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Abstract Background Lung adenocarcinoma (LUAD) is the most common lung cancer subtype, and the prognosis of affected patients is generally poor. The traditional Chinese medicine Uncaria rhychophaylla has been reported to exhibit anti-lung cancer properties. Accordingly, the main bioactive ingredient in Uncaria rhychophaylla, Corynoxine, may hold great value as a treatment for lung cancer. Methods The impact of Corynoxine on the viability of LUAD cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Apoptosis in A549 cells was evaluated via flow cytometry. Migration and invasion capabilities were determined through wound healing and Transwell assays, respectively. The key pathways targeted by Corynoxine in LUAD were identified using a network pharmacology approach. Additionally, Western immunoblotting, quantitative real-time PCR (qRT-PCR), and ELISA assays were conducted to validate the underlying mechanisms. The in vivo anti-tumor efficacy of Corynoxine was assessed in xenograft nude mice. Results In this study, Corynoxine treatment was found to markedly suppress in vitro LUAD cell proliferative, migratory, and invasive activity. It additionally downregulated Vimentin and promoted E-cadherin upregulation consistent with the disruption of epithelial-mesenchymal transition (EMT) induction while also accelerating apoptotic death. Furthermore, network pharmacology analysis revealed that the PI3K/AKT pathway is a potential target of Corynoxine in LUAD. In vitro assays demonstrated that treatment with Corynoxine resulted in the suppression of PI3K/AKT signaling and a consequent drop in cyclooxygenase-2 (COX-2) expression. These findings were further confirmed in vivo in mice harboring A549 tumor xenografts in which Corynoxine was able to interfere with the PI3K/AKT/COX-2 signaling axis. Conclusion This study elucidated the potential effects of Corynoxine in suppressing proliferation and metastasis in LUAD, along with investigating the underlying mechanisms. These data highlight the promise of Corynoxine as a novel therapeutic tool for the treatment of individuals diagnosed with LUAD.

Abstract Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic joint inflammation and cartilage damage. Current therapeutic strategies often result in side effects, necessitating the development of targeted and safer treatment options. This study introduces a novel nanotherapeutic system, 2-APB@DGP-MM, which utilizes macrophage membrane (MM)-encapsulated nanoparticles (NPs) for the targeted delivery of 2-Aminoethyl diphenylborinate (2-APB) to inflamed joints more effectively. The NPs are designed with a matrix metalloproteinase (MMP)-cleavable peptide, allowing for MMP-responsive drug release within RA microenvironment. Comprehensive in vitro and in vivo assays confirmed the successful synthesis and loading of 2-APB into the DSPE-GPLGVRGC-PEG (DGP) NPs, as well as their ability to repolarize macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. The NPs demonstrated high biocompatibility, low cytotoxicity, and enhanced cellular uptake. In a collagen-induced arthritis (CIA) mouse model, intra-articular injection of 2-APB@DGP-MM significantly reduced synovial inflammation and cartilage destruction. Histological analysis corroborated these findings, demonstrating marked improvements in joint structure and delayed disease progression. Above all, the 2-APB@DGP-MM nanotherapeutic system offers a promising and safe approach for RA treatment by modulating macrophage polarization and delivering effective agents to inflamed joints. Graphical Abstract

Abstract We appreciate your interest in our study. This study contrasts with Dorney et al.‘s focus on the first 21 days. We conducted a re-analysis regarding selection bias and found consistent results. Our research highlights the elevated risk of retinal vascular occlusion after vaccination, which can last up to two years. We also discussed the differences in study design and the effects of different vaccine brands.

Abstract Objective To investigate the association between caesarean scar defects and abnormal uterine bleeding through systematic literature review. Methods PubMed, Web of Science, Cochrane Library and Embase databases were searched based on PRISMA 2020 to include studies exploring abnormal uterine bleeding in women with caesarean scar defects. The combined relative risk (RR) of uterine bleeding, combined prevalence of abnormal uterine bleeding and combined RR of intermenstrual uterine bleeding were calculated using a fixed- or random-effects model. Results Ten studies involving 1,183 women with caesarean scar defects met the inclusion criteria for this study. Compared with women without caesarean scar defects, those with caesarean scar defects had a higher risk of abnormal uterine bleeding (RR: 3.22, 95% CI: 1.83–5.66) and intermenstrual bleeding (RR: 2.93, 95% CI: 1.91–4.50). The prevalence of abnormal uterine bleeding was approximately 0.46 (95% CI: 0.27–0.64), and across populations, women with a previous caesarean section who had undergone imaging specifically for gynaecological disease had a significantly higher prevalence of abnormal uterine bleeding (0.77, 95% CI: 0.65–0.89) than those with at least one caesarean Sect. (0.25, 95% CI: 0.10–0.39). Conclusion A significant association was observed between caesarean scar defects and abnormal uterine bleeding, with the former being a risk factor for the latter. However, previous studies have differed in the definition of caesarean scar defects and abnormal uterine bleeding, and more high-quality studies are needed to further investigate the relevant definitions and study results in the future.

