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Abstract Background Workplace violence is a global public health issue and a major occupational hazard cross borders and environments. Nurses are the primary victims of workplace violence due to their frontline roles and continuous interactions. Objective The present study aimed to investigate the status of workplace violence, turnover intention, compassion fatigue, and psychological resilience among Chinese nurses, and explore the mediating role of compassion fatigue and the moderating role of psychological resilience on relationship between workplace violence and turnover intention among Chinese nurses. Method A cross-sectional study was conducted among a convenience sample of clinical registered nurses from public hospitals in Changsha, Hunan, China. Data was collected through an online questionnaire, which included a demographic information form, the Workplace Violence Scale (WVS), the Turnover Intention Questionnaire (TIQ), the Compassion Fatigue Scale (CF-CN), and the Connor-Davidson Resilience Scale (CD-RISC). Descriptive statistics and correlation analysis were employed to examine the relationships among the main variables. A moderated mediation analysis was further conducted using the PROCESS macro for SPSS (Model 4 and Model 8) to examine the mediating role of compassion fatigue and the moderating role of psychological resilience. Result The present survey recruited a convenience sample of 1,141 clinical registered nurses, who reported experiencing multiple types of workplace violence during the past year. Correlation analysis revealed significant positive correlations between workplace violence and turnover intention (r = 0.466, P

Abstract Currently, there is still debate over the effectiveness of transcranial direct current stimulation (tDCS) in treating obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD) and anxiety disorders (ADs). To investigate the immediate and long-term effectiveness of tDCS in these diseases, we conducted a systematic review and quantitative analysis of existing literature on the treatment of OCD, PTSD, and ADs with tDCS. Following the PRISMA guidelines, we searched seven electronic databases and systematically retrieved articles published from May 2012 to June 2024 that compared the effects of active tDCS with sham stimulation in the treatment of these disorders. We included primary outcome measures such as the change scores in disorder-specific and general anxiety symptoms before and after treatment, as well as secondary outcomes such as changes in disorder-specific and general anxiety symptoms at follow-up. We also assessed the impact of tDCS on depressive symptoms. Fifteen papers met the eligibility criteria. Overall, the results of meta-analysis indicated that tDCS had a high effect in improving specific symptoms (SMD = −0.73, 95% CI: −1.09 to −0.37) and general anxiety symptoms (SMD = −0.75; 95% CI: −1.23 to −0.26) in OCD, PTSD and ADs, with effects lasting up to 1 month and showing a moderate effect size. Furthermore, tDCS demonstrated immediate and significant alleviation of depressive symptoms in these diseases. This study concludes that tDCS can serve as a non-invasive brain stimulation technology for treating these disorders, and the therapeutic effects can be maintained for a period of time.

Abstract The primary cilium behaves as a platform for sensing and integrating extracellular cues to control a plethora of cellular activities. However, the functional interaction of this sensory organelle with epithelial-mesenchymal transition (EMT) during pulmonary fibrosis remains unclear. Here, we reveal a critical role for cylindromatosis (CYLD) in reciprocally linking the EMT program and ciliary homeostasis during pulmonary fibrosis. A close correlation between the EMT program and primary cilia is observed in bleomycin-induced pulmonary fibrosis as well as TGF-β-induced EMT model. Mechanistic study reveals that downregulation of CYLD underlies the crosstalk between EMT and ciliary homeostasis by inactivating histone deacetylase 6 (HDAC6) during pulmonary fibrosis. Moreover, manipulation of primary cilia is an effective means to modulate the EMT program. Collectively, these results identify a pivotal role for the CYLD/HDAC6 signaling in regulating the reciprocal interplay between the EMT program and ciliary homeostasis during pulmonary fibrosis.

Abstract Background The potentially fatal attacks experienced by porphyria carriers are triggered by various porphyrinogenic drugs. However, determining the safety of particular drugs is challenging. Methods We retrospectively used the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) to identify drugs associated with porphyria as an adverse event (AE) extracted from data from January 2004 to March 2022. The associated search terms included “Porphyria,” “Porphyria screen,” “Porphyria non-acute,” “Porphyria acute,” “Acquired porphyria,” and “Pseudoporphyria.” Signal mining analysis was performed to identify the association between drugs and AEs by four algorithms, namely the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results FAERS reported 1470 cases of porphyria-related AEs, and 406 drugs were screened after combining trade and generic names. All four algorithms identified 52 drugs with signals. The characteristics of all the reports and signaling drugs were analyzed. Conclusions This is the first report of drug-associated porphyria that provides critical information on drug porphyrogenicity, facilitating rational and evidence-based drug prescription and improving the accuracy of porphyrogenicity prediction based on model algorithms. Moreover, this study serves a reference for clinicians to ensure that porphyrinogenic drugs are not prescribed to carriers of porphyria genetic mutations.

Abstract High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.

Abstract Background Dry eyes can cause discomfort. To treat dry eye disease, cyclosporine A (CsA) and Lifitegrast are two eye drugs approved by the U.S. Food and Drug Administration (FDA). However, frequent use of eye drops can be challenging and lead to poor compliance, especially in elderly patients. Therefore, this study aimed to develop a drug sustained-release vector and explore its therapeutic effect in animal models of dry eye. Methods Firstly, drug membranes loaded with both CsA and Lifitegrast using a carrier called poly(lactate-co-ε-caprolactone) (P(LLA-CL)) were prepared and evaluated for their physicochemical properties, release behavior in vitro, and safety in vivo. Next, a rabbit dry eye model using a 0.1% benzalkonium chloride (BAC) solution was developed and treated by drug-loaded micro membranes. We observed and recorded conjunctival hyperemia, corneal staining, corneal edema, corneal neovascularization, conjunctival goblet cells and hematoxylin and eosin (H&E) staining. Finally, we detected the MUC5AC and MMP-9 by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Results The composite film released both CsA and Lifitegrast for at least one month. Compared to the blank membrane group, conjunctival hyperemia, corneal fluorescein staining, corneal edema, corneal neovascularization and conjunctival goblet cells recovered faster in the drug membrane group, and the difference was statistically significant. At the molecular level, the drug membrane group showed an increase in mucin density and a significant anti-inflammatory effect. Conclusions The implantation of CsA/Lifitegrast loaded P(LLA-CL) membrane under the subconjunctival of the rabbit eye is safe. The study suggests that this subconjunctival administration could be developed into a minimally invasive delivery system to help patients with dry eye disease who require multiple daily eyedrops but have poor compliance.

