of FAPI (1.53 ± 0.37). The Le/Li ratio on FDG is 3.38 ± 1.81, TBR is 5.81 ± 1.98, while the Le/Li ratio on FAPI is 3.57 ± 1.26, TBR is 0.94 ± 0.19.Conclusion: Our research shows that ovarian functional or pathological changes can be manifested as FDG avid, while 68Ga-DOTA-FAPI-04 has no physiological accumulation in the ovary and is not affected by the menstrual cycle. Therefore, 68Ga-DOTA-FAPI-04 has unique advantages in the diagnosis of ovarian diseases, and can identify them early and accurately.

Cigarette smoke (CS) is the main etiological factor in the pathogenesis of emphysema/chronic obstructive pulmonary disease (COPD), which is associated with abnormal epithelial-mesenchymal transition (EMT). Previously, we have shown an association among circadian rhythms, CS-induced lung inflammation, and nuclear heme receptor α (REV-ERBα), acting as an antiinflammatory target in both pulmonary epithelial cells and fibroblasts. We hypothesized that molecular clock REV-ERBα plays an important role in CS-induced circadian dysfunction and EMT alteration. C57BL/6J WT and REV-ERBα heterozygous (Het) and –KO mice were exposed to CS for 30 days (subchronic) and 4 months (chronic), and WT mice were exposed to CS for 10 days with or without REV-ERBα agonist (SR9009) administration. Subchronic/chronic CS exposure caused circadian disruption and dysregulated EMT in the lungs of WT and REV-ERBα–KO mice; both circadian and EMT dysregulation were exaggerated in the REV-ERBα–KO condition. REV-ERBα agonist, SR9009 treatment reduced acute CS-induced inflammatory response and abnormal EMT in the lungs. Moreover, REV-ERBα agonist (GSK4112) inhibited TGF-β/CS–induced fibroblast differentiation in human fetal lung fibroblast 1 (HFL-1). Thus, CS-induced circadian gene alterations and EMT activation are mediated through a Rev-erbα–dependent mechanism, which suggests activation of REV-ERBα as a novel therapeutic approach for smoking-induced chronic inflammatory lung diseases.

Abstract Nicotine inhalation via electronic cigarettes (e‐cigs) is an emerging concern. However, little is known about the acute toxicity in the lungs following inhalation of nicotine‐containing e‐cig aerosols. We hypothesized that acute exposure to aerosolized nicotine causes lung toxicity by eliciting inflammatory and dysregulated repair responses. Adult C57BL/6J mice were exposed 2 hours daily for 3 days to e‐cig aerosols containing propylene glycol (PG) with or without nicotine. Acute exposure to nicotine‐containing e‐cig aerosols induced inflammatory cell influx (neutrophils and CD8a+ T lymphocytes), and release of pro‐inflammatory cytokines in bronchoalveolar lavage fluid in a sex‐dependent manner. Inhalation of e‐cig aerosol containing PG alone significantly augmented the lung levels of various homeostasis/repair mediators (PPARγ, ADRP, ACTA2, CTNNB1, LEF1, β‐catenin, E‐cadherin, and MMP2) in a sex‐dependent manner when compared to air controls. These findings were accompanied by an increase in protein abundance and altered gene expression of lipogenic markers (PPARγ, ADRP) and myogenic markers (fibronectin, α‐smooth muscle actin and β‐catenin), suggesting a dysregulated repair response in mouse lungs. Furthermore, exposure to nicotine‐containing e‐cig aerosols or PG alone differentially affected the release of pro‐inflammatory cytokines in healthy and COPD human 3D EpiAirway tissues. Overall, acute exposure to nicotine‐containing e‐cig aerosols was sufficient to elicit a pro‐inflammatory response and altered mRNA and protein levels of myogenic, lipogenic, and extracellular matrix markers in mouse lung in a sex‐dependent manner. Thus, acute exposure to inhaled nicotine via e‐cig leads to dysregulated repair and inflammatory responses, which may lead to airway remodeling in the lungs.