Abstract Background Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process. Methods Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography–mass spectrometry (LC–MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α. Results The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth. Conclusion These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.

Cardiotoxicity is a common side effect of cisplatin in cancer treatment, often complicating patient care. Tangeretin (TG), a natural compound found in citrus peel, shows promise in protecting against cisplatin-induced heart damage. Our study investigated TG’s protective effects both in cell culture and in animal models. TG effectively countered cisplatin-induced damage in heart cells, promoting mitochondrial health and glucose transporter expression. In animal studies, TG reduced markers of heart damage and improved cardiac function. Mechanistically, TG activated AMPK, reduced the inactivation of Acetyl-CoA Carboxylase (ACC) protein and inhibited p38 MAPK and prevented mitochondrial dysfunction and cell death. This research sheds light on TG’s potential in safeguarding the heart from cisplatin-induced harm.

Head and neck cancer ranks as the sixth most common cancer worldwide, highlighting the critical need for the development of new therapies to enhance treatment efficacy. The activation of innate immune receptors given their potent immune stimulatory properties aid in the eradication of cancer cells. In this study, we investigated the immune mechanism and anti-tumor function of a Toll-like receptor 9 (TLR9) agonist, CpG-oligodeoxynucleotide-2722 (CpG-2722), in combination with cyclic dinucleotides, which are agonists of stimulator of interferon genes (STING). Our results revealed that CpG-2722 stimulation increased the expression of Th1 pro-inflammatory cytokines. Stimulation by STING agonists exhibited lower expression of Th1 cytokines but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of these two agonists significantly enhanced Th1 cytokines while reducing Th2 cytokines. Moreover, in vivo experiment showed that both CpG-2722 and 2’3’-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than the use of these agonists alone. The combined treatment cooperatively promoted the production of Th1 cytokines and type I interferons, while suppressing Th2 cytokines in the tumors as observed in vitro. Additionally, it led to the accumulation of M1 macrophages, dendritic cells, and T cells, shaping a favorable tumor microenvironment for T cell-mediated tumor killing. The anti-tumor activity of the CpG-2722 and 2’3’-c-di-AMP combination depends on the macrophage presence but does not directly activate M1 macrophage polarization, instead working through a reprogrammed cytokine profile. Furthermore, this combination shows a cooperative anti-tumor activity with anti-PD-1 in treating head and neck tumors. Overall, these findings highlight a Th response and macrophage phenotype reprograming involved functional mechanism underlying the cooperative activity of the combination of TLR9 and STING agonists in the immunotherapy of head and neck cancer.

Abstract Background Lung cancer is a malignant tumor with the highest mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to be contributed to lung cancer progression with deleterious effects. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role in lung cancer remains unknown. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in lung adenocarcinoma (LUAD). Methods So as to investigate the effect of DCAF13 on lung adenocarcinoma cell function using in vivo and in vitro. Mechanistically, we have identified the downstream targets of DCAF13 by using RNA-sequencing, as well as ubiquitination assays, co-immunoprecipitation, immunofluorescence, immunohistochemistry and chromatin immunoprecipitation - qPCR experiments. Results Our findings reveal that DCAF13 is a carcinogenic factor in LUAD, as it is highly expressed and negatively correlated with clinical outcomes in LUAD patients. Through RNA-sequencing, it has been shown that DCAF13 negatively regulates the p53 signaling pathway and inhibits p53 downstream targets including p21, BAX, FAS, and PIDD1. We also demonstrate that DCAF13 can bind to p53 protein, leading to K48-linked ubiquitination and degradation of p53. Functionally, we have shown that DCAF13 knockdown inhibits cell proliferation and migration. Our results highlight the significant role of DCAF13 in promoting LUAD progression by inhibiting p53 protein stabilization and the p53 signaling pathway. Furthermore, our findings suggest that high DCAF13 expression is a poor prognostic indicator in LUAD, and DCAF13 may be a potential therapeutic target for treating with this aggressive cancer. Conclusions The DCAF13 as a novel negative regulator of p53 to promote LUAD progression via facilitating p53 ubiquitination and degradation, suggesting that DCAF13 might be a novel biomarker and therapeutical target for LUAD.