Abstract Biochar-based sulfidized nano-sized zero-valent iron (SNZVI/BC) can effectively immobilize cadmium (Cd) in contaminated paddy soils. However, the synergistic effects between biochar and SNZVI on Cd immobilization, as well as the underlying mechanisms remain unclear. Herein, a soil microcosm incubation experiment was performed to investigate the immobilization performance of SNZVI/BC towards Cd in the contaminated paddy soil. Results indicated that the addition of SNZVI/BC at a dosage of 3% significantly lessened the concentration of available Cd in the contaminated soil from 14.9 (without addition) to 9.9 mg kg−1 with an immobilization efficiency of 33.3%, indicating a synergistic effect. The sequential extraction results indicated that the proportion of the residual Cd in the contaminated soil increased from 8.1 to 10.3%, manifesting the transformation of the unstable Cd fractions to the steadier specie after application of SNZVI/BC. Also, the addition of SNZVI/BC increased soil pH, organic matter, and dissolved organic carbon, which significantly altered the bacterial community in the soil, enriching the relative abundances of functional microbes (e.g., Bacillus, Clostridium, and Desulfosporosinus). These functional microorganisms further facilitated the generation of ammonium, nitrate, and ferrous iron in the contaminated paddy soil, enhancing nutrients’ availability. The direct interaction between SNZVI/BC and Cd2+, the altered soil physicochemical properties, and the responded bacterial community played important roles in Cd immobilization in the contaminated soil. Overall, the biochar-based SNZVI is a promising candidate for the effective immobilization of Cd and the improvement of nutrients’ availability in the contaminated paddy soil. Graphical Abstract

Summary: Major depressive disorder (MDD) is a prevalent mental disorder with serious impacts on life and health. Neuroimaging offers valuable diagnostic insights. However, traditional computer-aided diagnosis methods are limited by reliance on researchers’ experience. To address this, we proposed an evolutionary neural architecture search (M-ENAS) framework for automatically diagnosing MDD using multi-modal magnetic resonance imaging (MRI). M-ENAS determines the optimal weight and network architecture through a two-stage search method. Specifically, we designed a one-shot network architecture search (NAS) strategy to train supernet weights and a self-defined evolutionary search to optimize the network structure. Finally, M-ENAS was evaluated on two datasets, demonstrating that M-ENAS outperforms existing hand-designed methods. Additionally, our findings reveal that brain regions within the somatomotor network play important roles in the diagnosis of MDD, providing additional insight into the biological mechanisms underlying the disorder.

Abstract Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

Abstract Background To investigate the diagnostic efficacy of high-frame-rate contrast-enhanced ultrasound (H-CEUS) in differentiating between clear cell renal cell carcinoma (CCRCC) and angiomyolipoma (AML). Methods A retrospective study was performed on the clinical data of 79 patients diagnosed with CCRCC and 31 patients diagnosed with AML at the First Affiliated Hospital of Nanchang University between October 2022 and December 2023. Conventional ultrasound (US) and H-CEUS examinations were conducted on all patients prior to surgery, dynamic images were recorded from the US, and the qualitative and quantitative parameters of H-CEUS were collected. The t-test, χ² test and non-parametric Mann-Whitney test were employed to assess differences in clinical data, US characteristics, and qualitative and quantitative parameters of H-CEUS between the CCRCC and AML groups. The independent risk factors of CCRCC were identified using binary logistic regression. The receiver operator characteristic (ROC) curve was constructed to evaluate the diagnostic effectiveness of clinical + US and H-CEUS in differentiating between CCRCC and AML. Results The CCRCC group and the AML group exhibited significant differences in patient gender, operation mode, nodular echo, and nodule blood flow (χ²=11.698, -, -,=10.582; P

Abstract Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.

Background: Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have become integral elements within the current landscape of breast cancer treatment modalities; however, they are associated with interstitial lung disease (ILD), which is rare but potentially fatal. Notably, only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors. Therefore, this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors. We also reported three cases of ILD after PD-1 inhibitor treatment. Methods: We comprehensively searched PubMed, EMBASE, and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer. Pooled overall estimates of incidence and risk ratio (RR) were calculated with a 95% confidence interval (CI), and a mirror group analysis was performed using eligible studies. Results: This meta-analysis included 29 studies with 4639 patients who received PD-1/PD-L1 inhibitor treatment. A higher ILD incidence was observed among 2508 patients treated with PD-1 inhibitors than among 2131 patients treated with PD-L1 inhibitors (0.05 vs. 0.02). The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors (RR = 2.34, 95% CI, 1.13–4.82, P = 0.02). Conclusion: Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors. These findings are instrumental for clinicians in treatment deliberations, and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.

Abstract Close correlation between vitamin D (VitD) deficiency and Parkinson’s Disease (PD) risk, VitD as an adjuvant treatment promising to improve PD progression. However, VitD excessive intake could induce hypercalcemia and renal damage. Therefore, upregulation of vitD receptor (VDR) is considered a compensatory strategy to overcome VitD insufficiency and alleviate PD symptoms. In this study, we discovered that VDR played antioxidative roles in dopaminergic neurons by decreasing reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. Further, we newly identified VDR downstream events in C. elegans, including glutathione S-transferase (gst) and forkhead box transcription factor class O (daf-16) mediated oxidative stress resistance. VDR upregulation also mitigated microglial activation through inhibition of NLRP3/caspase-1-mediated inflammation and membrane permeabilization. These findings highlight the multifaceted protective effects of VDR in both neurons and microglia against the development of PD. Importantly, we discovered a novel deubiquitinase DUB3, whose N-terminal catalytic domain interacted with the C-terminal ligand-binding domain of VDR to reduce VDR ubiquitination. Identification of DUB3 as an essential player in the deubiquitinating mechanism of VDR provides valuable insights into VDR regulation and its potential as a therapeutic target for PD.

Abstract Background This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma (MM) during the induction phase of treatment with bortezomib, cyclophosphamide, and dexamethasone (BCD). Methods We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front‐line regimen at Peking Union Medical College Hospital from January 1, 2013 to December 31, 2018. Results There were 107 patients with International Staging System (ISS) III and 51 with paraprotein of light chain. Of these, 77 completed nine cycles of the BCD regimen. As the number of treatment cycles increased, the proportions of serum and urine immunofixation electrophoresis (IFE) tests elevated from 40.39% to 62.22% and 16.75% to 37.78%, respectively. More than 90% of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle, but that of urinary M protein was less than 60%. The detection rate of urinary M protein in light chain MM was more than 70% per cycle. Patients with a very good partial response (VGPR) had longer progression‐free survival (PFS) than those with uncertain VGPR (32 vs. 26 months, p = 0.0336). Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation, those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly (27 vs. 22 months, p = 0.059). Conclusion Urinary M protein detection rate is significantly lower than that in serum, leading to an overestimation of efficacy, premature reduction of treatment intensity, and shortened PFS. Precise response assessments are critical to treatment decisions and clinical diagnoses.

