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Abstract Intestinal fibrosis is the primary cause of disability in patients with Crohn’s disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.

Abstract Heavy Meiyu-Baiu rainfall can pose threat to the dense population in East Asia by catastrophic flooding. Although previous studies have identified Indian Ocean (IO) warming as the major cause of heavy Meiyu-Baiu rainfall, it failed to predict the record-breaking rainfall in July 2020. Synthesizing observational analysis, large-ensemble climate simulations, and atmospheric simulations, we show that sea-ice loss in the Kara Sea in May can intensify the IO warming-induced heavy Meiyu-Baiu rainfall and well explains the record-breaking rainfall in July 2020. In the precondition of IO warming, sea-ice loss tends to prolong Meiyu-Baiu season and strengthen convective activity over the Meiyu-Baiu region, thereby enhancing the IO warming-induced heavy Meiyu-Baiu rainfall by ~50% and doubling the risk of extreme events comparable to or greater than the one in 2020. A statistical model is further constructed to demonstrate that taking Arctic sea ice into consideration can significantly improve the seasonal prediction of extreme Meiyu-Baiu rainfall.

ABSTRACT Although preterm birth (PTB) is one of the major causes of perinatal mortality and neonatal morbidity, little is known about its complex etiology. An abnormal cervicovaginal microbiome during pregnancy is associated with an increased risk of PTB. The cervicovaginal microbiota and its active metabolites, such as short-chain fatty acids (SCFAs), might be effectively used to predict and diagnose PTB. However, the roles of these proteins and the underlying mechanisms involved remain elusive. We conducted 16S rRNA gene sequencing and used a targeted metabolomics approach to study cervicovaginal swabs obtained from 51 singleton pregnancies and 52 twin pregnancies in the second trimester. Next, functional in vitro experiments were performed to investigate the roles and mechanisms of SCFAs in placental trophoblast cells (HTR8/SVneo cells). Significant cervicovaginal microbiome dysbiosis, characterized by a substantial reduction in the abundance of lactobacilli and overgrowth of anaerobes, was revealed in the second trimester and was strongly associated with subsequent PTB (P = 0.036). Among the paired samples (n = 103), acetic acid was significantly greater in the preterm group than in the term group (P = 0.047). Data obtained from integrated gas chromatography‒mass spectrometry and 16S RNA studies revealed metabolites that were distinctly associated with particular microbial communities. Gardnerella vaginalis was the species most positively associated with acetic acid content. In addition, we identified a marker set consisting of the pregnancy type, acetic acid concentration, and community state type to accurately diagnose PTB. Acetate was associated with increased interleukin (IL)-8 and IL-6 levels and extravillous trophoblast cell migration and invasion through the activation of the extracellular signal-regulated kinase 1/2 signaling pathway in HTR8/SVneo cells. Cervicovaginal microbiota dysbiosis is an important etiological factor of PTB. The cervicovaginal microbiota and its active metabolites can be efficiently used to predict and diagnose PTB. Our findings enrich the microbiota–placenta axis theory and contribute to the development of microecological products for pregnancy.IMPORTANCEPreterm birth (PTB) is a leading cause of infant mortality and long-term health issues, affecting millions of families worldwide. Despite its prevalence, the exact causes of PTB remain unclear. Our study reveals that certain bacteria and their metabolic byproducts in the cervicovaginal environment, specifically short-chain fatty acids (SCFAs), are linked to the risk of preterm birth. By analyzing samples from pregnant women, we found that an imbalance in the vaginal microbiota and increased levels of SCFAs are associated with changes in cells that can lead to early labor. This research provides new insights into how the microbiome influences pregnancy outcomes and highlights potential biomarkers for predicting preterm birth. Understanding these microbial influences could lead to innovative strategies for early diagnosis and prevention, ultimately improving maternal and infant health.

A crucial strategic choice for China’s sustainable growth in the new era is the carbon peak & carbon neutral (30–60) aim, which has set new and higher requirements for the green and sustainable development of cities in the new era, and the carbon peak & carbon neutral level is gradually becoming one of the important indicators of the green and sustainable development of cities. Based on disentangling the connotation of urban green development under the vision of carbon neutrality, this study constructed a framework system for assessing urban green development in the new era, measured and portrayed the spatial and temporal variation characteristics of green development efficiency (C-GDE) under the carbon neutrality constraint in 284 prefecture-level and above cities in China using the SBM-Undesirable model, and further explored the effect of multi-subject factors on urban C-GDE using the panel Tobit model. The main findings are as follows. (1) The average allocation level of C-GDE in Chinese cities has remained at a low level from 2009 to 2019, with an overall “V”-shaped trend of “down → up”, increasing from 0.4031 to 0.5206, an overall increase of 29.15 %. (2) The overall C-GDE of Chinese cities showed the decreasing characteristics of “western cities > eastern cities > central cities”, “super cities > small cities > medium cities > large cities > mega cities > mega cities”, “non class cluster cities > class II cities > class III cities > class I cities”, and “agriculture-led cities > industry-led cities > balanced development cities > business and tourism service cities”. (3) The spatio-temporal pattern of urban C-GDE was influenced by multiple factors such as individual-level factors, enterprise-level factors, government-level factors, and other basic-level characteristic factors. Each factor, through its own evolution or coupling with other factors, continuously shaped the internal development of the urban system and promotes the greening process and urban C-GDE. Finally, targeted recommendations were made based on the findings of the study.

Abstract The Atlantic Multidecadal Oscillation (AMO) has garnered attention for its important role in shaping surface air temperature (SAT) patterns over Eurasia. While Eurasian winter SAT was traditionally attributed to changes in large-scale atmospheric circulations associated with the AMO, a careful examination of the latest unforced CMIP6 simulations in this study unveils a significant contribution of the AMO’s thermodynamic effects. Specifically, the heat released from the North Atlantic Ocean and transported to northern Eurasia through westerlies takes precedence over the effect of dynamic Rossby waves, resulting in warm (cold) phases during positive (negative) AMO cycles, along with increased (decreased) warm extremes and reduced (enhanced) cold extremes. This study contributes to an improved understanding of the dominating mechanism of the AMO’s impact on Eurasian SAT.

