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Abstract Neuroimaging studies have revealed that the mechanisms of auditory hallucinations are related to morphological changes in multiple cortical regions, but studies on brain network properties are lacking. This study aims to construct intra-individual structural covariance networks and reveal network changes related to auditory hallucinations. T1-weighted MRI images were acquired from 90 schizophrenia patients with persistent auditory hallucinations (pAH group), 55 schizophrenia patients without auditory hallucinations (non-pAH group), and 83 healthy controls (HC group). Networks were constructed using the voxel-based gray matter volume and the intra-individual structural covariance was based on the similarity between the morphological variations of any two regions. One-way ANCOVA was employed to compare global and local network metrics among the three groups, and edge analysis was conducted via network-based statistics. In the pAH group, Pearson correlation analysis between network metrics and clinical symptoms was conducted. Compared with the HC group, both the pAH group (p = 0.01) and the non-pAH group (p = 3.56 × 10−4) had lower nodal efficiency of the left medial superior frontal gyrus. Compared to the non-pAH group and HC group, the pAH group presented lower nodal efficiency of the temporal pole of the left superior temporal gyrus (p = 1.09 × 10−3; p = 7.67 × 10−4) and right insula (p = 0.02; p = 8.99 × 10−6), and lower degree centrality of the right insula (p = 0.04; p = 1.65 × 10−5). The pAH group had a subnetwork with reduced structural covariance centered by the left temporal pole of the superior temporal gyrus. In the pAH group, the normalized clustering coefficient (r = −0.36, p = 8.45 × 10−3) and small-worldness (r = −0.35, p = 9.89 × 10−3) were negatively correlated with the PANSS positive scale score. This study revealed network changes in schizophrenia patients with persistent auditory hallucinations, and provided new insights into the structural architecture related to auditory hallucinations at the network level.

Abstract Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex and the crystal structure of the isolated NTNH protein. Unexpectedly, the BoNT/X complex is stable and protease-resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents very weak ganglioside binding and exposed hydrophobic surfaces.

Abstract Background This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. Methods Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. Results A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80–4.94) ng/mL and 1.64 (1.47–1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. Conclusion ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.

With inspiration from natural systems, various soft actuators and robots have been explored in recent years with versatile applications in biomedical and engineering fields. Soft active materials with rich stimulus-responsive characteristics have been an ideal candidate to devise these soft machines by using different manufacturing technologies. Among these technologies, three-dimensional (3D) printing shows advantages in fabricating constructs with multiple materials and sophisticated architectures. In this Review, we aim to provide an overview of recent progress on 3D printing of soft materials, robotics performances, and representative applications. Typical 3D printing techniques are briefly introduced, followed by state-of-the-art advances in 3D printing of hydrogels, shape memory polymers, liquid crystalline elastomers, and their hybrids as soft actuators and robots. From the perspective of material properties, the commonly used printing techniques and action-generation principles for typical printed constructs are discussed. Actuation performances, locomotive behaviors, and representative applications of printed soft materials are summarized. The relationship between printing structures and action performances of soft actuators and robots is also briefly discussed. Finally, the advantages and limitations of each soft material are compared, and the remaining challenges and future directions in this field are prospected.

Abstract Background The Quick Delay Questionnaire (QDQ) is a short questionnaire designed to assess delay-related difficulties in adults. This study aimed to examine the reliability and validity of the Chinese version of the QDQ (C-QDQ) in Chinese adults, and explore the ecological characteristics of delay-related impulsivity in Chinese adults with attention-deficit/hyperactivity disorder (ADHD). Methods Data was collected from 302 adults, including ADHD (n = 209) and healthy controls (HCs) (n = 93). All participants completed the C-QDQ. The convergent validity, internal consistency, retest reliability and confirmatory factor analysis (CFA) of the C-QDQ were analyzed. The correlations between C-QDQ and two laboratory measures of delay-related difficulties and Barratt Impulsiveness Scale-11 (BIS-11), the comparison of C-QDQ scores between ADHD subgroups and HCs were also analyzed. Results The Cronbach’s α of C-QDQ was between 0.83 and 0.89. The intraclass correlation coefficient of C-QDQ was between 0.80 and 0.83. The results of CFA of C-QDQ favoured the original two-factor model (delay aversion and delay discounting). Significant positive associations were found between C-QDQ scores and BIS-11 total score and performance on the laboratory measure of delay-related difficulties. Participants with ADHD had higher C-QDQ scores than HCs, and female ADHD reported higher scores on delay discounting subscale than male. ADHD-combined type (ADHD-C) reported higher scores on delay aversion subscale than ADHD-inattention type (ADHD-I). Conclusion The C-QDQ is a valid and reliable tool to measure delay-related responses that appears to have clinical utility. It can present the delay-related impulsivity of patients with ADHD. Compared to HCs, the level of reward-delay impulsivity was higher in ADHD.

Abstract Clostridioides difficile is a leading cause of healthcare‐associated infections, causing billions of economic losses every year. Its symptoms range from mild diarrhea to life‐threatening damage to the colon. Transmission and recurrence of C. difficile infection (CDI) are mediated by the metabolically dormant spores, while the virulence of C. difficile is mainly due to the two large clostridial toxins, TcdA and TcdB. Producing toxins or forming spores are two different strategies for C. difficile to cope with harsh environmental conditions. It is of great significance to understand the molecular mechanisms for C. difficile to skew to either of the cellular processes. Here, we summarize the current understanding of the regulation and connections between toxin production and sporulation in C. difficile and further discuss the potential solutions for yet‐to‐be‐answered questions.