ABSTRACTBackground: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy.Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared.Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05).Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Summary: The core of telomerase consists of the protein subunit telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). So far, the role of TERC in cancer development has remained elusive. Here, we found TERC expression elevated in non-small cell lung cancer (NSCLC) tissues, which was associated with disease progression and poor prognosis in patients. Using NSCLC cell lines and xenograft models, we showed that knockdown of TERC caused cell cycle arrest, and inhibition of cell proliferation and migration. Mechanistically, TERC was exported to the cytoplasm by nuclear RNA export factor 1 (NXF1), where it mediated the interaction of TERT with other telomerase subunits. Depletion of TERC hindered the assembly and subsequent nuclear localization of the telomerase complex, preventing TERT from functioning in telomere maintenance and transcription regulation. Our findings suggest that TERC is a potential biomarker for NSCLC diagnosis and prognosis and can be a target for NSCLC treatment.

Abstract Background Telomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length. Methods Independent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships. Results The genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847–0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959–0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115–2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust. Conclusion Our findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.

Depression ranks among the most prevalent mood-related psychiatric disorders. Existing clinical diagnostic approaches relying on scale interviews are susceptible to individual and environmental variations. In contrast, the integration of neuroimaging techniques and computer science has provided compelling evidence for the quantitative assessment of major depressive disorder (MDD). However, one of the major challenges in computer-aided diagnosis of MDD is to automatically and effectively mine the complementary cross-modal information from limited datasets. In this study, we proposed a few-shot learning framework that integrates multi-modal MRI data based on contrastive learning. In the upstream task, it is designed to extract knowledge from heterogeneous data. Subsequently, the downstream task is dedicated to transferring the acquired knowledge to the target dataset, where a hierarchical fusion paradigm is also designed to integrate features across inter- and intra-modalities. Lastly, the proposed model was evaluated on a set of multi-modal clinical data, achieving average scores of 73.52% and 73.09% for accuracy and AUC, respectively. Our findings also reveal that the brain regions within the default mode network and cerebellum play a crucial role in the diagnosis, which provides further direction in exploring reproducible biomarkers for MDD diagnosis.

Abstract The widespread organic pollutants in wastewater are one of the global environmental problems. Advanced oxidation processes (AOPs) are widely used because of their characteristics of high efficiency and strong oxidation. However, AOPs may have some defects, such as incomplete mineralization of organic pollutants and the generation of toxic by-products during the degradation process, thus it is essential to seek efficient and green wastewater treatment technologies. Coupling different AOPs or other processes is beneficial for the mineralization of pollutants and reduces ecological risks to the environment. It is worth noting that carbonaceous materials (CMs) have received widespread attention and application in the degradation of organic pollutants in water by advanced oxidation coupling processes (C-AOPs) due to their excellent physicochemical properties in recent years. However, the behaviors and mechanisms of C-AOPs based on CMs on the degradation of organic pollutants are still unknown. Therefore, it is essential to comprehensively summarize the recent research progress. In this review, the applications of different CMs in C-AOPs were reviewed first. Secondly, the synergistic mechanisms of the C-AOPs based on different CMs were discussed. Then, toxic intermediates were explored and important toxicity assessment methods were proposed. Finally, the application potential of the C-AOPs in the future and the challenges were proposed. This review provides an important reference for the application and optimization of the C-AOPs in organic wastewater treatment in the future. Graphical Abstract

Stevia rebaudiana (Bertoni) is a valuable sweetener plant whose sweetness primarily derives from steviol glycosides (SGs), especially rebaudioside A (RA). Polyploidization has the potential to enhance the content of active ingredients in medicinal plants, making this strategy a promising avenue for genetic improvement. However, the underlying regulatory mechanisms that contribute to the fluctuating SGs content between autotetraploid and diploid stevia remain unclear. In this study, we employed metabolic analysis to identify 916 differentially accumulated metabolites (DAMs), with the majority, specifically terpenoids, flavonoids, and lipids, exhibiting upregulation due to polyploidization. Notably, the content of stevia’s signature metabolite SGs (including RA, steviolbioside, and rebaudioside C), along with their precursor steviol, increased significantly after polyploidization. Furthermore, a comprehensive analysis of the transcriptome and metabolome revealed that the majority of differentially expressed genes (DEGs) involved in the SG-synthesis pathway (ent-KAH, ent-KS1, UGT73E1, UGT74G1, UGT76G1, UGT85C2, and UGT91D2) were upregulated in autotetraploid stevia, and these DEGs exhibited a positive correlation with the polyploidization-enhanced SGs. Additionally, multi-omics network analysis indicated that several transcription factor families (such as five NACs, four WRKYs, three MYBs, eight bHLHs, and three AP2/ERFs), various transporter genes (four ABC transporters, three triose-phosphate transporters, and two sugar efflux transporters for intercellular exchange), as well as microorganisms (including Ceratobasidium and Flavobacterium) were positively correlated with the accumulation of RA and steviol. Overall, our results indicate the presence of a regulatory circuit orchestrated by polyploidization, which recruits beneficial rhizosphere microbes and modulates the expression of genes associated with SG biosynthesis, ultimately enhancing the SG content in stevia. This finding will provide new insights for promoting the propagation and industrial development of stevia.

Abstract Background Colorectal cancer (CRC) is the third frequently diagnosed cancer with high incidence and mortality rate worldwide. Our previous report has demonstrated that circCOL1A1 (hsa_circ_0044556) functions as an oncogene in CRC, and Gene Ontology (GO) analysis has also revealed the strong association between circCOL1A1 and angiogenesis. However, the mechanism of circCOL1A1 or exosomal circCOL1A1 in CRC angiogenesis remains elusive. Methods Purified exosomes from CRC cells were characterized by nanoparticle tracking analyzing, electron microscopy and western blot. qRT-PCR, immunohistochemistry or western blot were employed to test the expression of circCOL1A1, EIF4A3, Smad pathway and angiogenic markers. Cell proliferation of HUVECs was monitored by CCK-8 assay. The migratory and angiogenic capabilities of HUVECs were detected by wound healing and tube formation assay, respectively. Bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down and FISH assays were used to detect the interactions among circCOL1A1, EIF4A3 and Smad2/3 mRNA. The in vitro findings were verified in xenograft model. Results CRC cell-derived exosomal circCOL1A1 promoted angiogenesis of HUVECs via recruiting EIF4A3. EIF4A3 was elevated in CRC tissues, and it stimulated angiogenesis of HUVECs through directly binding and stabilizing Smad2/3 mRNA. Moreover, exosomal circCOL1A1 promoted angiogenesis via inducing Smad2/3 signaling pathway in vitro, and it also accelerated tumor growth and angiogenesis in vivo. Conclusion CRC cell-derived exosomal circCOL1A1 promoted angiogenesis via recruiting EIF4A3 and activating Smad2/3 signaling.