Abstract Hematoma expansion (HE) is a high risky symptom with high rate of occurrence for patients who have undergone spontaneous intracerebral hemorrhage (ICH) after a major accident or illness. Correct prediction of the occurrence of HE in advance is critical to help the doctors to determine the next step medical treatment. Most existing studies focus only on the occurrence of HE within 6 h after the occurrence of ICH, while in reality a considerable number of patients have HE after the first 6 h but within 24 h. In this study, based on the medical doctors recommendation, we focus on prediction of the occurrence of HE within 24 h, as well as the occurrence of HE every 6 h within 24 h. Based on the demographics and computer tomography (CT) image extraction information, we used the XGBoost method to predict the occurrence of HE within 24 h. In this study, to solve the issue of highly imbalanced data set, which is a frequent case in medical data analysis, we used the SMOTE algorithm for data augmentation. To evaluate our method, we used a data set consisting of 582 patients records, and compared the results of proposed method as well as few machine learning methods. Our experiments show that XGBoost achieved the best prediction performance on the balanced dataset processed by the SMOTE algorithm with an accuracy of 0.82 and F1-score of 0.82. Moreover, our proposed method predicts the occurrence of HE within 6, 12, 18 and 24 h at the accuracy of 0.89, 0.82, 0.87 and 0.94, indicating that the HE occurrence within 24 h can be predicted accurately by the proposed method.

Abstract The cold surges have frequently attacked North America (NA) in recent decades, which has been tied to the diminished sea‐ice over the Bering Sea. However, we find that the contribution of sea‐ice loss to NA winter coldness is state‐dependent on the Pacific Decadal Oscillation (PDO) phase. Using observations and CAM6 model simulations, we find that the phase regulates the atmospheric response to Bering ice loss. During the negative PDO phase (PDO−), there is an apparent eastward‐propagating wave train, accompanied by a strengthened Alaskan ridge and NA cold high, resulting in a robust cold over Central NA. Meanwhile, enhanced upward‐propagating planetary waves weaken the stratospheric polar vortex over the Pacific‐NA regions. During the positive phase (PDO+), the NA temperature response to Bering ice loss is quite weak or even warm. We speculate that more NA cold extremes will appear as the PDO− continues and less as the PDO− shifts to PDO+.

Laser Shock Peening (LSP) is an advanced technique for enhancing surface properties, drawing significant interest for its ability to induce beneficial residual stresses in materials. Traditional LSP design processes, reliant on manual parameter selection, often result in imprecise control over the stress distribution, necessitating multiple iterations and high costs. This study introduces a machine learning (ML)-based approach, utilizing the Random Forest (RF) algorithm, to automate and optimize the design of LSP parameters for nickel-aluminium bronze surfaces. Our findings demonstrate the RF model’s capability to accurately predict and optimize residual stress distributions, achieving compressive stresses up to 472 MPa with a notable reduction in design iterations. The model forecasts both uniform and non-uniform stress patterns, particularly identifying areas susceptible to Residual Stress Holes (RSH) with improved precision. With an Absolute Percentage Error (APE) of only 6.2 %, our approach significantly outperforms traditional ML algorithms, offering a novel method for efficiently designing complex residual stress fields in LSP applications.

Mimicking the structure of natural bone collagen fibers/hydroxyapatite (HA) to synthesize large size of HA for accelerated bone repair remains a challenge. Herein, silicon nitride nanowires (SN)-graphene (GE) was designed by the chemical vapor deposition, forming SN-GE (SG) similar to collagen fibers. Then, the large size HA was assembled onto SG by pulsed electrochemical deposition, the SG/HA (SGH) mimics the collagen fibers/HA structure of bone. The introduction of SG induces HA to large size grow in the form of coral-like. HA can be grown on a large size inextricably with the existence of GE modified layers. On the one hand, the upright GE sheets effectively increases the surface roughness which enhances the nucleation site of HA. On the other hand, the CO provides chemical bonding and induces HA nucleation. Compared with SN/HA(SH), the porosity of SGH decreased by 71%. The average diameter of the SGH is (9.76 ± 0.25) μm. Compared with SH, the diameter of SGH is 22 times larger than the diameter of SH. Indicating that SG induces large size growth of HA. Our work can provide a general strategy for the efficient preparation of biological scaffolds with large size HA that can be used in bone tissue engineering.

Unbalanced traffic distribution in cellular networks results in congestion and degrades spectrum efficiency. To tackle this problem, we propose an Unmanned Aerial Vehicle (UAV)-assisted wireless network in which the UAV acts as an aerial relay to divert some traffic from the overloaded cell to its adjacent underloaded cell. To fully exploit its potential, we jointly optimize the UAV position, user association, spectrum allocation, and power allocation to maximize the sum-log-rate of all users in two adjacent cells. To tackle the complicated joint optimization problem, we first design a genetic-based algorithm to optimize the UAV position. Then, we simplify the problem by theoretical analysis and devise a low-complexity algorithm according to the branch-and-bound method, so as to obtain the optimal user association and spectrum allocation schemes. We further propose an iterative power allocation algorithm based on the sequential convex approximation theory. The simulation results indicate that the proposed UAV-assisted wireless network is superior to the terrestrial network in both utility and throughput, and the proposed algorithms can substantially improve the network performance in comparison with the other schemes.

Abstract Background D-mannose, an epimer of glucose, which is abundant in some fruits, such as cranberry, has been previously reported to inhibit urinary tract infection. In recent years, the potential function of D-mannose has been broadened into the regulation of other inflammation diseases and cancer. It was reported that D-mannose can increase reactive oxygen species (ROS) production, while IDH2 is important for the generation of NADPH, the crucial reducing factor. These findings prompted us to determine whether D-mannose can regulate IDH2 and IDH2-mediated NADPH production in tumor. Methods The breast cancer cell line MDA-MB-231 was cultured and treated with 100mM D-mannose. IDH2 expression was detected by Western Blot and qRT-PCR. RNA-seq was conducted to identify the differentially expressed genes. BioGRID database was used to find the IDH2 interactors. Tumor cells were collected to measure the NADPH production using the NADP+/NADPH detection Kit. Colony formation assay and CCK-8 assay were conducted to evaluate the proliferation of cells. Results D-mannose can promote IDH2 protein degradation through ubiquitination-proteasome pathway. Mechanistically, D-mannose treatment upregulated the expression of an E3 ligase - RNF185, which can interact with IDH2 and promotes its proteasomal degradation. Consequently, IDH2-mediated NADPH production was inhibited by D-mannose, the proliferation of breast cancer cells was retarded, and the sensitivity to pro-oxidant of breast cancer cells was elevated. Conclusions Our study demonstrated that D-mannose can degrade IDH2 and inhibit the production of NADPH to suppress the proliferation of breast cancer cells and render the breast cancer cells more sensitive to pro-oxidant treatment. Furthermore, we illustrated the E3 ligase RNF185 plays an important role in D-mannose-mediated proteasomal degradation of IDH2.