Abstract Background The long-term effectiveness of cognitive behavioural therapy (CBT) in medicated attention-deficit/hyperactivity disorder (ADHD) adults with residual symptoms needs to be verified across multiple dimensions, especially with respect to maladaptive cognitions and psychological quality of life (QoL). An exploration of the mechanisms underlying the additive benefits of CBT on QoL in clinical samples may be helpful for a better understanding of the CBT conceptual model and how CBT works in medicated ADHD. Methods We conducted a secondary analysis of a randomised controlled trial including 98 medicated ADHD adults with residual symptoms who were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M)-only group. Outcomes included ADHD-core symptoms (ADHD Rating Scale), depression symptoms (Self-rating Depression Scale), maladaptive cognitions (Automatic Thoughts Questionnaire and Dysfunctional Attitude Scale), and psychological QoL (World Health Organization Quality of Life-Brief Version-psychological domain). Mixed linear models (MLMs) were used to analyse the long-term effectiveness at one-year follow-up, and structural equation modeling (SEM) was performed to explore the potential mechanisms of CBT on psychological QoL. Results ADHD patients in the CBT + M group outperformed the M-only group in reduction of ADHD core symptoms (d = 0.491), depression symptoms (d = 0.570), a trend of reduction of maladaptive cognitions (d = 0.387 and 0.395, respectively), and improvement of psychological QoL (d = − 0.433). The changes in above dimensions correlated with each other (r = 0.201 ~ 0.636). The influence of CBT on QoL was mediated through the following four pathways: 1) changes in ADHD core symptoms; 2) changes in depressive symptoms; 3) changes in depressive symptoms and then maladaptive cognitions; and 4) changes firstly in depressive symptoms, maladaptive cognitions, and then ADHD core symptoms. Conclusions The long-term effectiveness of CBT in medicated ADHD adults with residual symptoms was further confirmed. The CBT conceptual model was verified in clinical samples, which would be helpful for a deeper understanding of how CBT works for a better psychological QoL outcome. Trial registration ChiCTR1900021705 (2019-03-05).

Airport tower control plays an instrumental role in ensuring airport safety. However, obtaining objective, quantitative safety evaluations is challenging due to the unavailability of pertinent human operation data. This study introduces a probabilistic model that combines aircraft dynamics and the peak-over-threshold (POT) approach to assess the safety performance of airport controllers. We applied the POT approach to model reaction times extracted from a radiotelephony dataset via a voice event detection algorithm. The model couples the risks of tower control and aircraft operation to analyze the influence of human factors. Using data from radiotelephony communications and the Base of Aircraft Data (BADA) database, we compared risk levels across scenarios. Our findings revealed heightened airport control risks under low demand (0.374) compared to typical conditions (0.197). Furthermore, the risks associated with coupling under low demand exceeded those under typical demand, with the final approach stage presenting the highest risk (4.929×10−7). Our model underscores the significance of human factors and the implications of mental disconnects between pilots and controllers for safety risks. Collectively, these consistent findings affirm the reliability of our probabilistic model as an evaluative tool for evaluating the safety performance of airport tower controllers. The results also illuminate the path toward quantitative real-time safety evaluations for airport controllers within the industry. We recommend that airport regulators focus on the performance of airport controllers, particularly during the final approach stage.

In order to avoid cancer, it is imperative that microcalcification in the breast be found. It is sufficiently small to be difficult to discern with the unassisted eye. Computer-based detection output is modest and tends to stay concealed from the radiologist doing the examination, which might help the radiologist increase diagnostic accuracy. According to this study, the best Wiener Linear Time Invariant Filter method with Tophat Transformation (LFWT) can identify microcalcification in the breast with an accuracy rate of 99.5%. In this work, we focused on the identification of microcalcifications in images, an essential initial step towards precisely identifying all the indicators in a mammography-based early breast cancer diagnosis. To make the cancer region visible and prominent, the Wiener and CLAHE filters are used. Tophat morphological operators were applied to mask detection, and edges were extracted. The analytical performance of the proposed model for microcalcification identification in mammograms was evaluated and compared with other approaches using Mammographic Image Analysis Society (MIAS) and Mini-Mammographic imaging datasets. Additionally, three techniques- The Local Contrast Method (LCM), the Local Relative Contrast Measure Method (LRCMM), and the High-Boost-Based Multiscale Local Contrast Measure (HBBMLCM) are used to identify microcalcification linked to cancer on mammography images. Performance Evaluation of the Proposed Model: the LFWT methodology had the best level of efficacy in detecting microcalcification linked to breast cancer. The suggested LFWT technique finds each and every tiny point on the MIAS dataset’s mammography.

Federated learning (FL) with over-the-air computation can efficiently utilize the communication bandwidth but is susceptible to analog aggregation error. Excluding those devices with weak channel conditions can reduce the aggregation error, but it also limits the amount of local training data for FL, which can reduce the training convergence rate. In this work, we jointly design uplink receiver beamforming and device selection for over-the-air FL over time-varying wireless channels to maximize the training convergence rate. We reformulate this stochastic optimization problem into a mixed-integer program using an upper bound on the global training loss over communication rounds. We then propose a Greedy Spatial Device Selection (GSDS) approach, which uses a sequential procedure to select devices based on a measure capturing both the channel strength and the channel correlation to the selected devices. We show that given the selected devices, the receiver beamforming optimization problem is equivalent to downlink single-group multicast beamforming. To reduce the computational complexity, we also propose an Alternating-optimization-based Device Selection and Beamforming (ADSBF) approach, which solves the receiver beamforming and device selection subproblems alternatingly. In particular, despite the device selection being an integer problem, we are able to develop an efficient algorithm to find its optimal solution. Simulation results with real-world image classification demonstrate that our proposed methods achieve faster convergence with significantly lower computational complexity than existing alternatives. Furthermore, although ADSBF shows marginally inferior performance to GSDS, it offers the advantage of lower computational complexity when the number of devices is large.

Abstract Molecular-genetic imaging has greatly advanced clinical diagnosis and prognosis monitoring. However, the specific visualization of intracellular proteins such as estrogen receptor (ER) and progesterone receptor (PR) remains an elusive goal. Here, we highlight a novel method for selectively detecting ER/PR positive tumors using genetically engineered responsive elements. Our study demonstrates that the double responsive elements of ER/PR exhibit the most sensitivity to the steroid receptors in breast cancers. By utilizing a cationic polymer vector, we constructed a responsive element-fluorescence protein system that can selectively image ER/PR positive breast cancers in murine models under a near-infrared laser. This non-invasive imaging achieved high-resolution detection without death or serious anaphylactic activity in the animals. Our findings suggest that the reporter system consisting of steroid receptor response elements and near-infrared proteins provides a practical system for identifying biomarkers and advancing cancer diagnosis and therapy.