Abstract Background Heart failure (HF) seriously threatens human health worldwide. However, the pathological mechanisms underlying HF are still not fully clear. Results In this study, we performed proteomics and transcriptomics analyses on samples from human HF patients and healthy donors to obtain an overview of the detailed changes in protein and mRNA expression that occur during HF. We found substantial differences in protein expression changes between the atria and ventricles of myocardial tissues from patients with HF. Interestingly, the metabolic state of ventricular tissues was altered in HF samples, and inflammatory pathways were activated in atrial tissues. Through analysis of differentially expressed genes in HF samples, we found that several glutathione S-transferase (GST) family members, especially glutathione S-transferase M2-2 (GSTM2), were decreased in all the ventricular samples. Furthermore, GSTM2 overexpression effectively relieved the progression of cardiac hypertrophy in a transverse aortic constriction (TAC) surgery-induced HF mouse model. Moreover, we found that GSTM2 attenuated DNA damage and extrachromosomal circular DNA (eccDNA) production in cardiomyocytes, thereby ameliorating interferon-I-stimulated macrophage inflammation in heart tissues. Conclusions Our study establishes a proteomic and transcriptomic map of human HF tissues, highlights the functional importance of GSTM2 in HF progression, and provides a novel therapeutic target for HF.

Abstract This trial compared eltrombopag (EPAG)+tacrolimus and EPAG monotherapy in patients with refractory/relapsed acquired aplastic anaemia (AA). Patients with refractory/relapsed AA were randomly assigned to receive either EPAG+tacrolimus or EPAG monotherapy at a ratio of 2:1. Patient response, safety, clonal evolution and survival were compared. In total, 114 patients were included in the analysis, with 76 patients receiving EPAG+tacrolimus and 38 receiving EPAG only. With a median follow-up of 18 (6–24) months, the overall response rate (ORR) for patients treated with EPAG+tacrolimus and EPAG alone was 38.2% vs. 31.6% (P = 0.490) at the 3rd month, 61.8% vs. 39.5% (P = 0.024) at the 6th month, 64.5% vs. 47.1% (P = 0.097) at the 12th month, and 60.5% vs. 34.2% (P = 0.008) at the last follow-up. The rate of each adverse event, overall survival curves (P = 0.635) and clonal evolution rate (P = 1.000) were comparable between the groups. A post hoc subgroup analysis showed that EPAG+tacrolimus could have advantage over EPAG monotherapy in terms of the ORR at the 6th month (P = 0.030)/last follow-up (P = 0.013) and the cumulative relapse-free survival (RFS) curves (P = 0.048) in patients

AIM: To investigate the effects of primary acquired nasolacrimal duct obstruction(PANDO)on the tear film and ocular surface using LipiView ocular surface interferometer and Keratograph 5M anterior segment analyzer.METHODS: A self-controlled clinical trials. A total of 40 patients diagnosed with unilateral PANDO for at least 6mo who were admitted to our department from September 2021 to March 2022 were enrolled in the study, and the healthy eyes of the patients were assessed as control group. The LipiView ocular surface interferometer and Keratograph 5M anterior segment analyzer were used to measure the changes in related parameters of the tear film and ocular surface in both eyes.RESULTS: The non-invasive tear meniscus height(NITMH), stimulated NITMH, loss rate of upper meibomian gland, nasal and temporal ciliary redness index, temporal conjunctival redness index of the affected eyes were higher than healthy eyes(P0.05).CONCLUSION: PANDO may lead to the aggravation of ocular surface inflammation and the loss of upper meibomian gland, and damage the ocular surface of patients. Attention should be paid to the early treatment of PANDO.

For jointed rock mass with anisotropy and discontinuity, the structure of the surrounding rock is constantly developing and changing during tunnel excavation. It is difficult to reasonably predict localized deformation of jointed rock mass by using the existing rock mechanics theory. In this paper, the failure characteristic of pre-holed jointed rock mass with three joint angles is experimentally investigated by adopting the digital image correlation and acoustic emission methods. To avoid the influence of measurement error on Digital Image Correlation (DIC) from discontinuous deformation, parametric studies and an optimized algorithm are also included in DIC tests. Results indicate that the perpendicular-jointed condition (0° joints) is the most dangerous situation because of its comparatively lower strength and brittle failure mode with a shift energy release. For rocks with different jointed angles, localized deformation emerges after the material enters the plasticity. Significant localization occurs after the failure with cracks surrounding the center hole and pre-existing joints.

Astragalin (AG), a typical flavonoid found in Thesium chinense Turcz (T. chinense), is abundant in various edible plants and possesses high nutritional value, as well as antioxidant and antibacterial effects. In this study, we initially predicted the mechanism of action of AG with two anti-aging and antioxidant-related protein targets (CD38 and IGFR) by molecular docking and molecular dynamics simulation techniques. Subsequently, we examined the anti-aging effects of AG in Caenorhabditis elegans (C. elegans), the antioxidant effects in zebrafish, and verified the related molecular mechanisms. In C. elegans, AG synergistically extended the lifespan of C. elegans by up-regulating the expression of daf-16 through inhibiting the expression of daf-2/IGFR and also activating the AMPK and MAPK pathways to up-regulate the expression of sir-2.1, sir-2.4, and skn-1. In oxidatively damaged zebrafish embryos, AG demonstrated a synergistic effect in augmenting the resistance of zebrafish embryos to oxidative stress by up-regulating the expression levels of SIRT1 and SIRT6 within the zebrafish embryos system via the suppression of CD38 enzymatic activity and then inhibiting the expression of IGFR through high levels of SIRT6. These findings highlight the antioxidant and anti-aging properties of AG and indicate its potential application as a supplementary ingredient in aquaculture for enhancing fish health and growth.

Abstract Objective To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK‐positive non‐small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK‐positive NSCLC. Methods The effectiveness of ALKis was evaluated by assessing progression‐free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model. Results Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%). Conclusion Alectinib was the first choice for patients with ALK‐positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long‐term follow‐up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.

Abstract Despite the growing importance of fluorinated organic compounds in pharmaceuticals, agrochemicals, and materials science, the introduction of fluorine into organic molecules is still a challenge, and no catalytic fluorocarbonylation of aryl/alkyl boron compounds has been reported to date. Herein, we present the development of palladium and phosphine synergistic redox catalysis of fluorocarbonylation of potassium aryl/alkyl trifluoroborate. Trifluoromethyl arylsulfonate (TFMS), which was used as a trifluoromethoxylation reagent, an easily handled and bench-scale reagent, has been employed as an efficient source of COF2. The reaction operates under mild conditions with good to excellent yields and tolerates diverse complex scaffolds, which allows efficient late-stage fluorocarbonylation of marked small-molecule drugs. Mechanistically, the key intermediates of labile Brettphos-Pd(II)-OCF3 complex and difluoro-Brettphos were synthesized and spectroscopically characterized, including X-ray crystallography. A detailed reaction mechanism involving the synergistic redox catalytic cycles Pd(II)/(0) and P(III)/(V) was proposed, and multifunction of phosphine ligand was identified based on 19F NMR, isotope tracing, synthetic, and computational studies.