In K444 alloy, the evolution of carbides during stress aging (creep) and stress-free aging at 900 °C for 5000 h, and interrupted at 3000 h were investigated, combining microstructure characterization and quantitative statistics method. After stress-free aging for 5000 h, the volume fraction of intragranular MC and M6C carbides decrease from 0.48 % to 0.66 %–0.26 % and 0.48 %, respectively, while that of M23C6 carbides increase to 0.28 %. The two degradation behaviors can be concluded as MC + γ → M6C + M23C6 + γ′ and M6C + γ → M23C6 + γ′ respectively. The former controlled by the diffusion of Ti occurred earlier, while the latter determined by the diffusion of W and Mo mainly happened later. The applied stress did not change degradation reactions while accelerate the degradation rate slightly. During stress-free aging, the morphology of grain boundaries (GBs) changed from discrete distribution to semi-continuous and then to continuous chain, and the content of MC and M6C carbides decreases while that of M23C6 carbides increases. The applied stress markedly promotes above behaviors. Especially, the completed continuous chain formed before 3000 h. Moreover, the applied stress induced the formation of cavitation on the GBs, which is attributed to the following reasons. First, it can accelerate the degradation of GBs and decline the GBs strength. What's more, dislocations pile up on the GBs and cause a high level of stress concentration. Finally, the new generated phase interfaces have a greater deviation with its adjacent carbides, weakening the binding force of GBs.

The filamentous fungus Trichoderma reesei is widely used for the production of lignocellulolytic enzymes in industry. XYR1 is the major transcriptional activator of cellulases and hemicellulases in T. reesei. However, rational engineering of XYR1 for improved lignocellulolytic enzymes production has been limited by the lack of structure information. Here, alanine 873 was identified as a new potential target for the engineering of XYR1 based on its structure predicted by AlphaFold2. The mutation of this residue to tyrosine enabled significantly enhanced production of xylanolytic enzymes in the medium with cellulose as the carbon source. Moreover, xylanase and cellulase production increased by 56.7- and 3.3-fold, respectively, when glucose was used as the sole carbon source. Under both conditions, the improvements of lignocellulolytic enzyme production were higher than those in the previously reported V821F mutant. With the enriched hemicellulases and cellulases, the crude enzymes secreted by the A873Y mutant strain produced 51 % more glucose and 52 % more xylose from pretreated corn stover than those of the parent strain. The results provide a novel strategy for engineering the lignocellulolytic enzyme-producing capacity of T. reesei, and would be helpful for understanding the molecular mechanisms of XYR1 regulation.

Modular Multilevel Converter (MMC) is widely used in applications such as High Voltage Direct Current (HVDC) transmission, AC/DC power conversion centers, and large-scale power quality management in electrical grids due to its highly modular structure, strong redundancy and low harmonic content in AC output. The application of the traditional deadbeat predictive current control to MMC enhances the fast tracking ability of the output current, but it still has the problems of low output current accuracy and high dependence on bridge arm inductor. Based on this, this paper proposes an improved two-beat deadbeat synchronous predictive current control based on Newton interpolation method. By improving the two-beat deadbeat synchronous predictive current control strategy, the accuracy of the output current can be further improved and its fast tracking ability can be enhanced. Newton interpolation is introduced to improve the accuracy of the output current while reducing the dependence on the bridge arm inductor. The results show that the control strategy proposed in this paper reduces the output current THD by 2.88% compared with the two-beat deadbeat predictive current control, thus improving the accuracy; the bridge arm inductor value is reduced by 1.28%, thus reducing the dependence; and under the transient environment, the output current can be tracked to its predicted reference value 843 μs in advance, which enhances the fast tracking capability.

Objective: The substantial prevalence of nonadherence to analgesic medication among individuals diagnosed with cancer imposes a significant strain on both patients and healthcare resources. The objective of this study is to develop and authenticate a nomogram model for assessing nonadherence to analgesic medication in cancer patients. Methods: Clinical information, demographic data, and medication adherence records of cancer pain patients were gathered from the Affiliated Hospital of Chengde Medical University between April 2020 and March 2023. The risk factors associated with analgesic medication nonadherence in cancer patients were analyzed using the least absolute selection operator (LASSO) regression model and multivariate logistic regression. Additionally, a nomogram model was developed. The bootstrap method was employed to internally verify the model. Discrimination and accuracy of the nomogram model were evaluated using the Concordance index (C-index), area under the receiver Operating characteristic (ROC) curve (AUC), and calibration curve. The potential clinical value of the nomogram model was established through decision curve analysis (DCA) and clinical impact curve. Results: The study included a total of 450 patients, with a nonadherence rate of 43.33%. The model incorporated seven factors: age, address, smoking history, number of comorbidities, use of nonsteroidal antiinflammatory drugs (NSAIDs), use of opioids, and PHQ-8. The C-index of the model was found to be 0.93 (95% CI: 0.907–0.953), and the ROC curve demonstrated an AUC of 0.929. Furthermore, the DCA and clinical impact curves indicate that the built model can accurately predict cancer pain patients' medication adherence performance. Conclusions: A nomogram model based on 7 risk factors has been successfully developed and validated for long-term analgesic management of cancer patients.