Abstract Background GT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to determine the recommended phase 2 dose (RP2D) of GT90001 plus nivolumab, and assess the safety and anti-tumor activity in patients with advanced HCC. Methods Patients with advanced HCC were recruited from 3 centers. Eligible patients in the dose de-escalation stage received the GT90001 on day 1 of a 14-day cycle in a rolling-six design with a fixed dose of nivolumab (3.0 mg/kg). Patients in dose-expansion stage received the RP2D of GT90001 plus nivolumab. Primary endpoint was safety. Key secondary endpoint was objective response rate (ORR) as per RECIST 1.1. Results Between July 9, 2019, and August 8, 2022, 20 patients were treated (6 in phase 1b; 14 in phase 2) and evaluable for analysis. In phase 1b, no dose-limiting toxicities were observed, and GT90001 7.0 mg/kg was confirmed as the RP2D. Common grade 3/4 adverse events (AEs) were platelet count decreased (15%). No deaths due to AEs were reported. Confirmed ORR and disease control rate were 30% (95% CI, 14.6%-51.9%) and 40% (95% CI, 21.9%-61.3%), respectively. Median duration of response was not calculated (95% CI, 7.39 months to not calculated). Median progression-free survival (PFS) was 2.81 months (95% CI, 1.71–9.33), with 6-month and 12-month PFS rates of 35% and 25%, respectively. One patient with multiple intra- and extra-hepatic metastases was diagnosed with pseudo-progression upon GT90001 plus nivolumab exposure. Conclusions GT90001 plus nivolumab has a manageable safety profile and promising anti-tumor activity in patients with advanced HCC. Trial registration number ClinicalTrials.gov identifier NCT03893695.

Abstract Glioma is the most common malignant tumor of the brain and enhancing the efficacy of chemotherapy in glioma is critical for improving patients’ prognosis. In this study, a glioma-targeting drug delivery system is constructed using biodegradable periodic mesoporous organosilica nanoparticles (PMO) that are modified with lactoferrin (Lf) ligands. The obtained PMO is doped with thioether groups and can be degraded in the high concentration of glutathione in tumor cells. The surface area and pore volume of PMO are 772 cm2/g and 0.98 cm3/g, respectively and the loading capacity of doxorubicin (Dox) is as high as 20%. The results of the confocal laser scanning microscope show that the uptake of PMO-Lf@Dox by C6 cells is higher than PMO@Dox. The quantitative analysis of the flow cytometer further demonstrates that more PMO-Lf@Dox enter C6 cells, indicating that the modification of lactoferrin can significantly increase the uptake of C6 cells. Finally, the therapeutic efficacy results show that Lf-modified PMO enhances the inhibitory effect of Dox on C6 cells when incubated for 24 h and 72 h. In summary, this lactoferrin receptor-mediated PMO drug carrier with biodegradability in glutathione in tumor cells can be used to enhance drug delivery into glioma without long-term accumulation in vivo. Graphical abstract In this study, a glioma-targeting drug delivery system is constructed using periodic mesoporous organosilica nanoparticles (PMO) that modified with lactoferrin (Lf) ligands. This lactoferrin receptor-mediated PMO drug carrier can be used to enhance drug delivery into brain glioma.

With the increasing proportion of installed renewable energy power generation capacity and the introduction of quantitative energy storage policies for new energy power generation. In view of the influence of intermittent and volatility of distributed generation on the safe of power grid, it is​ particularly important in the future to equip reasonable energy storage to ensure the flexibility of power system. In this paper, a load frequency control (LFC) strategy of hybrid energy storage based on fractional order proportion integral derivative (FOPID) is proposed to solve the frequency modulation problem of battery energy storage system (BESS) and pumped storage station (PSS) participating in the interconnection network. Firstly, the LFC model is established under the nonlinear factors such as regulator dead zone and generation rate constraint on a two-area reheat steam turbine. Secondly, a FOPID controller is designed. Furthermore, the combined LFC simulation is carried out by adding BESS under the two working operations of PSS generating and pumping. Finally, the influence of demand response is considered in the hybrid energy storage control.

Abstract Background Patients with liver cirrhosis (LC) are prone to gastric mucosa damage. We investigated the alterations of gastric mucosa in LC patients and their possible mechanisms through multi-omics. Results We observed significant gastric mucosa microbial dysbiosis in LC subjects. Gastric mucosal microbiomes of LC patients contained a higher relative abundance of Streptococcus, Neisseria, Prevotella, Veillonella, and Porphyromonas, as well as a decreased abundance in Helicobacter and Achromobacter, than control subjects. The LC patients had higher levels of bile acids (BAs) and long-chain acylcarnitines (long-chain ACs) in serum. The gastric mucosal microbiomes were associated with serum levels of BAs and long-chain ACs. Transcriptome analyses of gastric mucosa revealed an upregulation of endothelial cell specific molecule 1, serpin family E member 1, mucin 2, caudal type homeobox 2, retinol binding protein 2, and defensin alpha 5 in LC group. Besides, the bile secretion signaling pathway was significantly upregulated in the LC group. Conclusions The alterations in the gastric mucosal microbiome and transcriptome of LC patients were identified. The impaired energy metabolism in gastric mucosal cells and bile acids might aggravate the inflammation of gastric mucosa and even exacerbate the Correa’s cascade process. The gastric mucosal cells might reduce bile acid toxicity by bile acid efflux and detoxification. Trial registration: ChiCTR2100051070.

Abstract The analysis of microbial genomes from human archaeological samples offers a historic snapshot of ancient pathogens and provides insights into the origins of modern infectious diseases. Here, we analyze metagenomic datasets from 38 human archaeological samples and identify bacterial genomic sequences related to modern-day Clostridium tetani, which produces the tetanus neurotoxin (TeNT) and causes the disease tetanus. These genomic assemblies had varying levels of completeness, and a subset of them displayed hallmarks of ancient DNA damage. Phylogenetic analyses revealed known C. tetani clades as well as potentially new Clostridium lineages closely related to C. tetani. The genomic assemblies encode 13 TeNT variants with unique substitution profiles, including a subgroup of TeNT variants found exclusively in ancient samples from South America. We experimentally tested a TeNT variant selected from an ancient Chilean mummy sample and found that it induced tetanus muscle paralysis in mice, with potency comparable to modern TeNT. Thus, our ancient DNA analysis identifies DNA from neurotoxigenic C. tetani in archaeological human samples, and a novel variant of TeNT that can cause disease in mammals.

Background: Heart failure (HF) is the main cause of death in middle-aged and older people and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. Nicotinamide adenine dinucleotide (NAD+) is widely present in the mitochondria of cardiomyocytes and maintains the redox balance in the body, which can effectively treat HF. We sought to evaluate whether NAD+ therapy has some clinical efficacy in patients with HF. Methods: Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD+ with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Results: Among the 60 patients with HF who were treated with NAD+ for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD+ because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. Conclusions: According to the results of this study, it is believed that 7 days of NAD+ injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Clinical Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/) ChiCTR2300074326; retrospectively registered on 3 August 2023.