Abstract. Background:. Reports on the prevalence of psoriatic arthritis (PsA) among Chinese patients with psoriasis are very limited. This study, conducted by rheumatologists, estimated the prevalence of PsA in a large number of Chinese patients with psoriasis. Methods:. Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited. All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA. All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists. Results:. A total of 2434 psoriasis patients, including 1561 males and 873 females, were enrolled. Both the questionnaire and rheumatologists' examinations were completed in the dermatology clinics. The results identified 252 patients with PsA, comprising 168 males and 84 females. The overall prevalence of PsA among psoriasis patients was 10.4% (95% confidence interval [95% CI], 9.1%–11.7%). By sex, the prevalence was 10.8% (95% CI, 9.2%–12.5%) for males and 9.6% (95% CI, 7.7%–11.9%) for females and there was no significant sex difference in the prevalence of PsA (P = 0.38). Of the 252 PsA patients, 125 (49.6%, 95% CI, 41.3%–59.1%) were newly diagnosed by rheumatologists. Consequently, the prevalence of undiagnosed PsA among psoriasis patients was 5.2% (95% CI, 4.4%–6.2%). Conclusion:. The prevalence of PsA in the Chinese population with psoriasis is about 10.4%, which is almost double that of previous reports in the Chinese population, but lower than that in Caucasians.

AimThe objective of this study is to investigate the relationship between visceral fat area (VFA) and diabetic retinopathy (DR) in the context of type 2 diabetes mellitus (T2DM) within Ningbo, China.MethodsThe data of a total of 3,707 subjects with T2DM treated at The First Affiliated Hospital of Ningbo University were enrolled. The existence and severity of diabetic retinopathy were assessed by employing the 45° two-field stereoscopic digital photography. Subjects were categorized into four distinct groups: those without DR (NDR), individuals with mild non-proliferative DR (mild NPDR), people with moderate non-proliferative DR (moderate NPDR), and those suffering from vision-threatening DR (VTDR). Bio-electrical impedance was employed to estimate the Visceral fat area (VFA). Multinomial logistic regression models were utilized to evaluate the association between VFA and DR.ResultsThe mean VFA in patients without diabetic retinopathy (NDR) was notably lower compared to that of patients with diabetic retinopathy (DR) (85.21 ± 37.78 vs. 97.37 ± 44.58 cm2, p

Objectives. To explore the efficacy and the mechanism of the umbilical cord-derived cells combined with cyclosporine A (CsA) in treating aplastic anemia (AA) in mice. Methods. Immune-mediated AA model mice were treated with CsA + UC mesenchymal stem cells (UC-MSC), CsA + umbilical cord blood regulatory T cells (UCB-Treg), UC-MSC, UCB-Treg, CsA alone, or blank control, respectively (n = 9 mice/group). CsA and the cell infusion was administered on d0. Routine peripheral blood testing was performed once weekly; bone marrow colony culture, bone marrow cell flow cytometry, peripheral blood T cell subsets, and serum inflammatory cytokines tests were performed on d14. Transcriptome sequencing was performed for cells from CsA + UC-MSC, CsA + UCB-Treg, and CsA groups to detect the possible related genes. Gene function cluster and signal pathway enrichment analysis were also performed. Results. Blank control mice died due to pancytopenia within 21 days, whereas mice in other groups survived for >28 days. On d14, the CsA + UC-MSC and CsA + UCB-Treg groups had higher white blood cell (WBC) counts than the other groups (p

BackgroundMultiple clinical studies have found a significant correlation between elevated galectin-3 (Gal-3) in circulation and the diagnosis and severity of peripheral arterial disease (PAD). The current study used the Mendelian randomization (MR) technique to evaluate the possible causal relationship between Gal-3 and PAD.MethodsGenome-wide association study (GWAS) data of Gal-3 and PAD were obtained through the MR-Base platform. Then, using Gal-3 as the exposure and PAD as the outcome, a two-sample MR analysis was performed utilizing several regression techniques, including MR-Egger regression, inverse variance weighted (IVW), weighted median, and weighted mode.ResultsSix single-nucleotide polymorphisms (SNPs) were identified and designated as instrumental variables (IVs) that exhibited significant correlations with Gal-3 (linkage disequilibrium r2

Summary: CircRNAs are implicated in colorectal cancer (CRC) development and progression. Protein O-fucosyltransferase 1 (POFUT1) plays an oncogenic role via activating Notch1 signaling in CRC. However, the roles of circPOFUT1, which is originated from POFUT1, have not been investigated. Our study showed circPOFUT1 was highly expressed in CRC tissues and cells. CircPOFUT1 enhanced the proliferation, migration and invasion of CRC cells, and promoted tumor growth and liver metastasis in vivo. It also reinforced stemness and chemoresistance of CRC cells. Mechanistically, circPOFUT1 regulated the function of E2F7 via sponging miR-653-5p, thereby transcriptionally inducing WDR66 expression and further promoting metastasis in CRC. On the other hand, circPOFUT1 promoted stemness and chemoresistance of CRC cells via stabilizing BMI1 in an IGF2BP1-dependent manner. In conclusion, circPOFUT1 fosters CRC metastasis and chemoresistance via decoying miR-653-5p/E2F7/WDR66 axis and stabilizing BMI1.

Microplastics (MPs) pollution is becoming an emerging global stressor for soil ecosystems. However, studies on the impacts of biodegradable MPs on soil C sequestration have been mainly based on bulk C quantity, without considering the storage form of C, its persistency and N demand. To address this issue, the common poly (butylene adipate-co-terephthalate) (PBAT) was used as the model, and its effects on soil functional organic pools, including mineral-associated (MAOM), particulate (POM) and dissolved organic matter (DOM), were investigated from the novel coupled perspective of C and N stocks. After adding PBAT-MPs, the contents of soil POM-C, DOM-C, and MAOM-C were increased by 546.9 %–697.8 %, 54.2 %–90.3 %, and 13.7 %–18.9 %, respectively. Accordingly, the total C increased by 116.0 %–191.1 %. Structural equation modeling showed that soil C pools were regulated by PBAT input and microbial metabolism associated with C and N enzymes. Specifically, PBAT debris could be disguised as soil C to promote POM formation, which was the main pathway for C accumulation. Inversely, the MAOM-C and DOM-C formation was attributed to the PBAT microbial product and the selective consumption in DOM-N. Random forest model confirmed that N-activated (e.g., Nitrospirae) and PBAT-degrading bacteria (e.g., Gemmatinadetes) were important taxa for soil C accumulation, and the key enzymes were rhizopus oryzae lipas, invertase, and ammonia monooxygenase. The soil N accumulation was mainly related to the oligotrophic taxa (e.g., Chloroflexi and Ascomycota) associated with aggregate formation, decreasing the DOM-N by 46.9 %–84.3 %, but did not significantly change the total N storage and other N pools. Collectively, the findings highlight the urgency to control the nutrient imbalance risk of labile N loss and recalcitrant C enrichment in POM to avoid the depressed turnover rate of organic matter in MPs-polluted soil.