Objective: A biological system's internal morphological structure or function can be changed as a result of the mechanical effect of focused ultrasound. Pulsed low-intensity focused ultrasound (LIFU) has mechanical effects that might induce follicle development with less damage to ovarian tissue. The potential development of LIFU as a non-invasive method for the treatment of female infertility is being considered, and this study sought to explore and confirm that LIFU can activate ovarian follicles. Results: We found a 50% increase in ovarian weight and in the number of mature follicles on the ultrasound-stimulated side with pulsed LIFU and intraperitoneal injection of 10 IU PMSG in 10-day-old rats. After ultrasound stimulation, the PCOS-like rats had a decrease in androgen levels, restoration of regular estrous cycle and increase in the number of mature follicles and corpora lutea, and the ratio of M1 and M2 type macrophages was altered in antral follicles of PCOS-like rats, consequently promoting further development and maturation of antral follicles. Conclusion: LIFU treatment could trigger actin changes in ovarian cells, which might disrupt the Hippo signal pathway to promote follicle formation, and the mechanical impact on the ovaries of PCOS-like rats improved antral follicle development.

Abstract Purpose To develop a CT-based radiomics model combining with VAT and bowel features to improve the predictive efficacy of IFX therapy on the basis of bowel model. Methods This retrospective study included 231 CD patients (training cohort, n = 112; internal validation cohort, n = 48; external validation cohort, n = 71) from two tertiary centers. Machine-learning VAT model and bowel model were developed separately to identify CD patients with primary nonresponse to IFX. A comprehensive model incorporating VAT and bowel radiomics features was further established to verify whether CT features extracted from VAT would improve the predictive efficacy of bowel model. Area under the curve (AUC) and decision curve analysis were used to compare the prediction performance. Clinical utility was assessed by integrated differentiation improvement (IDI). Results VAT model and bowel model exhibited comparable performance for identifying patients with primary nonresponse in both internal (AUC: VAT model vs bowel model, 0.737 (95% CI, 0.590–0.854) vs. 0.832 (95% CI, 0.750–0.896)) and external validation cohort [AUC: VAT model vs. bowel model, 0.714 (95% CI, 0.595–0.815) vs. 0.799 (95% CI, 0.687–0.885)), exhibiting a relatively good net benefit. The comprehensive model incorporating VAT into bowel model yielded a satisfactory predictive efficacy in both internal (AUC, 0.840 (95% CI, 0.706–0.930)) and external validation cohort (AUC, 0.833 (95% CI, 0.726–0.911)), significantly better than bowel alone (IDI = 4.2% and 3.7% in internal and external validation cohorts, both p < 0.05). Conclusion VAT has an effect on IFX treatment response. It improves the performance for identification of CD patients at high risk of primary nonresponse to IFX therapy with selected features from RM. Critical relevance statement Our radiomics model (RM) for VAT-bowel analysis captured the pathophysiological changes occurring in VAT and whole bowel lesion, which could help to identify CD patients who would not response to infliximab at the beginning of therapy. Key points • Radiomics signatures with VAT and bowel alone or in combination predicting infliximab efficacy. • VAT features contribute to the prediction of IFX treatment efficacy. • Comprehensive model improved the performance compared with the bowel model alone. Graphical abstract

Abstract Purpose This research was conducted to investigate the potential of short-chain fatty acids (SCFAs) in protecting organs from heat stress-induced injuries and gut microbiota modulation. Methods Sprague–Dawley rats were randomly assigned to various groups including a control group, a room temperature training group, a hyperthermia training group, SCFAs pretreatment group, and recipients received feces from the HT group. After strenuous training at high temperatures, the levels of plasma enzymes AST, ALT, BUN, and Cr were evaluated. The changes in gut microbiota and fecal metabolites were detected using 16S rRNA sequencing and GC–MS methods. Pathological examination of colon and liver tissues was conducted, and immunohistochemical techniques were employed to assess intestinal barrier function. Results The findings indicate that SCFAs hold the potential for mitigating liver and colon damage caused by heat stress. With the intervention of SCFAs, there were observable changes in the structure and metabolites of the intestinal microbiota, as well as improvements in intestinal barrier function. Further support for the benefits of SCFAs was found through fecal microbiota transplantation, which demonstrated that modified gut microbiota can effectively reduce organ damage. Conclusions This study provides evidence that SCFAs, as metabolites of the gut microbiota, have a valuable role to play in regulating gut health and mitigating the harmful effects of heat stress.

Rice planthoppers, including Nilaparvata lugens, Sogatella furcifera, and Laodelphax striatellus, are major agricultural pests. Serpins, which function as serine protease inhibitors, play a pivotal role in the immune systems of these insects, especially within the Toll signaling pathway and the prophenoloxidase (PPO) cascade. This study presents a comparative analysis of serpin genes among these species, highlighting their roles in immunity and development. Utilizing genomic and bioinformatics approaches, we identified 11, 11, and 14 serpin genes in N. lugens, S. furcifera, and L. striatellus, respectively. Phylogenetic analysis revealed a close evolutionary relationship between these serpin genes and Bombyx mori BmSerpins, emphasizing the functional diversity of the serpin family. Structural analysis confirmed the presence of the reactive center loop (RCL) in all serpin proteins, with the Serpin7 subfamily showing a unique dual RCL configuration. Expression profiling showed species-specific serpin expression patterns across different life stages and adult tissues. Moreover, transcriptional analysis of serpin genes in the three planthoppers following Metarhizium infection uncovered distinct immune regulatory patterns two days post-infection. Notably, the expression of NlSerpin2-2/6, SfSerpin4/6/7-1, and LsSerpin4/5-2/6 was upregulated post-infection, potentially enhancing antifungal capabilities. In contrast, the expressions of NlSerpin1/7-1/9 and LsSerpin1/2/3/8/13 were downregulated, possibly suppressing immune responses. Moreover, Serpin6s, which share a conserved phylogenetic lineage, exhibited enhanced immune activity in response to fungal invasion. These insights into serpin-mediated immune regulation could contribute to the development of novel pest-control strategies.

