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Abstract 4‐Coumarate‐CoA ligase (4CL) gene plays vital roles in plant growth and development, especially the regulation of lignin metabolism and flavonoid synthesis. To investigate the potential function of 4CL in the lignin biosynthesis of Ginkgo biloba, this study identified two 4CL genes, Gb4CL1 and Gb4CL2, from G. biloba genome. Based on the phylogenetic tree analysis, Gb4CL1 and Gb4CL2 protein were classified into Class I, which has been confirmed to be involved in lignin biosynthesis. Therefore, it can be inferred that these two genes may also participate in lignin metabolism. The tissue‐specific expression patterns of these two genes revealed that Gb4CL1 was highly expressed in microstrobilus, whereas Gb4CL2 was abundant in immature leaves. The onion transient expression assay indicated that Gb4CL1 was predominantly localized in the nucleus, indicating its potential involvement in nuclear functions, while Gb4CL2 was observed in the cell wall, suggesting its role in cell wall‐related processes. Phytohormone response analysis revealed that the expression of both genes was upregulated in response to indole acetic acid, while methyl jasmonate suppressed it, gibberellin exhibited opposite effects on these genes. Furthermore, Gb4CL1 and Gb4CL2 expressed in all tissues containing lignin that showed a positive correlation with lignin content. Thus, these findings suggest that Gb4CL1 and Gb4CL2 are likely involved in lignin biosynthesis. Gb4CL1 and Gb4CL2 target proteins were successfully induced in Escherichia coli BL21 with molecular weights of 85.5 and 89.2 kDa, proving the integrity of target proteins. Our findings provided a basis for revealing that Gb4CL participated in lignin synthesis in G. biloba.

Abstract Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

In 2004, it was the first time that Wollensak and Spoerl had applied physical and chemical cross-linking methods to scleral tissue. They found that the biomechanical strength of cross-linked sclera, induced by riboflavin/ultraviolet A, glyceraldehyde and glutaraldehyde, could be improved and proposed that scleral collagen cross-linking is expected to be a new method for the treatment of pathologic myopia. In recent years, a series of explorations have been made on the effectiveness and adverse reactions of physical and chemical cross-linking in the prevention and treatment of pathologic myopia, including the establishment of various animal models and different myopia modeling methods, the improvement of cross-linking methods, the amelioration of the measurement of biomechanical strength of scleral tissue and the attention of biological parameters such as the thickness of retinal nerve fiber layer and the amplitude of electroretinogram in vivo. Genipin-crosslinking of the scleral collagen combined with posterior scleral contraction/reinforcement has been applied to clinical research. This review summarizes physical cross-linking and the genipin-crosslinking of scleral collagen to explore the effectiveness and safety of the methods in the prevention and treatment of the pathologic myopia.

Background: Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. Objectives: To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Design: Retrospective, single-arm study. Methods: From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. Results: A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5–16.0) years. The median initial WBC count was 23.74 × 10 9 /L, 11 of whom ⩾100 × 10 9 /L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2–9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC

ObjectiveThis study explored the impact of a family intervention on the relapse rate of Chinese patients with alcohol dependence.MethodsA total of 151 male patients with alcohol dependence who were discharged from the Substance Dependence Department of the Wenzhou Seventh People’s Hospital from January to December 2020 were selected. They were divided into the control (n = 73) and experimental (n = 78) groups. Patients in both groups received routine alcohol cessation treatment. Moreover, patients in the experimental group were followed up by a professional psychiatrist to carry out individual family intervention. The Family Function Rating Scale (FAD), a Self-made general information questionnaire, and the Chinese version of the Family Intimacy and Adaptability Scale (FACESI-CV) were performed. Re-drinking rate and readmission rate were assessed.ResultsFamily intervention could reduce relapse rate (31, 39.74%) and rehospitalization (27, 34.62%) compared with the control group. After family training, FAD factor scores were improved in the experiment group in comparison with the control group. Family training improved communication (18.2 ± 3.7), role (20.8 ± 2.5), emotional response (10.8 ± 1.8), emotional involvement (13.7 ± 1.2), behavioral control (19.8 ± 1.2), and overall functionality (23.5 ± 2.1) in the experiment group in comparison with the control group. After family training, intimacy (70.5 ± 8.7) and adaptability (64.1 ± 6.9) in the experiment group was higher than in the control group. After family intervention, Michigan Alcohol Dependence Scale (MAST) (9.21 ± 0.68) and Short-Form 36 (SF-36) (80.32 ± 4.47) in the experiment group were higher than the control group.ConclusionFamily intervention for families of patients with alcohol dependence can improve their family function, increase their family intimacy and adaptability, and reduce the rate of relapse.