Abstract Background Pegylated interferon (PEG-IFN) alfa-2b is recommended for chronic hepatitis B (CHB). We aimed to investigate the sustainability of off-treatment responses among Chinese HBeAg-positive CHB patients treated with PEG-IFN alfa-2b from a randomized trial. Methods Eligible Chinese patients (n = 322) were followed up by one visit after a median of 6 years (LTFU) following their participation in a randomized trial evaluating the efficacy of three PEG-IFN alfa-2b dosing regimens (1.0 or 1.5 μg/kg/wk. 24 weeks or 1.5 μg/kg/wk. 48 weeks). Primary endpoints at the LTFU were sustained SR and CR (SR/CR at the end of original study [EOS] and at the LTFU). SR was defined as HBeAg loss and seroconversion to anti-HBe and CR as HBeAg loss and seroconversion to anti-HBe and HBV-DNA

In the civil aviation industry, security risk management has shifted from post-accident investigations and analyses to pre-accident warnings in an attempt to reduce flight risks by identifying currently untracked flight events and their trends and effectively preventing risks before they occur. The use of flight monitoring data for flight anomaly detection is effective in discovering unknown and potential flight incidents. In this paper, we propose a time-feature attention mechanism and construct a deep hybrid model for flight anomaly detection. The hybrid model combines a time-feature attention-based convolutional autoencoder with the HDBSCAN clustering algorithm, where the autoencoder is constructed and trained to extract flight features while the HDBSCAN works as an anomaly detector. Quick access record (QAR) flight data containing information of aircraft landing at Kunming Changshui International and Chengdu Shuangliu International airports are used as the experimental data, and the results show that (1) the time-feature-based convolutional autoencoder proposed in this paper can better extract the flight features and further discover the different landing patterns; (2) in the representation space of the flights, anomalous flight objects are better separated from normal objects to provide a quality database for subsequent anomaly detection; and (3) the discovered flight patterns are consistent with those at the airports, resulting in anomalies that could be interpreted with the corresponding pattern. Moreover, several examples of anomalous flights at each airport are presented to analyze the characteristics of anomalies.

We propose and numerically demonstrate an 800 Gbps silicon photonic transmitter with sub-decibel surface-normal optical interfaces. The silicon photonic transmitter is composed of eight silicon Mach–Zehnder optical modulators and an interleaved AMMI WDM device. This WDM device comprises two 1 × 4 angled MMI and a Mach–Zehnder interferometer (MZI) optical interleaver with an apodized bidirectional grating which has about −0.5 dB coupling loss. Both the Mach–Zehnder electro-optical modulators and MZI optical interleaver regard the bidirectional grating coupler as vertical optical coupler and 3-dB power splitter/combiner. By importing the S-parameter matrices of all the components which have been carefully designed in simulation software, the circuit-level model of the optical transmitter can be built up. On this basis, the static and dynamic performance characterization were carried out numerically. For NRZ modulation, the optical transmitter exhibits the overall optical loss of 4.86–6.72 dB for eight wavelength channels. For PAM4 modulation, the optical loss is about 0.5 dB larger than that of NRZ modulation, which varies between 5.38–7.27 dB. From the eye diagram test results, the WDM silicon photonic transmitter can achieve single channel data transmission at 100 Gb/s NRZ data or 50 GBaud/s PAM4 symbol rate with acceptable bit error rate.

Electronic cigarette (e-cig) usage has risen dramatically worldwide over the past decade. While they are touted as a safe alternative to cigarettes, recent studies indicate that high levels of nicotine and flavoring chemicals present in e-cigs may still cause adverse health effects. We hypothesized that an e-liquid containing a mixture of tobacco, coconut, vanilla, and cookie flavors would induce senescence and disrupt wound healing processes in pulmonary fibroblasts. To test this hypothesis, we exposed pulmonary fibroblasts (HFL-1) to e-liquid at varying doses and assessed cytotoxicity, inflammation, senescence, and myofibroblast differentiation. We found that e-liquid exposure caused cytotoxicity, which was accompanied by an increase in IL-8 release in the conditioned media. E-liquid exposure resulted in elevated senescence-associated beta-galactosidase (SA-β-gal) activity. Transforming growth factor-β1 (TGF-β1) induced myofibroblast differentiation was inhibited by e-liquid exposure, resulting in decreased α-smooth muscle actin and fibronectin protein levels. Together, our data suggest that an e-liquid containing a mixture of flavors induces inflammation, senescence and dysregulated wound healing responses.