Infection of tomato leaves and fruits by necrotrophic fungal pathogen Botrytis cinerea causes considerable economic loss. Melatonin has multiple physiological functions and is considered a potential biocontrol agent for its positive effects on plant innate immunity. In tomato, melatonin reduces Botrytis-caused post-harvest fruit decay by activating jasmonic acid (JA) signaling. In this study, we analyzed the effects of melatonin on resistance to Botrytis and associated defense mechanisms in tomato leaves. Treatment of detached tomato leaves with melatonin at a concentration as low as 100 µM induced resistance to Botrytis based on reduced lesion size and fungal growth. Melatonin-induced resistance to gray mold was associated with activation of a complex set of defense mechanisms in tomato leaves. First, melatonin suppressed Botrytis-induced cell death and accumulation of reactive oxygen species (ROS), which was correlated with increased activities of ROS-scavenging enzymes and enhanced expression of their corresponding genes. Second, melatonin treatment induced callose synthase genes and promoted rapid and strong callose deposition in tomato leaves. Melatonin also induced other anti-microbial genes encoding chitinases, β-1,3-glucanases, phenylalanine ammonialyases and polyphenol oxidases. Third, melatonin increased Botrytis-induced expression of genes encoding SlWRKY33, SlMYC2 and SlERF transcription factors, which activate defense-related genes expression through JA and ethylene (ET) signaling pathways. By contrast, melatonin suppressed salicylic acid (SA) signaling based on reduced expression of the SlPR1 marker gene, which is known to antagonize defense against Botrytis. These results collectively indicate that exogenous melatonin orchestrates multiple signaling pathways to activate a complex set of defense mechanisms against Botrytis in tomato leaves.

The quenching of light and heavy flavor hadrons in relativistic heavy-ion collisions probes the color and flavor dependences of parton energy loss through a color-deconfined quark-gluon plasma (QGP), and thus offers an important test of QCD-based calculation at extremely high density and temperature. By combining a next-to-leading order perturbative QCD calculation of parton production, a general ansatz of parton energy loss functions and parton fragmentation functions, we calculate the nuclear modification of various hadron species – charged hadrons, D mesons and B-decayed J/ψ – over a wide transverse momentum regime. Comparing our calculations to the experimental data using the Bayesian statistical analysis, we perform a first simultaneous extraction of the energy loss functions of gluons (g), light quarks (q), charm quarks (c) and bottom quarks (b) inside the QGP. We find that the average parton energy loss at high energies follows the expected hierarchy of 〈ΔEg〉>〈ΔEq〉∼〈ΔEc〉>〈ΔEb〉, while the parton energy loss distribution can further test the QCD calculations of parton interaction with the dense nuclear matter. We also find that the reduction of experimental uncertainties can significantly improve the precision of the extracted parton energy loss functions inside the QGP.

Abstract To investigate how sodium-glucose co-transporter 2 inhibitors (SGLT2is) add-on therapy for metformin affects diabetic retinopathy (DR) progression in patients with type 2 diabetes mellitus (T2DM). This nationwide population-based study conducted from January 1, 2016, to December 31, 2018 involved 3,432,911 adults with T2DM in Taiwan. To adjust for potential confounders, data on sex, age, income, comorbidities, diabetes complication severity index score, staging of kidney disease, anti-diabetic medications, and index year were included. The outcome was DR progression, determined by procedure codes or the addition of ICD-9-CM or ICD-10-CM codes to the medical records of the patients during the study. Sensitivity analyses were performed to validate the findings. The adjusted hazard ratio (aHR) of DR progression was 0.89 for the SGLT2is add-on group, relative to the control group [95% confidence interval (CI) 0.81–0.99, P = 0.026]. The Kaplan–Meier curve of the cumulative incidence rate showed that the cumulative incidence of DR progression was considerably decreased in the SGLT2is cohort (log-rank P = 0.0261). The use of SGLT2is for less than 1 year and 1–2 years were associated with a significant increase in the risk of DR progression (aHR 1.56 and 1.88, respectively); however, the risk markedly reduced if the SGLT2is regimen was used for more than 2 years (aHR 0.41, 95% Cl 0.35–0.48; P

Abstract Background Disseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-induction can be an operational cure for preventing metastases and relapse of PCa patients. Methods We used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developed in vitro 2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction. Results We found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients’ data. We predicted and validated the dormancy-mimicking effect of PF-562,271 (PF-271), an inhibitor of focal adhesion kinase (FAK) in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy. Conclusions Our study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper.