In this study, a deep learning-based system for apple defect detection and quality grading was developed, integrating various advanced image-processing technologies and machine learning algorithms to enhance the automation and accuracy of apple quality monitoring. Experimental validation demonstrated the superior performance of the proposed model in handling complex image tasks. In the defect-segmentation experiments, the method achieved a precision of 93%, a recall of 90%, an accuracy of 91% and a mean Intersection over Union (mIoU) of 92%, significantly surpassing traditional deep learning models such as U-Net, SegNet, PSPNet, UNet++, DeepLabv3+ and HRNet. Similarly, in the quality-grading experiments, the method exhibited high efficiency with a precision of 91%, and both recall and accuracy reaching 90%. Additionally, ablation experiments with different loss functions confirmed the significant advantages of the Jump Loss in enhancing model performance, particularly in addressing class imbalance and improving feature learning. These results not only validate the effectiveness and reliability of the system in practical applications but also highlight its potential in automating the detection and grading processes in the apple industry. This integration of advanced technologies provides a new automated solution for quality control of agricultural products like apples, facilitating the modernization of agricultural production.

In this study, a novel approach integrating multimodal data processing and attention aggregation techniques is proposed for pear tree disease detection. The focus of the research is to enhance the accuracy and efficiency of disease detection by fusing data from diverse sources, including images and environmental sensors. The experimental results demonstrate that the proposed method outperforms in key performance metrics such as precision, recall, accuracy, and F1-Score. Specifically, the model was tested on the Kaggle dataset and compared with existing advanced models such as RetinaNet, EfficientDet, Detection Transformer (DETR), and the You Only Look Once (YOLO) series. The experimental outcomes indicate that the proposed model achieves a precision of 0.93, a recall of 0.90, an accuracy of 0.92, and an F1-Score of 0.91, surpassing those of the comparative models. Additionally, detailed ablation experiments were conducted on the multimodal weighting module and the dynamic regression loss function to verify their specific contributions to the model performance. These experiments not only validated the effectiveness of the proposed method but also demonstrate its potential application in pear tree disease detection. Through this research, an effective technological solution is provided for the agricultural disease detection domain, offering substantial practical value and broad application prospects.

Abstract Background N6-methyladenosine (m6A) has been confirmed to function critically in acute myeloid leukemia (AML) progression. Hitherto, the subtyping and prognostic predictive significance of m6A-correlated genes in AML is unclear. Method From The Cancer Genome Atlas (TCGA-LAML), Therapeutically Applicable Research to Generate Effective Treatments (TARGET-AML) and Gene Expression Omnibus (GEO, GSE71014) databases, we collected the sequencing data of AML patients. The batch effect was removed via limma package for TCGA-LAML and TARGET-AML, and the aggregated samples were AML cohorts. Samples in the AML cohort identified m6A models in AML by consensus clustering based on 23-m6A-related modulators. M6A-related differentially expressed genes (m6ARDEGs) influencing the overall survival (OS) of AML were determined by performing differential expression analysis and univariate COX analysis, and consensus-based clustering was utilized to access AML molecular subtypes. LASSO and multivariate COX analyses were performed to obtain the optimized m6ARDEGs to construct the m6A Prognostic Risk Score (m6APR_Score). Whether the model was robust was evaluated according to Kaplan–Meier (K-M) and receiver operator characteristic (ROC) curves. Further, the abundance of immune cell infiltration was explored in different m6A modification patterns and molecular subtypes and m6APR_Score groupings. Finally, nomogram was constructed to predict OS in AML. Quantitative real-time polymerase chain reaction (RT-qPCR) and cell counting kit-8 (CCK-8) assay were used to validate the genes in m6APR_Score in AML cells. Results The m6A models (m6AM1, m6AM2, m6AM3) and molecular subtypes (C1, C2, C3) were identified in the AML cohort, exhibiting different prognosis and immunoreactivity. We recognized novel prognostic biomarkers of AML such as CD83, NRIP1, ACSL1, METTL7B, OGT, and C4orf48. AML patients were grouped into high-m6APR_Score and low-m6APR_Score groups, with the later group showing a better prognosis than former one. Both the AML cohort and the validation cohort GSE71014 demonstrated excellent prediction. Finally, the nomogram accurately predicted the survival of patients suffering from AML. Further, the decision curves showed that both nomogram and m6APR_Score showed excellent prediction. It was confirmed in vitro experiments that mRNA expressions of NRIP1, ACSL1, METTL7B and OGT were elevated, while CD83 and C4orf48 mRNA expressions downregulated in AML cells. A significant increase in the viability of U937 and THP-1 cell lines after inhibition of CD83, while siMETTL7B had contrast results. Conclusion Our study demonstrated that m6APR_Score and CD83, NRIP1, ACSL1, METTL7B, OGT, and C4orf48 potentially provided novel and promising prognostic support for AML patients.

At 07:53 on May 2, 2022, a magnitude 3.4 earthquake occurred in Qingzhou City, Weifang City, Shandong Province (36.55°N，118.27°E), with a focal depth of 8 km. After the earthquake, Weifang Earthquake Monitoring Center Station responded quickly, immediately organized forces to carry out earthquake situation analysis and judgment, on-site mobile monitoring, disaster investigation and intensity assessment, emergency publicity and other works, and fully played the vanguard role of the provincial agency’s earthquake work. This paper discusses the emergency work of Qingzhou earthquake from three aspects: the current situation of Weifang Earthquake Monitoring Center Station and the layout of observation instruments, the response of earthquake emergency service, and the post-earthquake thinking and suggestions, and shares the specific measures taken to deal with the earthquake emergency, providing experience accumulation and scientific reference for other brother stations to effectively deal with the sudden earthquake, which has certain practical significance.

Summary: The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD1,2,7, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD7, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD7. The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.