Abstract Selenocompounds protect against damage to healthy cells and induce the death of tumor cells by apoptosis; for this reason, they are attractive compounds for cancer research. In the present study, two series of novel phenoxy-((phenylethynyl) selanyl) propan-2-ol derivatives were synthesized, and their anti-proliferation activities were evaluated. Of the 23 compounds synthesized, most showed potent anti-proliferative activity against human cancer cell lines. Specifically, compounds 3h, 3g, and 3h-2, which had a 2- or 4-position halogen substituent on 1-((phenylethynyl)selanyl)-3-phenoxypropan-2-ol, exhibited the best anti-proliferative activity against tumor cells. Flow cytometry demonstrated that 3h, 3g, and 3h-2 induced G2/M phase arrest and apoptosis in A549 cells. Cellular studies demonstrated that the induction of apoptosis by 3h correlated with changes in the expression of cell cycle-related proteins and apoptosis-related proteins. Xenograft tumor experiments in nude mice revealed that compound 3h has antitumor effects in vivo and no evident toxic effects in nude mice. In addition, compound 3h alleviated cisplatin-induced liver and kidney damage. These findings uncover the applicability of compound 3h as a novel lead compound for cancer treatment.

In this paper, we propose a vehicle pedestrian detection and tracking method based on the improved YOLOv7 and DeepSort algorithms. We aim to improve the quality of vehicle pedestrian detection and tracking, addressing the challenges that current commercially available autonomous driving technologies face in complex and changing road traffic situations. First, the NMS (non-maximum suppression) algorithm in YOLOv7 is replaced with a modified Soft-NMS algorithm to ensure that targets can be accurately detected at high densities, and second, the CCBA (coordinate channel attention module) attention mechanism is incorporated to improve the feature extraction and perception capabilities of the network. Finally, a multi-scale feature network is introduced to extract features of small targets more accurately. Finally, the MobileNetV3 lightweight module is introduced into the feature extraction network of DeepSort, which not only reduces the number of model parameters and network complexity, but also improves the tracking performance of the target. The experimental results show that the improved YOLOv7 algorithm improves the average detection accuracy by 3.77% compared to that of the original algorithm; on the MOT20 dataset, the refined DeepSort model achieves a 1.6% increase in MOTA and a 1.9% improvement in MOTP; in addition, the model volume is one-eighth of the original algorithm. In summary, our model is able to achieve the desired real-time and accuracy, which is more suitable for autonomous driving.

Abstract Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.

Abstract The cold Eurasia has been proposed to be closely linked to the weakening of the stratospheric polar vortex (SPV), however, how the Arctic sea ice modulates the surface impacts of the weak SPV is unclear. This study explores the critical modulating role of reduced Arctic sea ice in the surface cooling response to SPV stretching events in autumn. Here, through ERA5 reanalysis and Whole Atmosphere Community Climate Model simulations, we show that Eurasian cold events are more likely (45%) to occur in days 30–50 after the onset of SPV stretching events under lower Barents‐Kara Seas (BKS) sea ice conditions, in contrast to under heavy BKS sea ice conditions when robust surface cooling is absent. The stratospheric and tropospheric pathways explain 46.8% and 53.2% of the total variance of Siberian coldness, respectively. The downward extension of anomalous stratospheric wave‐2 ridge to the troposphere intensifies the Arctic‐North European high, favoring the subsequent colder Siberia.

Summary: Macroautophagy/autophagy is a conserved process in eukaryotic cells to degrade and recycle damaged intracellular components. Higher level of autophagy in the brain has been observed, and autophagy dysfunction has an impact on neuronal health, but the molecular mechanism is unclear. In this study, we showed that overexpression of Toll-1 and Toll-7 receptors, as well as active Spätzle proteins in Drosophila S2 cells enhanced autophagy, and Toll-1/Toll-7 activated autophagy was dependent on Tube-Pelle-PP2A. Interestingly, Toll-1 but not Toll-7 mediated autophagy was dMyd88 dependent. Importantly, we observed that loss of functions in Toll-1 and Toll-7 receptors and PP2A activity in flies decreased autophagy level, resulting in the loss of dopamine (DA) neurons and reduced fly motion. Our results indicated that proper activation of Toll-1 and Toll-7 pathways and PP2A activity in the brain are necessary to sustain autophagy level for DA neuron survival.

With the escalating frequency of space activities, particularly the launch of constellation satellites, the amount of space debris experienced gradually increases, posing threats to the safety and sustainability of the space environment. To counteract the growth of debris, active deorbit devices are imperative for spacecrafts. In low Earth orbit (LEO), the drag sail device has emerged as a highly effective solution due to its ability to increase the spacecraft’s windward area, facilitating rapid deorbit by leveraging atmospheric drag as the primary perturbation. In this study, recent developments of membrane drag sail deorbit technology for LEO satellites are summarized, as well as the current problems such as attitude instability, dangerous space environment, and folding and unfolding issues. Moreover, crucial technologies such as modeling and simulation of deorbit efficiency, attitude stabilization, collision risk analysis and protection design, sail surface atomic oxygen protection design, and folding and unfolding of the drag sail are discussed. Finally, the development trends and technology applications of membrane drag sail deorbit for LEO satellites are presented.

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. β-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between β-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether β-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and β-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of β-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, β-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, β-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. β-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.