Fully tapping into the role of user side regulation helps reduce the energy cost of integrated energy system (IES). Demand response (DR) and electric vehicle (EV) as schedulable resources on the user side are important regulation means for optimal scheduling of IES. However, in the actual operation process, due to the influence of load aggregator (LA) economic incentives and EV travel, the economic impact of the uncertainty of user side DR on IES cannot be ignored. Based on this, this paper proposes an IES optimal operation model considering the robust stochastic optimization of EV and the participation of LA which considers the energy purchase cost of IES from the superior network and the economic loss cost of LA. First, the response rate model and EV uncertainty model based on economic incentive are constructed. Then, the robust optimization model of EV is built, and the load demand of EV travel uncertainty is analyzed. Finally, a simulation example is given to analyze the impact of user DR uncertainty and EV uncertainty on IES operation economy and power balance. The simulation results show that considering the uncertainty of DR and EV can optimize the economic operation of IES and reduce the economic loss of LA and the total cost, which verifies the effectiveness and economy of the proposed models.

Studies revealed that cancer patients seemed more susceptible to COVID-19 and the clinical symptoms were serious. A recent study depicted that lymphocyte antigen 6 complex, locus E (LY6E) might inhibit coronavirus entry into cells by interfering with the membrane fusion process mediated through spike protein, and potently restricting the SARS-CoV-2 (Severe acute respiratory syndrome-associated coronavirus 2) infection. LY6E mRNA level in lung cancer was detected by publicly available datasets. Patient-specific features were used to analyze the potential factors that could affect LY6E level. Analysis of association between LY6E level and immune infiltration was also performed. In present study, it was found that smoker with lung adenocarcinoma showed lower LY6E level than non-smoker (p < 0.05). In LUSC (lung squamous cell carcinoma) patients, reformed smokers showed higher LY6E than smokers (p < 0.05). These results suggested that smoke can be a risk susceptible to COVID-19 in lung cancer patients. Further studies exhibited that LY6E was positively associated with immune cell infiltration in lung adenocarcinoma, indicating that LY6E may influence the infection severity of COVID-19 in lung cancer patients. In summary, smoke may downregulate LY6E level and exacerbate infection and deterioration of COVID-19 in lung cancer patients.

Objective:. The skin manifestations of dermatomyositis (DM) are complex and diverse, with some rashes having diagnostic significance, while others have a certain suggestive effect on the patient’s condition, visceral damage, and prognosis. This case-cohort study was performed to investigate the skin manifestations of 205 adult inpatients with DM. We then analyzed the association between the clinical characteristics and panniculitis in adult patients with DM. Methods:. This study was conducted at the First Medical Center of PLA General Hospital, Beijing, China from March 1, 2016 to December 30, 2020 with follow-up until December 31, 2021. This case-cohort study involved 205 eligible participants with DM who met the criteria for idiopathic inflammatory myopathy. Clinical data, cutaneous manifestations, and lesion locations were screened and analyzed. Serum samples were collected, and immunoblotting was used to detect 16 types of myositis-specific antibodies and myositis-associated antibodies. Results:. The results showed that 16 (7.8%) of the 205 adult patients with DM had panniculitis. The panniculitis was mainly distributed in the subcutaneous fat of the abdomen, buttocks, and thighs. This condition was often accompanied by skin ulcers, atrophic scars, and calcinosis. Moreover, 9 (72.7%) of the 16 patients with panniculitis were positive for antibodies to nuclear matrix protein 2 (anti-NXP2 antibodies). Conclusion:. The data showed that panniculitis is an uncommon skin manifestation in adult patients with DM, with a positivity rate of 7.8%. The appearance of panniculitis is likely associated with anti-NXP2 antibodies.

Soil salinization is a global environmental issue and a significant abiotic stress that threatens crop production. Root-associated rhizosphere microbiota play a pivotal role in enhancing plant tolerance to abiotic stresses. However, limited information is available concerning the specific variations in rhizosphere microbiota driven by different plant genotypes (varieties) in response to varying levels of salinity stress. In this study, we compared the growth performance of three alfalfa varieties with varying salt tolerance levels in soils with different degrees of salinization. High-throughput 16S rRNA and ITS sequencing were employed to analyze the rhizosphere microbial communities. Undoubtedly, the increasing salinity significantly inhibited alfalfa growth and reduced rhizosphere microbial diversity. However, intriguingly, salt-tolerant varieties exhibited relatively lower susceptibility to salinity, maintaining more stable rhizosphere bacterial community structure, whereas the reverse was observed for salt-sensitive varieties. Bacillus emerged as the dominant species in alfalfa's adaptation to salinity stress, constituting 21.20% of the shared bacterial genera among the three varieties. The higher abundance of Bacillus, Ensifer, and Pseudomonas in the rhizosphere of salt-tolerant alfalfa varieties is crucial in determining their elevated salt tolerance. As salinity levels increased, salt-sensitive varieties gradually accumulated a substantial population of pathogenic fungi, such as Fusarium and Rhizoctonia. Furthermore, rhizosphere bacteria of salt-tolerant varieties exhibited increased activity in various metabolic pathways, including biosynthesis of secondary metabolites, carbon metabolism, and biosynthesis of amino acids. It is suggested that salt-tolerant alfalfa varieties can provide more carbon sources to the rhizosphere, enriching more effective plant growth-promoting bacteria (PGPB) such as Pseudomonas to mitigate salinity stress. In conclusion, our results highlight the variety-mediated enrichment of rhizosphere microbiota in response to salinity stress, confirming that the high-abundance enrichment of specific dominant rhizosphere microbes and their vital roles play a significant role in conferring high salt adaptability to these varieties.