Objectives: Nadroparin, a low-molecular-weight-heparin is commonly used off-label in neonates and infants for thromboembolic events prevention. However, the recommended dosing regimen often fails to achieve therapeutic target ranges. This study aimed to develop a population pharmacokinetic (PK) model of nadroparin to determine an appropriate dosing regimen for neonates and infants less than 8 months.Methods: A retrospective chart review was conducted on patients treated with nadroparin at Children’s Hospital of Fudan University between July 2021 and December 2023. A population PK model was developed using anti-Xa levels, and its predictive performance was evaluated internally. Monte Carlo simulations were performed to design an initial dosing schedule targeting anti-Xa levels between 0.5 and 1 IU/mL.Results: A total of 40 neonates and infants aged less than 8 months with gestational age ranging from 25 to 41 weeks treated with nadroparin were enrolled in the study for analysis. A one-compartment PK model with first order absorption and elimination was adequately fitted to the data. Creatinine clearance was identified as a significant factor contributing to inter-individual variability in clearance. The typical population parameter estimates of clearance, distribution volume and absorption rate in this population were 0.211 L/h, 1.55 L and 0.495 h-1, respectively. Our findings suggest that current therapeutic doses of nadroparin (150–200 IU/kg q12 h) may result in subtherapeutic exposure, thus higher doses might be required.Conclusion: The present study offers the first estimation of PK parameters for nadroparin in preterm or term neonates and infants less than 8 months utilizing the model. Our findings have potential implications for recommending initial personalized dosages, particularly among patient populations exhibiting similar characteristics.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes.Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children’s Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19+ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19+ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens.Results: In total, 102 measurements of CD19+ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19+ lymphocyte counts, where the Emax and EC50 were estimated to be 99.6*106/L and 5.87 μg/mL, respectively. Simulations indicated that a single infusion of 750 mg/m2 and 2 infusions of 375 mg/m2 both yielded a 10-week suppression of CD19+ lymphocytes.Conclusion: This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.

Abstract Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (HCE) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between HCE and SV2 provide the crucial location and specificity information for HCE to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, HCE exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications.

An innovative framework for peach tree disease recognition and segmentation is proposed in this paper, with the aim of significantly enhancing model performance in complex agricultural settings through deep learning techniques and data fusion strategies. The core innovations include a tiny feature attention mechanism backbone network, an aligned-head module, a Transformer-based semantic segmentation network, and a specially designed alignment loss function. The integration of these technologies not only optimizes the model’s ability to capture subtle disease features but also improves the efficiency of integrating sensor and image data, further enhancing the accuracy of the segmentation tasks. Experimental results demonstrate the superiority of this framework. For disease detection, the proposed method achieved a precision of 94%, a recall of 92%, and an accuracy of 92%, surpassing classical models like AlexNet, GoogLeNet, VGGNet, ResNet, and EfficientNet. In lesion segmentation tasks, the proposed method achieved a precision of 95%, a recall of 90%, and an mIoU of 94%, significantly outperforming models such as SegNet, UNet, and UNet++. The introduction of the aligned-head module and alignment loss function provides an effective solution for processing images lacking sensor data, significantly enhancing the model’s capability to process real agricultural image data. Through detailed ablation experiments, the study further validates the critical role of the aligned-head module and alignment loss function in enhancing model performance, particularly in the attention-head ablation experiment where the aligned-head configuration surpassed other configurations across all metrics, highlighting its key role in the overall framework. These experiments not only showcase the theoretical effectiveness of the proposed method but also confirm its practical value in agricultural disease management practices.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

A cell-based assay for detecting SNAP25-cleaving Botulinum neurotoxins (BoNTs) is developed by combining hiPSC-derived motor neurons and a luminescent detection system based on split NanoLuc luciferase.

Clostridioides difficile (C. difficile) is a Gram-positive, spore-forming, toxin-producing, obligate anaerobic bacterium. C. difficile infection (CDI) is the leading cause of healthcare-associated infective diarrhoea. The infection is mediated by the spore, a metabolically inactive form of C. difficile. The spore coat acts as a physical barrier to defend against chemical insults from hosts and natural environments. The composition of spore coat has already been revealed; therefore, the interactive networks of spore coat proteins and the dynamic process of coat assembly are the keys to design strategies to control and cure CDI. This review gives a brief discussion of the signal processing and transcriptional regulation of C. difficile sporulation initiation. Following the discussion, the spore formation is also introduced. Finally, this review mainly focuses on the spore coat assembly, a poorly understood process in C. difficile, and important proteins that have been studied.

Toxin B (TcdB) is a major exotoxin responsible for diseases associated with C. difficile infection. Here, Tian et al. show that several TcdB subtypes do not recognize the established FZD receptors, and identify a different host protein (TFPI) as a receptor for subtypes TcdB4 and TcdB10.

Abstract Aims To develop a competency scale for operating room nurses and test its reliability and validity. Background The existing Chinese Registered Nurse Competency Scale and the core competency scale for operating room nurses developed abroad cannot fully meet the capacity needs of Chinese operating room nurses. Methods The scale was developed based on the results of qualitative interview and the Delphi method. Ten experts were selected for expert consultation, and 300 operating room nurses were recruited by convenience sampling for a cross‐sectional survey to test the reliability and validity of instrument.The reliability and validity of the scale was assessed based on internal consistency reliability, test–retest reliability and confirmatory factor analysis. Data collection was conducted between March to July, 2015. Results An initial scale with 42 items was confirmed, and 36 items remained. The internal consistency Cronbach's α was 0.97 for the overall scale and 0.88–0.94 for the subscales. The retest reliability ranged from 0.55–0.96. Five factors were extracted by exploratory factor analysis, and they explained 66% of the total variance. The fitting indices of the confirmatory factor analysis were as follows: χ2/df = 3.47, CFI = 0.83, TLI = 0.81, SRMR = 0.06 and RMSEA = 0.09. Conclusions The core competency scale for operating room nurses with 5 components and 36 items had acceptable reliability and validity. The scale could continue to be optimized in the future.

Background/objectivesAdults with attention-deficit/hyperactivity disorder (ADHD) have more maladaptive cognitions, emotional problems and a poorer quality of life (QoL). A verification of the psychological model in clinical samples is needed for a better understanding of the mechanisms of ADHD diagnosis on QoL via maladaptive cognitions, emotional symptoms, and their interactions.Methods299 ADHD participants and 122 healthy controls were recruited. ADHD core symptoms, maladaptive cognitions, emotional symptoms and psychological QoL were rated. Pearson’s correlation and structural equation modeling were analyzed to explore the relationship and influence of ADHD diagnosis on QoL.ResultsMore maladaptive cognitions, emotional symptoms, and poorer QoL were found in the ADHD group, and the dysfunctional attitudes were on par between ADHD with or without medication (p = 0.368). Moderate to strong correlations were found between emotional symptoms, maladaptive cognitions and QoL, and ADHD core symptoms presented correlations among the above scores (r = 0.157 ~ 0.416, p