The abnormal inflammatory responses due to the lung tissue damage and ineffective repair/resolution in response to the inhaled toxicants result in the pathological changes associated with chronic respiratory diseases. Investigation of such pathophysiological mechanisms provides the opportunity to develop the molecular phenotype-specific diagnostic assays and could help in designing the personalized medicine-based therapeutic approaches against these prevalent diseases. As the central hubs of cell metabolism and energetics, mitochondria integrate cellular responses and interorganellar signaling pathways to maintain cellular and extracellular redox status and the cellular senescence that dictate the lung tissue responses. Specifically, as observed in chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, the mitochondria-endoplasmic reticulum (ER) crosstalk is disrupted by the inhaled toxicants such as the combustible and emerging electronic nicotine-delivery system (ENDS) tobacco products. Thus, the recent research efforts have focused on understanding how the mitochondria-ER dysfunctions and oxidative stress responses can be targeted to improve inflammatory and cellular dysfunctions associated with these pathologic illnesses that are exacerbated by viral infections. The present review assesses the importance of these redox signaling and cellular senescence pathways that describe the role of mitochondria and ER on the development and function of lung epithelial responses, highlighting the cause and effect associations that reflect the disease pathogenesis and possible intervention strategies.

Macrophages play a pivotal role in myocardial remodeling (MR) process which could eventually lead to heart failure. Splenic monocytes could be mobilized and recruited under inflammatory conditions and differentiated into different types of macrophages in heart tissues. Inflammatory M1 macrophages could aggravate tissue damage whereas M2 macrophages could promote angiogenesis and tissue repair process. Unbalanced ratio of M1/M2 macrophages may eventually lead to adverse remodeling. Therefore, regulating differentiation and activities of macrophages are potential strategies for the management of myocardial remodeling. Qishen Granule (QSG) is an effective Chinese medicine for treating heart failure. Our previous studies demonstrated that QSG could inhibit myocardial fibrosis through regulating secretion of cytokines and activation of macrophages. However, the detailed effects of QSG on had not been elucidated yet. In this study, we aimed to explore the effect of QSG on the release of splenic monocytes, the recruitment of monocytes into heart tissues and the differentiation of macrophages under ischemic conditions. Our results showed that QSG could suppress the release of monocytes from the spleen and recruitment of monocytes to heart tissues via inhibiting splenic angiotensin (Ang) II/AT1-cardiac monocyte chemotactic protein (MCP)-1/CC chemokine receptor 2 (CCR2) pathway. The anti-fibrotic effect of QSG was exerted by inhibiting M1 macrophage-activated transforming growth factor (TGF)-β1/Smad3 pathway. Meanwhile, QSG could promote angiogenesis by promoting differentiation of M1 macrophages into M2 macrophages. Our results suggest that compounds of Chinese medicine have synergistic effects on cardiac and splenic organs through regulating differentiation of monocytes/macrophages in inhibiting myocardial remodeling.

Multi-walled carbon nanotubes are engineered nanomaterials (ENMs) that have a fiber-like structure which may be a concern for the development of cellular senescence. Premature senescence, a state of irreversible cell cycle arrest, is implicated in the pathogenesis of chronic lung diseases such as pulmonary fibrosis (PF). However, the crosstalk between downstream pathways mediating fibrotic and senescent responses of MWCNTs is not well-defined. Here, we exposed human bronchial epithelial cells (BEAS-2B) to MWCNTs for up to 72 h and demonstrate that MWCNTs increase reactive oxygen species (ROS) production accompanied by inhibition of cell proliferation. In addition, MWCNT exposure resulted in the increase of p21 protein abundance and senescence associated β-galactosidase (SA β-gal) activity. We also determined that co-exposure with the cytokine, transforming growth factor-β (TGF-β) exacerbated cellular senescence indicated by increased protein levels of p21, p16, and γH2A.X. Furthermore, the production of fibronectin and plasminogen activator inhibitor (PAI-1) was significantly elevated with the co-exposure compared to MWCNT or TGF-β alone. Together, our study suggests that the cellular senescence potential of MWCNTs may be enhanced by pro-fibrotic mediators, such as TGF-β in the surrounding microenvironment.