BackgroundPhosgene is a chemical material widely used worldwide. No effective method has been developed to reverse its pathological injuries. Some studies have shown that neuronal inflammation in lung tissue is involved, but the specific mechanism has not been reported.ObjectiveTo analyze the expression alterations of whole transcriptome gene sequencing bioinformatics and protein expression profile in lung tissue after phosgene aspiration lung injury (P-ALI) and find the main factors and pathways affecting the prognosis of P-ALI.MethodsRat models of P-ALI were made by phosgene. Rats were divided into a P-ALI group and a blank group. Hematoxylin-eosin (HE) staining and lung wet/dry ratio measurement were used to evaluate the lung injury. The levels of inflammatory factors were measured by ELISA. High-throughput sequencing was used to measure the expression profile of each gene. Protein expression profiles were determined by label-free relative quantification of the differential proteome.ResultsLung injury such as the disordered structure of alveolar wall and inflammatory factors (IL-1β, IL-18, and IL-33) were significantly increased in the P-ALI group (p < 0.05). There were 225 differentially expressed lncRNAs, including 85 upregulated and 140 downregulated genes. They were also the genomes with the most significant changes in transcriptome gene expression, mainly constituting cytoplasmic, synaptic structures and transporters, and involved in amino acid and carbon metabolism. There were 42 differentially expressed circRNAs, including 25 upregulated genes and 17 downregulated genes, mainly involved in cell composition, growth, differentiation, and division. There were only 10 differentially expressed miRNAs genes, all upregulated and mainly involved in the inflammatory response pathway. Proteome identification showed 79 differentially expressed proteins. KEGG enrichment analysis showed that it was mainly involved in the N-glycan biosynthesis pathway.ConclusionWe discovered that differentially regulated genes (lncRNAs, circRNAs, and miRNAs) were primarily associated with neuronal reflexes and synaptic signaling, including neurotransmitter transmission, ion signaling pathway conduction, neuronal projection, and synaptic vesicle circulation. They affected inflammatory factors and other metabolic pathways. This finding could be explored in future studies.

Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Background: The efficacy of acupuncture at Zusanli (ST36) in alleviating lower-limb pain is widely acknowledged in clinical practice, while its underlying mechanism remains incompletely elucidated. Our previous research had revealed that the prompt analgesia induced by needling-ST36 was accompanied by expression alterations in certain exco-nucleotidases within the sciatic nerve. Building upon this finding, the current work focused on NTPDase1, the primary ecto-nucleotidase in the human body, which converts ATP into AMP. Methods: A 20-min acupuncture was administered unilaterally at the ST36 on rats with acute ankle arthritis. The pain thresholds of the injured hind paws were determined. Pharmacological interference was carried out by introducing the corresponding reagents to the sciatic nerve. ATP levels around the excised nerve were measured using a luciferase-luciferin assay. Live calcium imaging, utilizing the Fura 2-related-F340/F380 ratio, was conducted on Schwann cells in excised nerves and cultured rat SCs line, RSC96 cells. Results: The analgesic effect induced by needling-ST36 was impaired when preventing ATP degradation via inhibiting NTPDase1 activities with ARL67156 or Ticlopidine. Conversely, increasing NTPDase1 activities with Apyrase duplicated the acupuncture effect. Similarly, preventing the conversion of AMP to adenosine via suppression of NT5E with AMP-CP hindered the acupuncture effect. Unexpectedly, impeded ATP hydrolysis ability and diminished NTPDase1 expression were observed in the treated group. Agonism at P2Y2Rs with ATP, UTP, or INS365 resulted in anti-nociception. Contrarily, antagonism at P2Y2Rs with Suramin or AR-C 118925xx prevented acupuncture analgesia. Immunofluorescent labeling demonstrated that the treated rats expressed more P2Y2Rs that were predominant in Schwann cells. Suppression of Schwann cells by inhibiting ErbB receptors also prevented acupuncture analgesia. Finally, living imaging on the excised nerves or RSC96 cells showed that agonism at P2Y2Rs indeed led to [Ca2+]i rise. Conclusion: These findings strongly suggest that the analgesic mechanism of needling-ST36 on the hypersensation in the lower limb partially relies on NTPDase1 activities in the sciatic nerve. In addition to facilitating adenosine signaling in conjunction with NT5E, most importantly, NTPDase1 may provide an appropriate low-level ATP milieu for the activation of P2Y2R in the sciatic nerve, particularly in Schwann cells.