Objective: Hyperlipidemia is a risk factor for cardiac damage that can lead to many cardiovascular diseases. A recent study reported the cardioprotective effects of luteolin in vitro and in vivo. In this study, we aimed to investigate the possible protective effects of luteolin against hyperlipidemia-induced cardiac damage in Sprague-Dawley (SD) rats. Methods: Six-week-old male SD rats were randomly divided into five groups: a normal diet (ND) group; a high-fat diet (HFD) group; and three high-fat diet mixed with luteolin (HFD + LUT) groups, where in a luteolin dosage 50, 100, or 200 mg/kg/day was administered. All groups were fed their respective diets for 12 weeks. Results: Left ventricular ejection fraction and fractional shortening (parameters of cardiac function) were lower in the HFD + LUT (100 mg/kg/day) group than in the HFD group. Metabolic parameters were lower in the HFD + LUT (100 mg/kg/day) group than in the HFD group. Collagen I, collagen III, and TGF-β expression levels were lower in the cardiac tissues of the HFD + LUT (100 mg/kg/day) group, compared to those of the HFD group. Expression of the profibrotic genes MMP2 and MMP9 was suppressed in the cardiac tissues of the HFD + LUT (100 mg/kg/day) group, compared to those of the HFD group. Furthermore, CD36 and lectin-like oxidized low-density lipoprotein receptor-1 protein levels were lower in the cardiac tissues of the HFD + LUT (100 mg/kg/day) group, compared to those of the HFD group. Conclusion: These findings would provide new insights into the role of luteolin in hyperlipidemia-induced cardiac damage and contribute to the development of novel therapeutic interventions to treat cardiovascular disease progression.

Abstract The key to designing and fabricating highly efficient mixed protonic–electronic conductors materials (MPECs) is to integrate the mixed conductive active sites into a single structure, to break through the shortcomings of traditional physical blending. Herein, based on the host–guest interaction, an MPEC is consisted of 2D metal–organic layers and hydrogen‐bonded inorganic layers by the assembly methods of layered intercalation. Noticeably, the 2D intercalated materials (≈1.3 nm) exhibit the proton conductivity and electron conductivity, which are 2.02 × 10−5 and 3.84 × 10−4 S cm−1 at 100 °C and 99% relative humidity, much higher than these of pure 2D metal–organic layers (>>1.0 × 10−10 and 2.01×10−8 S cm−1), respectively. Furthermore, combining accurate structural information and theoretical calculations reveals that the inserted hydrogen‐bonded inorganic layers provide the proton source and a networks of hydrogen−bonds leading to efficient proton transport, meanwhile reducing the bandgap of hybrid architecture and increasing the band electron delocalization of the metal–organic layer to greatly elevate the electron transport of intrinsic 2D metal–organic frameworks.

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment.Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at −80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449 nm detector and 5 micron C18 column; and 2) portable PolyLC with 415 nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania.Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000 µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%–20% of the actual values. Both HPLC systems measured hydroxyurea with 0.99.Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses.

Abstract Background Nutrient regulation has been proven to be an effective way to improve the flesh quality in fish. As a necessary nutrient for fish growth, protein accounts for the highest proportion in the fish diet and is expensive. Although our team found that the effect of protein on the muscle hardness of grass carp was probably related to an increased collagen content, the mechanism for this effect has not been deeply explored. Moreover, few studies have explored the protein requirements of sub-adult grass crap (Ctenopharyngodon idella). Therefore, the effects of different dietary protein levels on the growth performance, nutritional value, muscle hardness, muscle fiber growth, collagen metabolism and related molecule expression in grass carp were investigated. Methods A total of 450 healthy grass carp (721.16 ± 1.98 g) were selected and assigned randomly to six experimental groups with three replicates each (n = 25/replicate), and were fed six diets with 15.91%, 19.39%, 22.10%, 25.59%, 28.53% and 31.42% protein for 60 d. Results Appropriate levels of dietary protein increased the feed intake, percentage weight gain, specific growth rate, body composition, unsaturated fatty acid content in muscle, partial free amino acid content in muscle, and muscle hardness of grass carp. These protein levels also increased the muscle fiber density, the frequency of new muscle fibers, the contents of collagen and IGF-1, and the enzyme activities of prolyl 4-hydroxylases and lysyloxidase, and decreased the activity of matrix metalloproteinase-2. At the molecular level, the optimal dietary protein increased collagen type I α1 (Colα1), Colα2, PI3K, Akt, S6K1, La ribonucleoprotein domain family member 6a (LARP6a), TGF-β1, Smad2, Smad4, Smad3, tissue inhibitor of metalloproteinase-2, MyoD, Myf5, MyoG and MyHC relative mRNA levels. The levels of the myostatin-1 and myostatin-2 genes were downregulated, and the protein expression levels of p-Smad2, Smad2, Smad4, p-Akt, Akt, LARP6 and Smad3 were increased. Conclusions The appropriate levels of dietary protein promoted the growth of sub-adult grass carp and improved muscle hardness by promoting the growth of muscle fibers, improving collagen synthesis and depressing collagen degradation. In addition, the dietary protein requirements of sub-adult grass carp were 26.21% and 24.85% according to the quadratic regression analysis of growth performance (SGR) and the muscle hardness (collagen content), respectively.

Objective To analyze the expression and clinical significance of CD4+ CD69+ T cells in peripheral blood of patients with autoimmune hemolytic anemia. Methods A total of 206 cases of autoimmune hemolytic anemia admitted to our hospital from March 2018 to March 2021 were selected as the observation group, and 206 cases, who came for healthy physical examination during the same period, were selected as the control group. The levels of CD4+ CD69+ T cells in peripheral blood, CD69 mRNA in CD4+ T cells and CD69 in plasma were detected. The relationship between CD4+ CD69+ T cell level and Hb, reticulocyte ratio (Ret), total bilirubin (TBIL) and indirect bilirubin (IBIL) was analyzed by Pearson correlation analysis to observe the occurrence of venous thromboembolism. The AUC of receiver operating characteristic was used to evaluate the predictive efficacy of CD4+ CD69+ T cell expression in peripheral blood for venous thromboembolism. Results The levels of CD4+ CD69+ T cells in peripheral blood, CD69 mRNA in CD4+ T cells and CD69 in plasma of observation group were significantly higher than those of control group (P

Abstract Studies of schizophrenia (SCZ) have associated auditory verbal hallucinations (AVH) with structural and functional abnormalities in frontal cortex, especially medial prefrontal cortex (mPFC). Although abnormal prefrontal network connectivity associated with language production has been studied extensively, the relationship between mPFC dysfunction (highly relevant to the pathophysiology of SCZ) and AVH has been rarely investigated. In this study, proton magnetic resonance spectroscopy was used to measure metabolite levels in the mPFC in 61 SCZ patients with persistent AVH (pAVH), 53 SCZ patients without AVH (non-AVH), and 59 healthy controls (HC). The pAVH group showed significantly lower levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) and glutamate + glutamine (Glx), compared with the non-AVH (tNAA: p = 0.022, Glx: p = 0.012) and HC (tNAA: p = 0.001, Glx: p = 0.001) groups. No difference was found in the levels of tNAA and Glx between non-AVH and HC. The levels of tNAA and Glx in the mPFC was negatively correlated with the severity of pAVH (tNAA: r = −0.24, p = 0.014; Glx: r = −0.30, p = 0.002). In conclusion, pAVH in SCZ patients might be related to decreased levels of tNAA and Glx in the mPFC, indicating that tNAA or Glx might play a key role in the pathogenesis of pAVH.