Metabolites are essential intermediate products in metabolism, and metabolism dysregulation indicates different types of diseases. Previous studies have shown that cigarette smoke dysregulated metabolites; however, limited information is available with electronic cigarette (e-cig) vaping. We hypothesized that e-cig vaping and cigarette smoking alters systemic metabolites, and we propose to understand the specific metabolic signature between e-cig users and cigarette smokers. Plasma from non-smoker controls, cigarette smokers, and e-cig users was collected, and metabolites were identified by UPLC-MS (ultra-performance liquid chromatography mass spectrometer). Nicotine degradation was activated by e-cig vaping and cigarette smoking with increased concentrations of cotinine, cotinine N-oxide, (S)-nicotine, and (R)-6-hydroxynicotine. Additionally, we found significantly decreased concentrations in metabolites associated with tricarboxylic acid (TCA) cycle pathways in e-cig users versus cigarette smokers, such as d-glucose, (2R,3S)-2,3-dimethylmalate, (R)-2-hydroxyglutarate, O-phosphoethanolamine, malathion, d-threo-isocitrate, malic acid, and 4-acetamidobutanoic acid. Cigarette smoking significant upregulated sphingolipid metabolites, such as d-sphingosine, ceramide, N-(octadecanoyl)-sphing-4-enine, N-(9Z-octadecenoyl)-sphing-4-enine, and N-[(13Z)-docosenoyl]-sphingosine, versus e-cig vaping. Overall, e-cig vaping dysregulated TCA cycle-related metabolites while cigarette smoking altered sphingolipid metabolites. Both e-cig and cigarette smoke increased nicotinic metabolites. Therefore, specific metabolic signatures altered by e-cig vaping and cigarette smoking could serve as potential systemic biomarkers for early pathogenesis of cardiopulmonary diseases.

The use of emerging tobacco products, such as waterpipe or hookah and electronic cigarettes (e-cigs), has gained significant popularity and are promoted as safer alternatives to conventional cigarettes. Circadian systems are internal biological oscillations that are considered important regulators of immune functions in mammals. Tobacco induced inflammatory lung diseases frequently exhibit time-of-day/night variation in lung function and symptom severity. We investigated the impact of inhaled e-cig vapor and waterpipe smoke (WPS) on pulmonary circadian molecular clock disruption by determining the changes in expression levels and abundance of core clock component genes (BMAL1, CLOCK) and clock-controlled output genes (Rev-erbα, Per2, Rev-erbβ, Cry2, Rorα) in mouse lungs. We showed that the expression levels of these pulmonary core clock genes and clock-controlled output genes were altered significantly following exposure to WPS (Bmal1, Clock, and Rev-erbα). We further showed a significant yet differential effect on expression levels of core clock and clock-controlled genes (Bmal1, Per2) in the lungs of mice exposed to e-cig vapor containing nicotine. Thus, acute exposure to WPS and e-cig vapor containing nicotine contributes to altered expression of circadian molecular clock genes in mouse lungs, which may have repercussions on lung cellular and biological functions.

Flavored tobacco products are increasing in popularity but remain unregulated, with the exception of the ban on flavored conventional cigarettes. Lack of regulation of cigarillos and little cigars allows vendors to have their own version of popular flavors, each with different chemical components. A new classification system was created for flavored cigars in order to easily communicate our results with the scientific community. To understand the physicochemical characteristics of flavored little cigars and cigarillo smoke, size distribution and concentration of particulate matter in smoke were determined. Acellular reactive oxygen species generation was measured as an indirect measurement of the potential to cause oxidative stress in cells. In addition, cigarillo smoke extract treatment on bronchial epithelial (Beas-2b) cells were assessed to determine the flavor-induced cellular toxicity. Flavored cigars/cigarillos showed significant variability in the tested parameters between flavors as well as brands of the same flavor, but most of the cigars showed higher potential of generating oxidative stress, than research grade cigarettes. Flavored cigars produced maximum particle concentrations at 1.0μm and 4.0 μm compared with 3R4F reference research cigarettes. A differential cytotoxic response was observed with cigarillo smoke extract treatments, with "fruits/candy" and "drinks" being the most toxic, but were not more cytotoxic than smoke from cigarettes. These cigarillos with flavors must be well characterized for toxicity in order to prevent adverse effects caused by exposure to flavor chemicals. Our study provides insight into understanding the potential health effects of flavor-infused cigars/cigarillos and the need for the regulation of those flavoring chemicals in these products. Future research is directed to determine the flavoring toxicity of little cigars and cigarillos in vivo studies.

Recently, there has been an outbreak of a condition named e-cigarette or vaping products-associated lung injury (EVALI). The primary components of vaping products include tetrahydrocannabinol (THC), vitamin E acetate (VEA) and medium-chain triglycerides (MCT), may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these CBD/counterfeit vape cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury. We studied the potential mechanisms of CBD/counterfeit vape cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse BALF, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to CBD/counterfeit vape cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined SARS-CoV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific CBD/counterfeit vape cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation and in vivo mouse exposure induces acute inflammation with elevated proinflammatory markers in the pathogenesis of EVALI.