AbstractObjective Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by chronic complement-mediated hemolysis. The concentrated outbreak of coronavirus disease 2019 (COVID-19) in China after 6 December 2022, provided an opportunity to observe the disease course of PNH during an active Omicron infection epidemic.Patients and method Patients diagnosed with PNH at Peking Union Medical College Hospital (PUMCH) before 6 December 2022, were followed up until 10 April 2023. Clinical data related to coronavirus infection and hemolysis were recorded. Factors influencing the infection and severity rate of Omicron, as well as hemolysis provocation, were analyzed.Results In total, 131 patients with PNH were included in this retrospective analysis; 87.8% were infected with Omicron. Among them, 15.7% met the criteria for severity, and 1 patient died (0.87%). No protective factors were identified against Omicron infections. However, patients with severe Omicron infection (n = 18) had a lower vaccination rate than those with non-severe infection (n = 97; p = 0.015). Among those infected (n = 115) with Omicron, there was a significant increase in lactate dehydrogenase (LDH) levels compared with those in the uninfected group (n = 16, p = 0.000). Patients with severe infections (n = 18) had even higher LDH increase rates than those without severe infections (n = 97; p = 0.002). 10 (37.0%) patients treated with complement inhibitors developed breakthrough hemolysis (BTH). Patients treated with complement inhibitors (n = 27) exhibited less severe hemolysis than treatment-naïve patients (n = 104; p = 0.003).Conclusions Omicron infection exacerbates hemolytic attacks in patients with PNH. Vaccination helps mitigate the severity of Omicron infection, and using complement inhibitors reduces hemolysis exacerbation.

Abstract Under diabetic conditions, blood glucose fluctuations and exacerbated immunopathological inflammatory environments pose significant challenges to periosteal regenerative repair strategies. Responsive immune regulation in damaged tissues is critical for the immune microenvironment, osteogenesis, and angiogenesis stabilization. Considering the high‐glucose microenvironment of such acute injury sites, a functional glucose‐responsive immunomodulation‐assisted periosteal regeneration composite material—PLA（Polylactic Acid）/COLI(Collagen I）/Lipo(Liposome）‐APY29 (PCLA)—is constructed. Aside from stimulating osteogenic differentiation, owing to the presence of surface self‐assembled type I collagen in the scaffolds, PCLA can directly respond to focal area high‐glucose microenvironments. The PCLA scaffolds trigger the release of APY29‐loaded liposomes, shifting the macrophages toward the M2 phenotype, inhibiting the release of inflammatory cytokines, improving the bone immune microenvironment, and promoting osteogenic differentiation and angiogenesis. Bioinformatics analyses show that PCLA enhances bone repair by inhibiting the inflammatory signal pathway regulating the polarization direction and promoting osteogenic and angiogenic gene expression. In the calvarial periosteal defect model of diabetic rats, PCLA scaffolds induce M2 macrophage polarization and improve the inflammatory microenvironment, significantly accelerating periosteal repair. Overall, the PCLA scaffold material regulates immunity in fluctuating high‐glucose inflammatory microenvironments, achieves relatively stable and favorable osteogenic microenvironments, and facilitates the effective design of functionalized biomaterials for bone regeneration therapy in patients with diabetes.

AbstractBackground Some patients with warm autoimmune haemolytic anaemia (wAIHA) or Evans syndrome (ES) have no response to glucocorticoid or relapse. Recent studies found that sirolimus was effective in autoimmune cytopenia with a low relapse rate.Methods Data from patients with refractory/relapsed wAIHA and ES in Peking Union Medical College Hospital from July 2016 to May 2022 who had been treated with sirolimus for at least 6 months and followed up for at least 12 months were collected retrospectively. Baseline and follow-up clinical data were recorded and the rate of complete response (CR), partial response (PR) at different time points, adverse events, relapse, outcomes, and factors that may affect the efficacy and relapse were analyzed.Results There were 44 patients enrolled, with 9 (20.5%) males and a median age of 44 (range: 18–86) years. 37 (84.1%) patients were diagnosed as wAIHA, and 7 (15.9%) as ES. Patients were treated with sirolimus for a median of 23 (range: 6–80) months and followed up for a median of 25 (range: 12–80) months. 35 (79.5%) patients responded to sirolimus, and 25 (56.8%) patients achieved an optimal response of CR. Mucositis (11.4%), infection (9.1%), and alanine aminotransferase elevation (9.1%) were the most common adverse events. 5/35 patients (14.3%) relapsed at a median of 19 (range: 15–50) months. Patients with a higher sirolimus plasma trough concentration had a higher overall response (OR) and CR rate (p = 0.009, 0.011, respectively). At the time of enrolment, patients were divided into two subgroups that relapsed or refractory to glucocorticoid, and the former had poorer relapse-free survival (p = 0.032) than the other group.Conclusion Sirolimus is effective for patients with primary refractory/relapsed wAIHA and ES, with a low relapse rate and mild side effects. Patients with a higher sirolimus plasma trough concentration had a higher OR and CR rate, and patients who relapsed to glucocorticoid treatment had poorer relapse-free survival than those who were refractory.

AbstractIntroduction The therapeutic options for thrombocytopenia in non-severe aplastic anaemia (NSAA) are limited. Avatrombopag (AVA) is prescribed for thrombocytopenic diseases but not for NSAA.Methods Herein, we conducted a phase 2, non-randomized, single-arm trial to explore the efficacy and safety of AVA in refractory/relapsed/intolerant NSAA. AVA dose was initiated at 20 mg/d and titrated to a maximum of 60 mg/d. The primary endpoint was the haematological response at 3 months.Results Twenty-five patients were analyzed. The overall response rate (ORR) at 3 months was 56% (14/25), with 12% (3/25) achieving a complete response (CR). At a median follow-up of 7 (3–10) months, the OR and CR rates were 52% and 20%, respectively. Responders had a shorter duration of diagnosis of AVA administration than non-responders (10 (6–80) vs 37 (6–480) months, p = 0.027) and belonged to the relapsed/intolerant NSAA type (71% vs 27%, p = 0.047); 44% (8/18) patients previously treated with eltrombopag before enrollment responded at 3 months, with an average prior eltrombopag dose of median 72.5 (50–100) mg/d and an average AVA dose for a response of median 43.5 (20–60) mg/d. 3-month ORR had no significant correlation with eltrombopag exposure (p = 0.09), prior eltrombopag length (R2=0.11), or cumulative eltrombopag dose (R2=0.30). Only one patient relapsed after stopping AVA for 1 month. No serious AVA-related side effects or clone evolution were detected.Conclusion AVA is effective and well-tolerated in NSAA patients who are refractory, relapsed, or intolerant to CsA/tacrolimus ± eltrombopag. Earlier treatment and relapsed/intolerant AA may show a better short-term response rate. More studies are needed to define the optimal dose and the long-term efficacy (NCT04728789).