Purpose. Dendritic cells (DC) are specialized antigen-presenting cells, and cytokine-induced killer (CIK) cells have a specific killing activity to a variety of tumors. However, the underlining mechanism and function of DC-CIK cells in acute myeloid leukemia (AML) remain largely elusive. Methods. Gene expression profiles of leukemia patients were obtained from TCGA, DC cell components were evaluated using the quanTIseq method, and cancer stem cell scores were estimated using machine learning methods. The transcriptomes were obtained in DC-CIK cells from normal and AML patients by high-throughput sequencing. Large differentially expressed mRNAs were verified by RT-qPCR assay, and MMP9 and CCL1 were selected for subsequent studies in vivo and in vitro experiments. Results. Significant positive correlations were found with DC versus cancer stem cells (p=0.008) and the expression of MMP9 versus cancer stem cells (p=0.018). MMP9 and CCL1 were found to be highly expressed in DC-CIK cells from AML patients. DC-CIK cells with MMP9 and CCL1 knockout alone had little effect on leukemia cells, while knockdown of MMP9 and CCL1 in DC-CIK cells increased cytotoxicity, suppressed proliferation, and induced apoptosis of leukemia cells. In addition, we proved that MMP9- and CCL1-silenced DC-CIK cells significantly elevated the CD3+CD4+ and CD3+CD8+ cells and lowered the CD4+PD-1+ and CD8+PD-1+ T cells. Meanwhile, blockage of MMP9 and CCL1 in DC-CIK cells dramatically increased IL-2 and IFN-γ, increased CD107aþ (LAMP-1) and granzyme B (GZMB), and downregulated PD-1, CTLA4, TIM3, and LAG3 T cells from AML patients and AML model mice. Furthermore, activated T cells in DC-CIK cells knocking down MMP9 and CCL1 also prevented proliferation and accelerated apoptosis of AML cells. Conclusion. Our findings demonstrated that blockage of MMP9 and CCL1 in DC-CIK cells could markedly enhance the therapeutic efficiency in AML via activating T cells.

As an essential structural, metabolic and signaling element, calcium shows low remobilization from old to young tissues in plants, restricting the nutrient-use efficiency and control efficacy against mosaic virus disease. Nanotechnology has been applied to prevent/minimize nutrient losses and improve the accessibility of poorly-available nutrients. Herein, the current study applied a star polycation (SPc) to prepare a calcium nutrition nanoagent. The SPc could assemble with calcium glycinate through hydrogen bond and Van der Waals force, forming stable spherical particles with nanoscale size (17.72 nm). Transcriptomic results revealed that the calcium glycinate/SPc complex could activate the expression of many transport-related genes and disease resistance genes in tomatoes, suggesting the enhanced transport and antiviral immunity of SPc-loaded calcium glycinate. Reasonably, the calcium transport was accelerated by 3.17 times into tomato leaves with the help of SPc, and the protective effect of calcium glycinate was remarkably improved to 77.40% and 67.31% toward tomato mosaic virus with the help of SPc after the third and fifth applications. Furthermore, SPc-loaded calcium glycinate could be applied to increase the leaf photosynthetic rate and control the unusual fast growth of tomatoes. The current study is the first success to apply nano-delivery system for enhanced calcium transport and antiviral immunity, which is beneficial for increasing nutrient-use efficiency and shows good prospects for field application.

BackgroundsGene polymorphisms are critical for variations in warfarin dose. To date, more than 70 CYP2C9 alleles have been identified. This study was designed to clarify the clinical significance of CYP2C9*non-3 variants to warfarin sensitivity in Chinese Han patients.MethodsThe entire CYP2C9 gene region was sequenced in 1,993 individuals, and clinical data and VKORC1 genotypes were collected from 986 patients with atrial fibrillation treated with warfarin. The SKAT-O method was used to analyze the effects of CYP2C9*non-3 variants on warfarin sensitivity.ResultsA total of 20 CYP2C9 variants were identified, of which four were novel. Carriers with CYP2C9*non-3 variants may have lower warfarin dose requirements, and similar to CYP2C9*3, CYP2C9*non-3 variants are clearly relevant to warfarin-sensitive and highly sensitive responders.ConclusionOur results showed that, besides CYP2C9*3, the series of CYP2C9*non-3 variants is an unignorable predictor for warfarin sensitivity in Chinese population. From a safety consideration, people carried such variants may need a preferred choice of NOACs when they started anticoagulation therapy.

Background Cancer immune escape is a main obstacle in designing effective anticancer therapeutic approaches. Our work was aimed to explore the function of cullin 3 (CUL3) in ovarian cancer cell immune escape and chemosensitivity.Method Gain and loss of function assays were conducted to investigate the interactions among CUL3, speckle type POZ protein (SPOP) and programmed death ligand-1 (PD-L1) as well as their effects on ovarian cell malignant phenotypes and chemosensitivity. A mouse model of xenografted ovarian cells was further established for in vivo substantiation.Result Poorly-expressed CUL3 and SPOP were found in ovarian cancer. Overexpression of CUL3 reduced malignant features as well as immune escape of ovarian cancer cells but enhanced chemosensitivity. Functionally, CUL3 degraded PD-L1 protein by forming complex with SPOP. Overexpression of CUL3 inhibited tumor formation and enhanced chemosensitivity of ovarian cancer cells in mice by degrading PD-L1 protein.Conclusion All in all, CUL3/SPOP formed a complex to promote PD-L1 degradation to inhibit ovarian cancer cell immune escape and increase chemosensitivity, offering a therapeutic target for ovarian cancer treatment.