ABSTRACT Innate lymphoid cells (ILCs) play a crucial role in mucosal protection and tissue homeostasis. However, the early mucosal defense mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have not been fully understood to date. This knowledge gap has motivated us to develop a coronavirus disease 2019-like mouse model to investigate the interactions between the virus, its receptor, and ILCs. In our study, we conducted intranasal challenges using pseudovirus expressing Spike (PSV-S) to examine the expression patterns of humanized ACE2 (chiACE2) and the transduction of PSV-S in lung and ileum tissues over a specified time period. Within a span of 72 hours, we observed an intense viral transduction induced by the spike protein, which was detected from the central bronchus to the bronchiole and alveolus in the lung (levels 3 to 8). Similarly, we observed the transduction of PSV-S in the villi and crypts of the ileum. Interestingly, our precise three-dimensional colocalization analysis revealed that only 73.74% ± 1.76% of the PSV-S transduction depended on chiACE2. Furthermore, type 2 innate lymphoid cells (ILC2s) exhibited the most pronounced activation in the gut mucosa. This finding indicates the significant role of ILC2s as contributors to the mucosal defense against viral infections. Our data shed light on the critical involvement of ILC2s and their intricate three-dimensional regulatory network in combating SARS-CoV-2 within the mucosa. IMPORTANCE Our study revealed the spatial interaction between humanized ACE2 and pseudovirus expressing Spike, emphasizing the role of type 2 innate lymphoid cells during the initial phase of viral infection. These findings provide a foundation for the development of mucosal vaccines and other treatment approaches for both pre- and post-infection management of coronavirus disease 2019.

Summary: Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8+ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8+ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.

Background In the past few years, immunotherapies of hepatocellular carcinoma (HCC) targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved durable clinical benefits. However, only a fraction of HCC patients showed objective clinical response to PD-1/PD-L1 blockade alone. Despite the impact on post-translational modifications of PD-L1 being substantial, its significance in resistance to HCC immunotherapy remains poorly defined.Methods Cyclin-dependent kinase 5 (CDK5) expression was knocked down in HCC cells, CDK5 and PD-L1 protein levels were examined by Western blot. Coimmunoprecipitation was conducted to evaluate the interaction between proteins. Preclinical HCC mice model was constructed to evaluate the effect of CDK5 inhibitor alone or in combination with PD-1 antibody. Clinical HCC samples were used to elucidate the clinical relevance of CDK5, PD-L1, and PD-L1 T290 phosphorylation in HCC.Results We find that CDK5 deficiency upregulates PD-L1 protein expression in HCC cells and decipher a novel molecular mechanism under which PD-L1 is downregulated by CDK5, that is, CDK5 mediated PD-L1 phosphorylation at T290 promotes its binding with chaperon protein heat-shock cognate protein 70 (HSC70) and degradation through chaperon-mediated autophagy. Notably, treatment of CDK5 inhibitor, PNU112455A, effectively upregulates the tumorous PD-L1 level, promotes the response to anti-PD-1 immunotherapy,and prolongs the survival time of mice bearing HCC tumors. What is more, the T290 phosphorylation status of PD-L1 correlates with the prognosis of HCC.Conclusions Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.

Arboviruses and symbiotic viruses can be paternally transmitted by male insects to their offspring, but the mechanism remains largely unknown. Here, the authors identify the sperm-specific serpin protein HongrES1 of the leafhopper Recilia dorsalis as a mediator of paternal transmission of the reovirus rice gall dwarf virus and of a previously undescribed symbiotic virus of the Virgaviridae family, Recilia dorsalis filamentous virus, via direct binding of virions to leafhopper sperm surfaces and subsequent paternal transmission via interaction with both viral capsid proteins.

The process of bone remodeling is connected with the regulated balance between bone cell populations (including bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte). And the mechanism of bone remodeling activity is related to the major pathway, receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling axis. Recently, researchers have found a novel cytokine secreted by activated T cells, which is related to osteoclastogenesis in the absence of osteoblasts or RANKL, leading to bone destruction. They name it the secreted osteoclastogenic factor of activated T cells (SOFAT). SOFAT has been proven to play an essential role in bone remodeling, like mediating the bone resorption in rheumatoid arthritis (RA) and periodontitis. In this review, we outline the latest research concerning SOFAT and discuss the characteristics, location, and regulation of SOFAT. We also summarize the clinical progress of SOFAT and assume the future therapeutic target in some diseases related to bone remodeling.

Abstract Widespread observed and projected increases in warm extremes, along with decreases in cold extremes, have been confirmed as being consistent with global and regional warming. Here we disclosed that the decadal variation in the frequency of the surface air temperature (SAT) extremes over Siberia in winter was primarily dominated by the Atlantic Meridional Overturning Circulation (AMOC) rather than anthropogenic forcing. The stronger AMOC induced more warm and cold extremes through increasing the variance of winter SAT over Siberia while the direct effect of external forcings, especially anthropogenic greenhouse gases, had little impact on the summation of warm and cold extremes due to equivalent effects on the increases in warm extremes and decreases in cold extremes. The possible mechanism can be deduced that the stronger AMOC stimulated the propagation of the wave train originated in the North Atlantic Ocean, across mid- to high latitudes, thereby increasing the variabilities in the circulations over the Ural blocking region and Siberia, which are critical to the SAT extremes there.

Abstract The Warm Arctic‐Cold Eurasia pattern in recent decades has attracted extensive attention and has been partly attributed to rapid sea‐ice loss; however, such a link has been unstable over the past century. Here, we use centennial reanalyzes to investigate the multi‐decadal changes in the linkage between autumn Barents‐Kara sea‐ice and winter Eurasian temperature during the 20th century. Results show a negative Arctic‐Eurasian connection in 1901–1945 (P1), an inconspicuous connection in 1946–1985 (P2), and a significantly positive correlation in 1986–2013 (P3), with distinct stratospheric and tropospheric pathways mechanisms. The contrasting relationships between P1 and P3 are likely due to the different magnitudes of sea‐ice loss and the predominant roles of the atmosphere or sea‐ice in driving different Eurasian temperature effects. As further verification, the best group of Coupled Model Intercomparison Project simulations, which captured the realistic stratospheric pathway in recent decades, can reproduce the historical decadal changes in the Arctic‐Eurasian linkage.