IntroductionThe pea aphid, Acyrthosiphon pisum, is a typical sap-feeding insect and an important worldwide pest. There is a primary symbiont-Buchnera aphidicola, which can synthesize and provide some essential nutrients for its host. At the same time, the hosts also can actively adjust the density of bacterial symbiosis to cope with the changes in environmental and physiological factors. However, it is still unclear how symbionts mediate the interaction between herbivorous insects’ nutrient metabolism and host plants.MethodsThe current study has studied the effects of different host plants on the biological characteristics, Buchnera titer, and nutritional metabolism of pea aphids. This study investigated the influence of different host plants on biological characteristics, Buchnera titer, and nutritional metabolism of pea aphids.Results and discussionThe titer of Buchnera was significantly higher on T. Pretense and M. officinalis, and the relative expression levels were 1.966±0.104 and 1.621±0.167, respectively. The content of soluble sugar (53.46±1.97µg/mg), glycogen (1.12±0.07µg/mg) and total energy (1341.51±39.37µg/mg) of the pea aphid on V. faba were significantly higher and showed high fecundity (143.86±11.31) and weight (10.46±0.77µg/mg). The content of total lipids was higher on P. sativum and T. pretense, which were 2.82±0.03µg/mg and 2.92±0.07µg/mg, respectively. Correlation analysis found that the difference in Buchnera titer was positively correlated with the protein content in M. officinalis and the content of total energy in T. pratense (P < 0.05). This study confirmed that host plants not only affected the biological characteristics and nutritional metabolism of pea aphids but also regulated the symbiotic density, thus interfering with the nutritional function of Buchnera. The results can provide a theoretical basis for further studies on the influence of different host plants on the development of pea aphids and other insects.

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent advances in targeted therapies and immunotherapies, the clinical benefit remains limited. Therefore, there is an urgent need to further investigate the molecular mechanisms underlying lung cancer. The aim of this study was to investigate the expression and function of NPM3 in the tumor microenvironment of lung adenocarcinoma (LUAD). Methods We utilized bioinformatics tools and databases, including UALCAN, GEPIA2, HPA, and Sangerbox, to analyze NPM3 expression in LUAD samples and its association with prognosis and mutational landscape. NPM3 expression in various cell types was assessed at the single cell level using the TISCH database. We also used algorithms such as TIMER and EPIC to explore the crosstalk between NPM3 expression and immune features. KEGG enrichment analysis was performed to identify potential signaling pathways of NPM3. Finally, we employed siRNA knockdown strategy to investigate the effect of NPM3 on LUAD cell proliferation and migration in vitro. Results NPM3 was significantly upregulated in LUAD tissues and was strongly associated with poor prognosis and TP53 gene mutations. Single-cell sequencing analysis revealed that NPM3 was expressed in immune cells (dendritic cells and monocytes/macrophages) in the tumor microenvironment. Moreover, NPM3 expression was negatively associated with immune B cell and CD4 T cell infiltration, as well as with several immune-related genes (including CCL22, CXCR2, CX3CR1, CCR6, HLA-DOA, HLA-DQA2). KEGG enrichment analysis indicated that NPM3 expression was associated with cell cycle, CAMs, and NSCLC pathway genes. Finally, in vitro experiments showed that NPM3 knockdown inhibited LUAD cell proliferation and migration in NCI-H1299 and SPC-A1 cells, and suppressed the expression of CCNA2 and MAD2L1. Conclusion Elevated NPM3 expression predicts poor clinical outcome and an immunosuppressive microenvironment in LUAD tissues. NPM3 promotes LUAD progression by promoting cell proliferation and migration, and targeting NPM3 may represent a novel therapeutic strategy for LUAD. Graphical Abstract

Abstract Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage.