Nitrite poses a serious threat to intensive aquaculture. Protein, as a major nutrient in animals, is vital for protecting animal tissues from damage. In this study, we investigated the protective effect of dietary protein on gill tissue structure and the underlying mechanisms in sub-adult grass carp (Ctenopharyngodon idella) exposed to nitrite stress. Six iso-energetic semi-purified diets containing different protein levels (16–31 %) were formulated, and fed to fish for 60 d. The fish were then exposed to a nitrite solution for 4 d. Histopathological observation and determination of related indices (serum glucose, serum cortisol, nitric oxide, peroxynitrite, reactive oxygen species, malondialdehyde, and protein carbonyl) showed that 22–25 % dietary protein significantly alleviated the nitrite-induced stress response, gill tissue damage and oxidative damage. Further research found that a suitable dietary protein suppressed the nitrite-induced endoplasmic reticulum stress (ERS) 78 kDa glucose-regulated protein (GRP78) related signaling pathway which possibly activated autophagy and apoptosis. Interestingly, we discovered that proper dietary protein reduced autophagy, probably through unc-51-like kinase 1 (Ulk1), BCL-2-interacting myosin-like coiled-coil protein (Beclin1), autophagy-related gene 5 (Atg5), Atg12, microtubule-associated protein1 light chain 3 (LC3), BCL-2 interacting protein 3 (BNIP3) and autophagy receptor P62 (p62). We also found that an appropriate dietary protein inhibited nitrite-induced apoptosis via mitochondrial and death receptor pathways. In summary, our findings are the first to demonstrate that 22–25 % of dietary protein levels can play a protective role against nitrite-induced gill injury.

Software for calibration and calculation of underground fluid water level based on Android mobile phone APP is a water level calibration table system with calculation，recording，storage and other functions. Its functions include calculation of water level calibration data，calibration information archiving，and inquiry of calibration information and other functions.

Given the fragmentation of public opinion dissemination and the lag of network users’ cognition, the paper analyzes public opinion dissemination with incomplete information, which can provide reference for us to control and guide the spread of public opinion. Based on the derivative and secondary radiation of public opinion dissemination with incomplete information, the Susceptible-Susceptible-Infected-Recovered-Recovered-Infected (SSIRR-I) model is proposed. Given the interaction between users, the Deffuant opinion dynamics model and evolutionary game theory are introduced to simulate the public opinion game between dissemination and immune nodes. Finally, the numerical simulation and results analysis are given. The results reveal that the rate of opinion convergence significantly affects disseminating public opinion, which is positively correlated with the promotion effect of the dissemination node and negatively correlated with the suppression effect of the immune node of public opinion dissemination. Derivative and secondary radiations have different effects on public opinion dissemination in the early stage, but promote public opinion dissemination in the later stage. The dominant immune nodes have an apparent inhibitory effect on the spread of public opinion; nevertheless, they cannot block the dissemination of public opinion.

Chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for C. difficile toxin B (TcdB) during C. difficile infections (CDIs). Here, the cryo-EM structure of a TcdB–CSPG4 complex and CDI mouse models offer insights into CSPG4 role in CDIs and suggest a therapeutic strategy targeting TcdB.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The effectiveness and mechanism of edoxaban in preventing stroke after atrial fibrillation remain unclear.Methods: The expressions of HBG1 and HBD in red blood cells were tested in AF. Sixty C57B/6J mice were randomly divided into the following groups: the control (CON) group, atrial fibrillation (AF) group, AF + edoxaban group, and AF + rivaroxaban group. H&E staining assay and reticular fiber staining were performed. Myocardial fibrosis was evaluated by the Masson staining assay, Sirius red staining assay, and immunohistochemical assay for the expressions of α-SMA and COL1A1. ELISA and RT-PCR assay were performed for the detection of inflammatory parameters (TNF-α, IL-1β, IL-6, and IL-10). Blood lipids were detected by using the Beckman automatic biochemical analyzer. Furthermore, four items of coagulation were detected, and molecular docking among HBG1, HBD, and MASP1 (Xa) was performed by PyMOL 2.1 software. The BP neural network model, cubic spline interpolation, and support vector machine model were constructed to predict prothrombin time based on HBG1 and HBD expressions. COIP assay was performed to construct the interaction between HBG1 and HBD. The functional enrichment analysis was performed by DAVID and Metascape tools.Results: The expressions of HBG1 and HBD in red blood cells of the patients with atrial fibrillation were decreased. The results showed a lower level of hemoglobin in red blood cells with HBG1-siRNA and HBG1-siRNA. Compared with the AF group, the collagen fiber percentage in the AF + edoxaban group was decreased (p < 0.05). After using edoxaban, the expressions of TNF-α, IL-1β, IL-6, and IL-10 were significantly decreased (p < 0.05). The LDL-C, TC, and TG levels were downregulated in the AF + edoxaban group. The PT and APTT levels in the AF + edoxaban group were more increasing than in the AF mice (p < 0.05). Compared with the AF group, the expressions of HBG1 and HBD were downregulated in the AF + edoxaban group (p < 0.05). HBG1 protein matched well with HBD and MASP1(Xa) protein surfaces. There exists a significant interaction between HBG1, HBD, and PT via the BP neural network and support vector machine. Enrichment analysis showed that HBG1 and HBD were mainly enriched in blood coagulation.Conclusion: Edoxaban could prevent atrial fibrillation and coagulation by reducing inflammation, lipids, and fibrosis via HBG1/HBD biomarkers effectively, and the effect was superior to that of rivaroxaban.

Maintaining the health of the endothelium is of critical importance to prevention against cell aging. The current study was performed to clarify the role of sirtuin1 (SIRT1) in platelet phagocytosis in cell aging and identified its downstream molecular mechanism. Platelet phagocytosis by human endometrial microvascular endothelial cells (HEMECs) was characterized by transmission electron and fluorescence microscopy. Functional experiments were conducted to examine platelet phagocytosis and cell aging using the overexpression or knockdown plasmids of SIRT1 and G alpha-interacting, vesicle-associated protein (GIRDIN) as well as Akt inhibitor and activator. It was found that SIRT1 facilitated platelet phagocytosis by HEMECs, contributing to inhibition of cell aging. Akt activation facilitated platelet phagocytosis and repressed cell aging. GIRDIN overexpression accelerated platelet phagocytosis by HEMECs, leading to a delay in cell aging. GIRDIN phosphorylation at Ser1417 was induced by Akt activation, while activation of Akt was induced by SIRT1-mediated deacetylation, consequently augmenting platelet phagocytosis and delaying cell aging. Taken together, SIRT1 delayed aging of HEMECs by deacetylating Akt, phosphorylating GIRDIN, and inducing platelet phagocytosis. The study highlights a possible target for the prevention of HEMEC aging.