Abstract As the main constituent cells of the human placenta, trophoblasts proliferate, differentiate, and invade the uterine endometrium via a series of processes, which are regulated exquisitely through intercellular signaling mediated by hormones, cytokines, and growth factors. Programmed cell death ligand 1 (PD-L1) is a biomarker of the response to immune checkpoint inhibitors and can regulate maternal-fetal immune tolerance during pregnancy progression. Recently, it was found that PD-L1 may regulate obstetric complications by affecting the function of trophoblasts. Therefore, we examined the expression and localization of PD-L1 in the human placenta and observed the effects of PD-L1 on trophoblasts migration and invasion in both the trophoblasts line HTR-8/SVneo and an extravillous explant culture model. Finally, we explored the molecular mechanisms underlying PD-L1-regulated trophoblasts migration and invasion through RNA sequencing and bioinformatics analysis. Our data showed that PD-L1 was mainly expressed in syncytiotrophoblasts and that its protein levels increased with gestational age. Interestingly, the protein expression of PD-L1 was significantly decreased in placentas from pregnancies with preeclampsia compared with normal placentas. Importantly, the migration and invasion abilities of trophoblasts were significantly changed after knockdown or overexpression of PD-L1 in HTR-8/SVneo cells and an extravillous explant culture model, which was partially mediated through the transcription factor PU.1 (encoded by Spi1)-regulated Rho GDP-dissociation inhibitor beta (ARHGDIB) expression. These results suggested that PD-L1 was highly involved in the regulation of trophoblasts migration and invasion, providing a potential target for the diagnosis and treatment of placenta-derived pregnancy disorders.

Curcumenol, an effective ingredient of Wenyujin, has been reported that exerted its antitumor potential in a few cancer types. However, the effect and molecular mechanism of curcumenol in lung cancer are largely unknown. Here, we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells. Next, we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time. Subsequently, using RNA sequencing, we found that the long non-coding RNA H19 (lncRNA H19) was significantly downregulated in lung cancer cells treated with curcumenol, when compared to untreated controls. Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol, while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis. In conclusion, our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Therefore, our findings will hopefully provide a valuable drug for treating lung cancer patients.

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.

Background: Transmural healing (TH) is a potential therapeutic goal of Crohn’s disease (CD) and is associated with better clinical outcomes. However, few studies have described early TH and its predictors. Objectives: We aimed to evaluate early TH and its predictors using magnetic resonance enterography (MRE) in patients with CD receiving ustekinumab (UST). Design: This was a retrospective observational study. Methods: Patients with active CD treated with UST and their intestinal segments with bowel wall thickness (BWT) ⩽ 3 mm at baseline were included. Clinical characteristics, laboratory indicators, endoscopic manifestations, and MRE indices were evaluated at baseline and week 26 (W26) of the therapy. The following MRE parameters were assessed: BWT, edema, apparent diffusion coefficient (ADC), Clermont score, Magnetic Resonance Index of Activity score, fat stranding, comb sign, and stricture. TH was defined as BWT ⩽ 3 mm without any signs of inflammation (i.e., ulceration, edema, diffusion-weighted hyperintensity, and increased contrast enhancement) at W26. Results: The study included 37 patients with 106 intestinal segments (including 15 proximal small intestines, 33 terminal ilea, and 58 colons). Clinical features, laboratory indicators, endoscopic results, and MRE parameters at W26 were significantly improved after UST treatment in both patient-based and intestinal segment-based analysis. Seven (18.9%) patients and 26 (24.5%) intestinal segments achieved TH at W26. Baseline BWT [odds ratio (OR) = 0.287, 95% confidence interval (CI), 0.090–0.918, p = 0.035] and ADC (OR = 2.997, 95% CI, 1.009–8.908, p = 0.048) predict TH of patients at W26. Baseline ADC (OR = 2.857, 95% CI, 1.285–6.349, p = 0.010) and presence of stenosis (OR = 0.196, 95% CI, 0.052–0.735, p = 0.016) were associated with TH of segments at W26. Conclusion: Early TH assessed by MRE was observed in nearly one-fifth of patients with CD and intestinal segments after UST treatment for 26 weeks. Baseline MRE indices such as BWT and presence of stenosis might negatively predict TH, while ADC might positively predict early TH.

Abstract Background Low-frequency electroacupuncture (EA) has been shown to ameliorate obesity and reproductive dysfunctions in patients with polycystic ovary syndrome (PCOS), and further explorations in PCOS-like rats showed that EA could affect white adipose tissue. However, the function and neuromodulation of brown adipose tissue (BAT) in PCOS and after EA treatment have remained unknown. The present study focused on the role of BAT in PCOS-like rats and its relationship with EA and characterized the three-dimensional (3D) innervation of BAT associated with activation molecules. Methods Female rats (21 days old) were implanted with dihydrotestosterone or fed with a high fat diet to establish PCOS-like and obesity models, respectively, and then EA treatment at “Guilai” (ST 29) and “Sanyinjiao” (SP 6) was carried out for 4 weeks. In the present study, morphological analysis, 3D imaging, molecular biology, and other experimental techniques were used to study the sympathetic nerves and activity of BAT. Results PCOS-like rats showed both obvious weight gain and reproductive dysfunction, similar to what was seen in obese rats except for the absence of reproductive dysfunction. The body weight gain was mainly caused by an increase in white adipose tissue, and there was an abnormal decrease in BAT. Because both the lipid metabolism and reproductive disorders could be improved with bilateral EA at “Guilai” (ST 29) and “Sanyinjiao” (SP 6), especially the restoration of BAT, we further investigated the neuromodulation and inflammation in BAT and identified the sympathetic marker tyrosine hydroxylase as one of the key factors of sympathetic nerves. Modified adipo-clearing technology and 3D high-resolution imaging showed that crooked or dispersed sympathetic nerves, but not the twisted vasculature, were reconstructed and associated with the activation of BAT and are likely to be the functional target for EA treatment. Conclusion Our study highlights the significant role of BAT and its sympathetic innervations in PCOS and in EA therapy.

In this paper, an event-triggered transmission scheme for the networked control systems is investigated. The probabilistic cyber attacks and extended dissipative are considered in the systems. Firstly, an event-triggered transmission scheme with aperiodic sampling is proposed to establish a time-delay closed-loop system model. Then, a novel two-sided Lyapunov-Krasovskii functional is constructed by use of the characteristic of sawtooth structure. As a result, the sufficient conditions are derived in terms of linear matrix inequalities, which ensure the global stability of the networked control systems. The feedback controller gain matrix is figured out to guarantee the stability with extended dissipative. Finally, two numerical examples are given to illustrate the feasibility and effectiveness of the theoretical findings.