Abstract Coronavirus disease 2019 (COVID-19) vaccines are associated with several ocular manifestations. Emerging evidence has been reported; however, the causality between the two is debatable. We aimed to investigate the risk of retinal vascular occlusion after COVID-19 vaccination. This retrospective cohort study used the TriNetX global network and included individuals vaccinated with COVID-19 vaccines between January 2020 and December 2022. We excluded individuals with a history of retinal vascular occlusion or those who used any systemic medication that could potentially affect blood coagulation prior to vaccination. To compare the risk of retinal vascular occlusion, we employed multivariable-adjusted Cox proportional hazards models after performing a 1:1 propensity score matching between the vaccinated and unvaccinated cohorts. Individuals with COVID-19 vaccination had a higher risk of all forms of retinal vascular occlusion in 2 years after vaccination, with an overall hazard ratio of 2.19 (95% confidence interval 2.00–2.39). The cumulative incidence of retinal vascular occlusion was significantly higher in the vaccinated cohort compared to the unvaccinated cohort, 2 years and 12 weeks after vaccination. The risk of retinal vascular occlusion significantly increased during the first 2 weeks after vaccination and persisted for 12 weeks. Additionally, individuals with first and second dose of BNT162b2 and mRNA-1273 had significantly increased risk of retinal vascular occlusion 2 years following vaccination, while no disparity was detected between brand and dose of vaccines. This large multicenter study strengthens the findings of previous cases. Retinal vascular occlusion may not be a coincidental finding after COVID-19 vaccination.

BackgroundDespite reports on the association between diabetes mellitus (DM) and lumbar disk herniation (LDH), large-scale, nationwide studies exploring this relationship are lacking. We aimed to examine the profiles of DM in individuals with LDH and explore the potential mechanisms underlying the development of these disorders.MethodsThis retrospective, population-based study was conducted between 2008 and 2019 using data from the National Health Insurance (NHI) research database in Taiwan. The primary outcome was the date of initial LDH diagnosis, death, withdrawal from the NHI program, or end of the study period.ResultsIn total, 2,662,930 individuals with and 16,922,546 individuals without DM were included in this study; 719,068 matched pairs were established following propensity score matching (1:1 ratio) for sex, age, comorbidities, smoking, alcohol consumption, antihyperglycemic medications, and index year. The adjusted risk for developing LDH was 2.33-fold (95% confidence interval: 2.29−2.37; P

Lymphocystis disease is frequently prevalent and transmissible in various teleost species worldwide due to lymphocystis disease virus (LCDV) infection, causing unsightly growths of benign lymphocystis nodules in fish and resulting in huge economic losses to aquaculture industry. However, the molecular mechanism of lymphocystis formation is unclear. In this study, LCDV was firstly detected in naturally infected flounder (Paralichthys olivaceus) by PCR, histopathological, and immunological techniques. To further understand lymphocystis formation, transcriptome sequencing of skin nodule tissue was performed by using healthy flounder skin as a control. In total, RNA-seq produced 99.36%-99.71% clean reads of raw reads, of which 91.11%-92.89% reads were successfully matched to the flounder genome. The transcriptome data showed good reproducibility between samples, with 3781 up-regulated and 2280 down-regulated differentially expressed genes. GSEA analysis revealed activation of Wnt signaling pathway, Hedgehog signaling pathway, Cell cycle, and Basal cell carcinoma associated with nodule formation. These pathways were analyzed to interact with multiple viral infection and tumor formation pathways. Heat map and protein interaction analysis revealed that these pathways regulated the expression of cell cycle-related genes such as ccnd1 and ccnd2 through key genes including ctnnb1, lef1, tcf3, gli2, and gli3 to promote cell proliferation. Additionally, cGMP-PKG signaling pathway, Calcium signaling pathway, ECM-receptor interaction, and Cytokine-cytokine receptor interaction associated with nodule formation were significantly down-regulated. Among these pathways, tnfsf12, tnfrsf1a, and tnfrsf19, associated with pro-apoptosis, and vdac2, which promotes viral replication by inhibiting apoptosis, were significantly up-regulated. Visual analysis revealed significant down-regulation of cytc, which expresses the pro-apoptotic protein cytochrome C, as well as phb and phb2, which have anti-tumor activity, however, casp3 was significantly up-regulated. Moreover, bcl9, bcl11a, and bcl-xl, which promote cell proliferation and inhibit apoptosis, were significantly upregulated, as were fgfr1, fgfr2, and fgfr3, which are related to tumor formation. Furthermore, RNA-seq data were validated by qRT-PCR, and LCDV copy numbers and expression patterns of focused genes in various tissues were also investigated. These results clarified the pathways and differentially expressed genes associated with lymphocystis nodule development caused by LCDV infection in flounder for the first time, providing a new breakthrough in molecular mechanisms of lymphocystis formation in fish.