AbstractA numerical hydro-mechanical damage model is proposed in this paper to investigate the stability and failure characteristics of artificial dam in coal mine underground water reservoir. The localized damage model for the coupled pore pressure and rock failure of a stressed rock is developed, and a local damage constitutive law is employed to describe its stress-strain relationship and fracture propagation. The Mohr-Coulomb criterion and maximum tension criterion are used to Judge the damage and failure of rock. Experimental data for rock samples are used to validate the proposed numerical model, and it accurately replicates the stress-strain curves and failure pattern compared with the experimental results. We then explore the influence of water pressures, cutting depth and dam strengths of artificial dam in coal mine underground water reservoir, and the simulation results show that the dam strength is the main factor affecting the strength of artificial dam. The modeling described herein is expected to assist in the management and optimization of underground water reservoirs.

The evolution of overburden movement is the basic reason for the occurrence of underground dynamic disasters. It is important to know the law of overburden movement under specific stratum conditions and the mechanism of its evolution and disasters for the prevention and control of dynamic disasters. Based on 3301 panel as engineering background, this paper studies the overall failure morphology and combined migration evolution law of bedrock, surface soil layer and subsidence basin under different thickness combinations of topsoil-bedrock, and reveals the migration evolution law of overburden structure under two typical topsoil-bedrock combinations, as well as the mechanism and mechanism of mining stress transfer. The quantitative expression of bearing pressure under the condition of thick topsoil and thin bedrock is deduced, and the macro criterion for disasters caused by high stress mutation is presented. The rationality of the model is verified by engineering. The main conclusions are as follows: ① After coal mining, the weak bedrock shows asymmetric “trapezoid-like” failure pattern, the huge thick and loose surface soil presents “inclined funnel” failure pattern, and the surface soil migration evolution has the characteristics of fast response, wide migration range and large subsidence factor; ② The movement and evolution rules of the surface-bedrock double-layer media under different thickness combinations are quite different. Under the condition of thick surface layer and thin bedrock (type I), the bedrock plastic fracture occurs from bottom to top, the fragmentation of rock mass is small, and it is difficult to form a stable structure; under the condition of thick topsoil thick bedrock (type II), the bedrock is gradually transformed from plastic fracture to block fracture, the breaking step is gradually increasing, the key layer effect is gradually highlighted, the bearing capacity of the structure formed after breaking is increased, which can prevent the movement and subsidence of the overlying topsoil layer, and the subsidence of the surface is reduced to a certain extent; ③ Under the condition of deep and thick topsoil and thin bedrock, a large range of topsoil layer in front of the panel moves to the mined-out area, and the load concentrates on the bedrock above the panel and the coal body ahead. Due to the characteristics of weak bedrock, small size of broken rock blocks and the inability to form large-scale suspended roof, the load is restricted to be transferred farther ahead of the coal wall, resulting in the characteristics of large peak stress, small influence range and large fluctuation; ④ An estimation model of support pressure considering large-scale movement of deep topsoil and plastic fracture of bedrock is established. The calculation method of support pressure is obtained. Taking 3301 panel body parameter as an example, the influence range of support pressure is estimated to be 72 m, the peak value is 44.2 MPa, and the peak stress is 23 m from the coal wall, which has certain impact risk. The ground subsidence characteristics and mining stress monitoring results verify the scientific results of theoretical analysis and similar simulation.

Abstract Background Growing evidence suggests that various reproductive factors, including early menarche, early menopause, and age at first birth, may increase the risk of developing cardiovascular disease (CVD) later in life. However, the associations between reproductive factors and CVDs are inconsistent and controversial. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential links between age at first sex (AFS) and age at first birth (AFB) and several CVDs. Methods We obtained summary statistics for exposure from the largest genome-wide association studies of AFS and AFB. To serve as instrumental variables, we selected 259 SNPs associated with AFS and 81 SNPs associated with AFB at the genome-wide significance level. We employed a random-effects inverse-variance weighted method to pool estimates, and conducted multivariable MR analysis to determine the direct association between AFS and AFB with CVDs, while accounting for the effects of confounders. Results The genetic liability to later AFS was associated with decreased risks of heart failure (odd ratio [OR] 0.700; 95% confidence interval [CI] 0.639–0.767; p = 2.23 × 10−14), coronary artery disease (OR 0.728; 95% CI 0.657–0.808; p = 1.82 × 10−9), myocardial infarction (OR 0.731; 95% CI 0.657–0.813; p = 8.33 × 10−9), stroke (OR 0.747; 95% CI 0.684–0.816; p = 6.89 × 10−11), and atrial fibrillation (OR 0.871; 95% CI 0.806–0.941; p = 4.48 × 10−4). The genetic liability to later AFB was also associated with decreased risks of CVDs, including myocardial infarction (OR 0.895; 95% CI 0.852–0.940; p = 8.66 × 10−6), coronary heart disease (OR 0.901; 95% CI 0.860–0.943; p = 9.02 × 10−6), heart failure (OR 0.925; 95% CI 0.891–0.961; p = 5.32 × 10−5), and atrial fibrillation (OR 0.944; 95% CI 0.911–0.978; p = 0.001). However, no association was found between AFB and stroke. The associations remained independent from the effects of AFS and AFB on potential confounders, including smoking, alcohol intake, body mass index, and depression. Mediation analysis suggested that education attainment partly mediates the link from AFS and AFB to CVD outcomes. Conclusion Our results observed a causal relationship between later AFS, AFB and lower CVDs risk; it emphasizes the importance of providing sex education since early sex and birth may have undesirable effects. Cardiovascular risk stratification that considers reproductive factors may help address CVD risk.

Seismic exploration is a key method for the study of underground structures. Active seismic surveys can acquire high signal-to-noise ratio reflection data; however, the operation of active seismic surveys is complicated, and the exploration cost is high. Passive seismic exploration is another type of seismic exploration, which requires no active human build source but utilizes the natural noise recorded by seismograph stations or geophones. As a low-cost and environmentally friendly method, passive seismic reflection exploration can be used to create higher resolution seismic profiles than the surface wave method and plays an increasingly important role in underground mineral exploration, dynamic monitoring of carbon storage, and urban underground structure detection. However, passive source reflection imaging technology faces several challenges. For example, because ambient noise is mainly controlled by surface wave energy, the reflected body wave signal can be weak and difficult to extract. Actual underground sources are limited in number and are unevenly distributed, which leads to artifacts in the virtual shot gathers reconstructed by seismic interference. There are also constraints of massive data computation and storage for long-term observation by a large number of geophones. With the rapid development of portable node geophones and high-performance computing, passive seismic reflection exploration has achieved considerable progress in both method research and practical applications in recent years. This paper briefly reviews the history of seismic interferometry and the construction of virtual shot gathers using various seismic interferometry methods and then introduces in detail how the reflection signals from ambient noise records dominated by surface waves are identified and extracted. We discuss the identification and extraction of weak body wave reflection signals based on various characteristics of surface and body waves, such as differences in signal-to-noise ratio, velocity, and azimuth angle. We then focus on the processing of passive source reflection data, including the beginning of raw data preprocessing, virtual shot gather static correction, coherent noise suppression, multiple suppression, velocity analysis, and direct migration imaging. We also introduce examples of passive seismic reflection applications, including CO2 storage site monitoring, metal mining, and coal mine underground structure research. Finally, we give an outlook for research prospects in passive seismic reflection exploration.