ABSTRACT: The effect of compound probiotics on the caecum of broilers under heat stress was assessed in this study. A total of 400 twenty-eight-day-old AA male broilers were randomly divided into 4 treatment groups, where each group had 5 replicates of 20 broilers. The 4 treatment groups were a heat stress control group (broilers receiving a normal diet) and groups HP I, HP II, and HP Ⅲ, consisting of broilers receiving 1, 5, and 10 g of compound probiotics added to each kilogram of feed, respectively. Compound probiotics (L. casei, L. acidophilus, and B. lactis at a ratio of 1:1:2) were used to formulate a compound probiotic powder, with 1 × 1010 CFU/g of effective viable bacteria. Heat stress treatment was performed at 32 ± 1°C from 9:00 to 17:00 every day from 28 d to 42 d. In d 28 to 42, compared with the HC group, the ADG of broilers in the HP II and III groups was significantly increased (P < 0.05); the ADFI difference between groups was not significant (P > 0.05); the FCR of HP II and III broilers was significantly decreased (P < 0.05); and the FCR of the HP I group increased, but the difference was not significant (P > 0.05). Transcriptome results demonstrate that 665 differential genes were screened (DEGs; upregulated: 366, downregulated: 299). The DEGs were enriched in the B cell receptor signaling pathway, the intestinal immune network for IgA synthesis, the Fc epsilon RI signaling pathway, and other signaling pathways, according to KEGG enrichment analysis. Metabolome analysis identified 92 differential metabolites (DAMs; upregulated: 48, downregulated: 44). KEGG enrichment analysis indicated significant enrichment of Pantothenate and CoA biosynthesis and beta-Alanine metabolism. The combined transcriptome and metabolome analysis revealed that the DAMs and DEGs were mostly involved in beta-alanine metabolism, arginine biosynthesis, amino sugar and nucleotide sugar, and alanine, aspartate, and glutamate metabolism. The results of this study suggest that the addition of compound probiotics has a positive effect on intestinal metabolites, improving the growth performance and contributing to the overall health of broilers under heat stress.

Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.

Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies, including bladder cancer. This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment. Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of inflammatory molecules and signals. Recently, it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer, which can be mediated through the stimulation of chronic inflammation. In effect, the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer. In other words, chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer. Here, we provide a detailed and comprehensive account of the link between chronic inflammation, the microbiome and bladder cancer. Finally, we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.

Background: Recent studies demonstrate that N6-methyladenosine (m6A) methylation plays a crucial role in colorectal cancer (CRC). Therefore, we conducted a comprehensive analysis to assess the m6A modification patterns and identify m6A-modified genes in patients with CRC recurrence.Methods: The m6A modification patterns were comprehensively evaluated by the NMF algorithm based on the levels of 27 m6A regulators, and tumor microenvironment (TME) cell-infiltrating characteristics of these modification patterns were systematically assessed by ssGSEA and CIBERSORT algorithms. The principal component analysis algorithm based on the m6A scoring scheme was used to explore the m6A modification patterns of individual tumors with immune responses. The weighted correlation network analysis and univariable and multivariable Cox regression analyses were applied to identify m6A-modified gene signatures. The single-cell expression dataset of CRC samples was used to explore the tumor microenvironment affected by these signatures.Results: Three distinct m6A modification patterns with significant recurrence-free survival (RFS) were identified in 804 CRC patients. The TME characterization revealed that the m6A modification pattern with longer RFS exhibited robust immune responses. CRC patients were divided into high- and low-score subgroups according to the m6A score individually, which was obtained from the m6A-related signature genes. The patients with low m6A scores had both longer RFS and overall survival (OS) with altered immune cell infiltration. Notably, m6A-modified genes showed significant differences related to the prognosis of CRC patients in the meta-GEO cohort and TCGA cohort. Single-cell expression indicated that ALVRL1 was centrally distributed in endothelial tip cells and stromal cells.Conclusion: The m6A modification plays an indispensable role in the formation of TME diversity and complexity. Importantly, the signatures (TOP2A, LRRC58, HAUS6, SMC4, ACVRL1, and KPNB1) were identified as m6A-modified genes associated with CRC recurrence, thereby serving as a promising predictive biomarker or therapeutic target for patients with CRC recurrence.

ObjectivesDrug-induced gingival overgrowth (DIGO) is a frequent adverse medication reaction that is generally caused by cyclosporine, phenytoin, and nifedipine, which belong to the category of immunosuppressants, anticonvulsants, and calcium channel blockers, respectively. This bibliometric analysis aims to depict the main citation characteristics and analyze the research trends in DIGO investigations.MethodsAn exhaustive search was performed in the Scopus database to create the bibliometric list of DIGO in the syntax. Furthermore, the information related to the number of citations, drugs related to DIGO, study topic and design, authorship, publication year, journal, contributing institution, country of origin, and the department was extracted.ResultsIn total, 399 papers on DIGO were retrieved in this study. The total number of citations and that after the removal of self-citations were 7,814 and 7,314, respectively. The mean number of citations was 19.6 in a range of 0–608. The main paper types were articles (76.94%) and reviews (19.55%). A remarkable increasing trend in the number of citations has been observed since 1994. Cyclosporine (44.89%) is the most commonly used drug that shares a close relationship with DIGO, followed by phenytoin (18.22%), nifedipine (17.93%), and amlodipine (6.81%). The review (27.82%) type constituted the most widely used design in the DIGO studies. According to the top 20 keywords, the risk factors and pathogenesis of DIGO have been prominent topics of research works for several years.ConclusionsThis bibliometric analysis will facilitate the understanding of researchers and clinicians, especially those at the beginning of their careers in periodontology on DIGO, by identifying landmark research and providing an overview of this field.