IntroductionCoronavirus disease 2019 (COVID-19) has caused more than 690 million deaths worldwide. Different results concerning the death rates of the Delta and Omicron variants have been recorded. We aimed to assess the secular trend of case fatality rate (CFR), identify risk factors associated with mortality following COVID-19 diagnosis, and investigate the risks of mortality and hospitalization during Delta and Omicron waves in the United States.MethodsThis study assessed 2,857,925 individuals diagnosed with COVID-19 in the United States from January 2020, to June 2022. The inclusion criterion was the presence of COVID-19 diagnostic codes in electronic medical record or a positive laboratory test of the SARS-CoV-2. Statistical analysis was bifurcated into two components, longitudinal analysis and comparative analysis. To assess the discrepancies in hospitalization and mortality rates for COVID-19, we identified the prevailing periods for the Delta and Omicron variants.ResultsLongitudinal analysis demonstrated four sharp surges in the number of deaths and CFR. The CFR was persistently higher in males and older age. The CFR of Black and White remained higher than Asians since January 2022. In comparative analysis, the adjusted hazard ratios for all-cause mortality and hospitalization were higher in Delta wave compared to the Omicron wave. Risk of all-cause mortality was found to be greater 14–30 days after a COVID-19 diagnosis, while the likelihood of hospitalization was higher in the first 14 days following a COVID-19 diagnosis in Delta wave compared with Omicron wave. Kaplan–Meier analysis revealed the cumulative probability of mortality was approximately 2-fold on day 30 in Delta than in Omicron cases (log-rank p

The SAM shows remarkable generalization and transformable capabilities for category-agnostic segmentation. Although the semantics in latent space are explored slightly, more researches are working on instance segmentation. And it’s unclear how to design the appropriate prompts for semantic segmentation, which have large impact the performance. In this paper, by summarizing several existing methods for semantic segmentation with SAM, we propose a learnable prompt method for semantic segmentation based on the SAM model, incorporating the latent semantic features with prompt learning by a grouping approach, referred as GroupPrompter. This enables SAM to perform semantic segmentation with the automatic learned prompts. And the experimental results on ADE20K, Pascal Context and COCO-Stuff datasets validate the effectiveness of the proposed method.

Hirame novirhabdovirus (HIRRV), which mainly infects the olive flounder (Paralichthys olivaceus), is considered to be one of the most serious viral pathogens threatening the global fish culture industry. However, little is known about the mechanism of host-pathogen interactions at the metabolomic level. In this study, in order to explore the metabolic response of olive flounder to HIRRV infection, liquid chromatography mass spectrometry (LC-MS) was used to detect the changes of endogenous compounds of the olive flounder after HIRRV infection. A total of 954 unique masses were obtained, including 495 metabolites and 459 lipids. Among them, 7 and 173 qualified differential metabolites were identified at 2 days and 7 days post-infection, respectively. Distinct metabolic profiles were observed along with viral infection. At the early stage of infection, only a few metabolites were perturbed. Among them, the level of inosine and carnosine were increased and the potential antiviral ability of these two metabolites was further confirmed by exogenous addition experiment. At the late stage of HIRRV infection, the metabolic profiles changed remarkably. The changes in amino acids and nucleotides especially the 7-methylguanine also accelerated the amplification of viral particles. And the down-regulation of glutathione (GSH) implied an elevated level of ROS (reactive oxygen species) that attenuated the immune system of flounders. HIRRV also induced the accumulation of purine and reduction of pyrimidine, and elevated LPC and LPE levels. The unbalanced purine/pyrimidine and altered lipid profile may be beneficial for the replication and infection of HIRRV at the late stage of infection. These findings provide new insights into the pathogenic mechanism of HIRRV infection in olive flounder.

For studying the effect mechanism and regularity of the transition layer thickness on the bonding properties of coatings, TiN coatings were prepared on the surface of titanium alloy through cathodic arc ion plating technology using Ti as the transition layer. The change rules of fracture toughness, micro - hardness, fracture morphology and bonding strength of the coating were studied by adjusting the thickness of the transition layer. Results showed that all TiN coatings showed a preferred orientation along (111) close - packed surface, and the coating fractures presented a columnar crystal structure. As the thickness of the transition layer increased, the fracture toughness of the coating first increased and then decreased, and the fracture dimples gradually became larger and deeper, resulting in a change from inter - granular fracture to trans - granular fracture. Meanwhile, the bonding force of the coating increased first and then decreased, and reached the highest value of 62 N when the transition time was 9 minutes. In general, the Ti transition layer with the optimal thickness could absorb deformation energy, control residual stress, and improve the bonding properties of the coating effectively.

Abstract In this paper, we propose a convolutional neural network (CNN) and clustering-based codebook design method. Specifically, we train two different CNNs, i.e., CNN1 and CNN2, to compress the channel state information (CSI) matrices into the channel vectors and recover the channel vectors back into the CSI matrices, respectively. After that, the clustering algorithm clusters the output of CNN1, i.e., the channel vectors into several clusters and outputs a centroid for each cluster. The sum distance between each centroid and the channel vectors in the corresponding cluster is the smallest, which can lead to the maximum sum rate of massive MIMO codebook design. Then, the centroids are recovered into matrices by CNN2. The output of CNN2 is our proposed codebook for massive multiple-input multiple-output (MIMO) systems. In the simulation, we compare the performance of different clustering algorithms. We also compare the proposed codebook with the traditional discrete Fourier transform (DFT) codebook. Simulation results show the superiority of the proposed algorithm.