Aim: C1q/TNF-related protein 6 (CTRP6) is a novel adipokine involved in insulin resistance. Thus, we aim to investigate the expression profile of CTRP6 in the plasma, adipose tissue and placenta of GDM patients and mice. Methods: Chinese Han pregnant women (GDM n = 9, control n = 10) with a scheduled caesarean section delivery were recruited. A number of high-fat diet (HFD) induced-pregnancy C57BL/6 mice were chosen as an animal model of GDM. Circulating levels of CTRP6 and adiponectin were examined by ELISA. CTRP6 expression in adipose tissue and placenta were detected by real-time qPCR and WB. Result: Plasma CTRP6 levels were decreased during the first and second trimesters in mice, as well as the second and third trimesters in patients, while they were increased at delivery in GDM patients and mice. Plasma CTRP6 levels were significantly correlated with WBC, systolic pressure, diastolic pressure and fasting blood glucose. Moreover, CTRP6 mRNA expression in the subcutaneous (sWAT) and omental white adipose tissue (oWAT), as well as in the placenta, was significantly higher in GDM human patients at cesarean delivery. Furthermore, the mRNA expression of Ctrp6 was increased in the sWAT and visceral WAT (vWAT), whilst decreased in the interscapular brown adipose tissue (iBAT), of GDM mice at cesarean delivery. Conclusion: Dynamically expressed CTRP6 may be served as a candidate target for treatment of GDM.

Accurately characterizing the mechanical behavior and fracture mechanisms of rock containing holes under dynamic loads is essential for ensuring the stability of underground rock structures. In this study, to enhance the understanding of the fracture processes in rock specimens with cavities subjected to dynamic impacts, experimental and numerical studies focusing on the influence of borehole geometry and strain rate are conducted. The results reveal that the strain rate affects the specimens’ dynamic mechanical strength and peak strain. However, the degree of such influence diminishes as the borehole diameter increases in specimens containing two holes. Fractures that lead to failure are primarily initiated at the axial and radial edges of the holes, the specimen extremities, and around the rock bridges in specimens with dual cavities, indicating significant stress concentration zones within the stress field distribution for specimens with a single hole. Further analysis using displacement field diagrams confirms that shear-induced fractures are the predominant cause of failure across all specimens. These findings provide critical insights for developing borehole pressure relief technology to protect against the risks of deep dynamic impacts.

Abstract Patients with metabolic syndrome (MetS) undergoing surgery are at high risk of developing peritoneal adhesions and other severe postoperative complications. However, the single shielding function and absence of physiological activity render conventional methods less useful in preventing adhesions in patients with MetS. To address this challenge, a convenient method is introduced for developing a novel tissue‐adhesive hydrogel called oxidized dextran–metformin (ODE–ME) via Schiff base linkages. This injectable ODE–ME hydrogel exhibits excellent tissue‐adhesive properties and various physiological functions, particularly enhanced antibacterial effects. Furthermore, in vivo experiments demonstrate that the hydrogel can effectively alleviate hyperglycemia, reduce excessive inflammation, and improve fibrinolytic activity in MetS mice, thereby preventing adhesions and promoting incisional healing. The hydrogel concurrently isolates injured tissues and lowers the blood glucose levels immediately after surgery in mice. Therefore, the ODE–ME hydrogel functions as a multifunctional barrier material and has potential for preventing postoperative peritoneal adhesions in patients with MetS in clinical settings.

Accurate recognition of pest categories is crucial for effective pest control. Due to issues such as the large variation in pest appearance, low data quality, and complex real-world environments, pest recognition poses challenges in practical applications. At present, many models have made great efforts on the real scene dataset IP102, but the highest recognition accuracy is only 75%. To improve pest recognition in practice, this paper proposes a multi-image fusion recognition method. Considering that farmers have easy access to data, the method performs fusion recognition on multiple images of the same pest instead of the conventional single image. Specifically, the method first uses convolutional neural network (CNN) to extract feature maps from these images. Then, an effective feature localization module (EFLM) captures the feature maps outputted by all blocks of the last convolutional stage of the CNN, marks the regions with large activation values as pest locations, and then integrates and crops them to obtain the localized features. Next, the adaptive filtering fusion module (AFFM) learns gate masks and selection masks for these features to eliminate interference from useless information, and uses the attention mechanism to select beneficial features for fusion. Finally, the classifier categorizes the fused features and the soft voting (SV) module integrates these results to obtain the final pest category. The principle of the model is activation value localization, feature filtering and fusion, and voting integration. The experimental results indicate that the proposed method can train high-performance feature extractors and classifiers, achieving recognition accuracy of 73.9%, 99.8%, and 99.7% on IP102, D0, and ETP, respectively, surpassing most single models. The results also show that thanks to the positive role of each module, the accuracy of multi-image fusion recognition reaches the state-of-the-art level of 96.1%, 100%, and 100% on IP102, D0, and ETP using 5, 2, and 2 images, respectively, which meets the requirements of practical applications. Additionally, we have developed a web application that applies our research findings in practice to assist farmers in reliable pest identification and drive the advancement of smart agriculture.

Plant phenology is essential for projecting changes in the ecosystem including growing seasons, plant communities and carbon storage. However, it is still unclear how the start of growing season (SOS) of tropical plants responds to climate change. This study examined SOS of natural rubber (NR) which grows in tropical areas using long-term satellite solar-induced chlorophyll fluorescence (SIF) data and nineteen monthly climate factors. “Phenofit” (a R package), Pearson correlation coefficient, random forest and structural equation modeling were used to extract SOS and find the relationship between SOS and climate factors at landscape scale. SOS mainly occurred during 53.3–69.9 day of the year, with a slight yet non-significant delaying trend (about 0.2 d/y) across more than 76% of the study area over 2001–2021. The sunshine duration (Sund), ground temperature at 20 cm depth and evaporation in June last year (pre-June) were the three climate drivers with substantial effects on SOS. Sund in pre-June played the most crucial role (r > 0.65, p