Background: While the grading of intestinal fibrosis is closely related to the therapeutic strategy of patients with Crohn’s disease (CD), it has not yet been well resolved. Mesenteric abnormalities are inextricably linked to intestinal fibrosis. Objectives: We aimed to establish an optimal model for assessing intestinal fibrosis using computed tomography enterography (CTE) and clinical markers. Design: A total of 174 patients with CD between January 2014 and June 2020 were included in this retrospective multicentre study. Methods: All patients underwent CTE within 3 months prior to surgery. Intestinal fibrosis was pathologically scored as non-mild or moderate-to-severe. Selected imaging of the intestinal walls and mesentery and/or clinical factors were used to develop the diagnostic models. The area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the discrimination performance of the models. A decision curve analysis was performed to evaluate the clinical usefulness of the models. Results: One-, two-, and three-variable models were identified as possible diagnostic models. Model 1 [mesenteric creeping fat index (MCFI)], Model 2 (mesenteric oedema and MCFI), and Model 3 (mesenteric oedema, MCFI, and disease duration) were established. The AUCs of Model 1 in training and test cohorts 1 and 2 were 0.799, 0.859, and 0.693, respectively; Model 2 was 0.851, 0.833, and 0.757, respectively; and Model 3 was 0.832, 0.821, and 0.850, respectively. We did not observe any significant difference in diagnostic performance between the training and total test cohorts in any model (all p > 0.05). The decision curves showed that Model 3 had the highest net clinical benefit in test cohort 2. The nomogram of this optimal model was constructed by considering the favourable and robust performance of Model 3. Conclusion: A nomogram integrating mesenteric abnormalities on CTE with a clinical marker was optimal for differentiating between non-mild and moderate-to-severe fibrosis in patients with CD.

BackgroundColorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy.MethodsCRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene.ResultsNine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells.ConclusionsImmune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.

Melanization in the hemolymph of arthropods is a conserved defense strategy against infection by invading pathogens. Numerous plant viruses are persistently transmitted by insect vectors, and must overcome hemolymph melanization. Here, we determine that the plant rhabdovirus rice stripe mosaic virus (RSMV) has evolved to evade the antiviral melanization response in the hemolymph in leafhopepr vectors. After virions enter vector hemolymph cells, viral nucleoprotein N is initially synthesized and directly interacts with prophenoloxidase (PPO), a core component of the melanization pathway and this process strongly activates the expression of PPO. Furthermore, such interaction could effectively inhibit the proteolytic cleavage of the zymogen PPO to active phenoloxidase (PO), finally suppressing hemolymph melanization. The knockdown of PPO expression or treatment with the PO inhibitor also suppresses hemolymph melanization and causes viral excessive accumulation, finally causing a high insect mortality rate. Consistent with this function, microinjection of N into leafhopper vectors attenuates melanization and promotes viral infection. These findings demonstrate that RSMV N serves as the effector to attenuate hemolymph melanization and facilitate viral persistent propagation in its insect vector. Our findings provide the insights in the understanding of ongoing arms race of insect immunity defense and viral counter-defense.

The purpose of this study was to investigate the effects of three probiotics and their interactions on growth performance, intestinal digestion and absorption, and nutrient transporters in broilers. A total of 350 one-day-old male Arbor Acres broilers were randomly divided into seven groups: the control group (broilers receiving normal drinking water), groups P1, P2 and P3 (broilers receiving drinking water with 1% Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium lactis , respectively) and groups CP1, CP2 and CP3 (broilers receiving drinking water with a 1% compound probiotic mixture in 2:1:1, 1:2:1, 1:1:2 ratios, respectively). The feeding period was divided into two experimental periods: 1∼21 days and 22∼42 days. Compared to those in the control group, the broiler slaughter indexes and average daily feed intakes in the probiotics groups were not significantly different (P > 0.05), but the villus height in the small intestine increased significantly, and the crypt depth decreased significantly (P

Zinc oxide (ZnO) lightning arresters have good protection performance and have been widely used in power systems. ZnO varistor is the core component of the arrester, and its electrical performance determines the overvoltage protection level of the arrester. ZnO varistor will produce space charge accumulation phenomenon under the action of electric field. In order to study the space charge characteristics of ZnO varistors more deeply, a bipolar carrier transport model considering the change of grain boundary structure was established, and the law of carrier migration in ZnO grain boundaries was simulated. From the three aspects of pressure time, ambient temperature, and depletion layer density, the space charge distribution inside the grain boundary, Schottky barrier height, and grain boundary leakage current are systematically studied.

Objective: In this study, we aimed to develop an amino-terminal fragment (ATF) peptide-targeted liposome carrying β-elemene (ATF24-PEG-Lipo-β-E) for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin (DDP) for bladder cancer treatment. Methods: The liposomes were prepared by ethanol injection and high-pressure microjet homogenization. The liposomes were characterized, and the drug content, entrapment efficiency, and in vitro release were studied. The targeting efficiency was investigated using confocal microscopy, ultra-fast liquid chromatography, and an orthotopic bladder cancer model. The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, and cell apoptosis and cell cycle analyses. The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model. Results: ATF24-PEG-Lipo-β-E had small and uniform sizes (˜79 nm), high drug loading capacity (˜5.24 mg/mL), high entrapment efficiency (98.37 ± 0.95%), and exhibited sustained drug release behavior. ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol (PEG)ylated β-elemene liposomes (PEG-Lipo-β-E). DDP, combined with ATF24-PEG-Lipo-β-E, exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase, and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways. Furthermore, the in vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors, using the combined strategy. Conclusions: The present study provided an effective strategy for the targeted delivery of β-elemene (β-E) to bladder cancer, and a combined strategy for bladder cancer treatment.

Objective: This study aimed to develop a new polyethylene glycol (PEG)ylated β-elemene liposome (PEG-Lipo-β-E) and evaluate its characterization, pharmacokinetics, antitumor effects and safety in vitro and in vivo. Methods: The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization. Characterization of the liposomes was conducted, and drug content, entrapment efficiency (EE), in vitro release and stability were studied by ultra-fast liquid chromatography (UFLC) and a liquid surface method. Blood was drawn from rats to establish the pharmacokinetic parameters. The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model. Histological analyses were performed to evaluate safety. Results: The PEG-Lipo-β-E showed good stability and was characterized as 83.31 ± 0.181 nm in size, 0.279 ± 0.004 in polydispersity index (PDI), −21.4 ± 1.06 mV in zeta potential, 6.65 ± 0.02 in pH, 5.024 ± 0.107 mg/mL in β-elemene (β-E) content, and 95.53 ± 1.712% in average EE. The Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) indicated the formation of PEG-Lipo-β-E. Compared to elemene injection, PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance, a 1.62-fold increase in half-life, and a 1.76-fold increase in area under the concentration-time curves (AUCs) from 0 hour to 1.5 hours (P < 0.05). PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo. Histological analyses showed that there was no evidence of toxicity to the heart, kidney, liver, lung or spleen. Conclusions: The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation, high EE, good stability, improved bioavailability and antitumor effects.