Background: Cerebral palsy (CP) is a condition resulting from perinatal brain injury and can lead to physical disabilities. Exosomes derived from human amniotic mesenchymal stromal cells (hAMSC-Exos) hold promise as potential therapeutic options. Objective: This study aimed to investigate the impact of hAMSC-Exos on neuronal cells and their role in regulating apoptosis both in vitro and in vivo. Methods: hAMSC-Exos were isolated via ultracentrifugation and characterized via transmission electron microscopy, particle size analysis, and flow cytometry. In vitro, neuronal damage was induced by lipopolysaccharide (LPS). CP rat models were established via left common carotid artery ligation. Apoptosis levels in cells and CP rats were assessed using flow cytometry, quantitative reverse transcription polymerase chain reaction (RT–qPCR), Western blotting, and TUNEL analysis. Results: The results demonstrated successful isolation of hAMSC-Exos via ultracentrifugation, as the isolated cells were positive for CD9 (79.7%) and CD63 (80.2%). Treatment with hAMSC-Exos significantly mitigated the reduction in cell viability induced by LPS. Flow cytometry revealed that LPS-induced damage promoted apoptosis, but this effect was attenuated by treatment with hAMSC-Exos. Additionally, the expression of caspase-3 and caspase-9 and the Bcl-2/Bax ratio indicated that excessive apoptosis could be attenuated by treatment with hAMSC-Exos. Furthermore, tail vein injection of hAMSC-Exos improved the neurobehavioral function of CP rats. Histological analysis via HE and TUNEL staining showed that apoptosis-related damage was attenuated following hAMSC-Exo treatment. Conclusions: In conclusion, hAMSC-Exos effectively promote neuronal cell survival by regulating apoptosis, indicating their potential as a promising therapeutic option for CP that merits further investigation.

As important yield-related traits, thousand-grain weight (TGW), grain number per spike (GNS) and grain weight per spike (GWS) are crucial components of wheat production. To dissect their underlying genetic basis, a double haploid (DH) population comprised of 198 lines derived from 8762/Keyi 5214 was constructed. We then used genechip to genotype the DH population and integrated the yield-related traits TGW, GNS and GWS for QTL mapping. Finally, we obtained a total of 18 942 polymorphic SNP markers and identified 41 crucial QTLs for these traits. Three stable QTLs for TGW were identified on chromosomes 2D (QTgw-2D.3 and QTgw-2D.4) and 6A (QTgw-6A.1), with additive alleles all from the parent 8762, explaining 4.81–18.67% of the phenotypic variations. Five stable QTLs for GNS on chromosomes 3D, 5B, 5D and 6A were identified. QGns-5D.1 was from parent 8762, while the other four QTLs were from parent Keyi 5214, explaining 5.89–7.08% of the GNS phenotypic variations. In addition, a stable GWS genetic locus QGws-4A.3 was detected from the parent 8762, which explained 6.08–6.14% of the phenotypic variations. To utilize the identified QTLs, we developed STARP markers for four important QTLs, Tgw2D.3-2, Tgw2D.4-1, Tgw6A.1 and Gns3D.1. Our results provide important basic resources and references for the identification and cloning of genes related to TGW, GNS and GWS in wheat.

Background Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA. Methods RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment. Results A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway. Conclusions The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.

BackgroundWe explored the characteristics of single-cell differentiation data in glioblastoma and established prognostic markers based on CRYAB to predict the prognosis of glioblastoma patients. Aberrant expression of CRYAB is associated with invasive behavior in various tumors, including glioblastoma. However, the specific role and mechanisms of CRYAB in glioblastoma are still unclear.MethodsWe assessed RNA-seq and microarray data from TCGA and GEO databases, combined with scRNA-seq data on glioma patients from GEO. Utilizing the Seurat R package, we identified distinct survival-related gene clusters in the scRNA-seq data. Prognostic pivotal genes were discovered through single-factor Cox analysis, and a prognostic model was established using LASSO and stepwise regression algorithms. Moreover, we investigated the predictive potential of these genes in the immune microenvironment and their applicability in immunotherapy. Finally, in vitro experiments confirmed the functional significance of the high-risk gene CRYAB.ResultsBy analyzing the ScRNA-seq data, we identified 28 cell clusters representing seven cell types. After dimensionality reduction and clustering analysis, we obtained four subpopulations within the oligodendrocyte lineage based on their differentiation trajectory. Using CRYAB as a marker gene for the terminal-stage subpopulation, we found that its expression was associated with poor prognosis. In vitro experiments demonstrated that knocking out CRYAB in U87 and LN229 cells reduced cell viability, proliferation, and invasiveness.ConclusionThe risk model based on CRYAB holds promise in accurately predicting glioblastoma. A comprehensive study of the specific mechanisms of CRYAB in glioblastoma would contribute to understanding its response to immunotherapy. Targeting the CRYAB gene may be beneficial for glioblastoma patients.

Abstract Objectives This study aimed to investigate the mechanism of cognitive control impairment in patients with schizophrenia (SPs) using electroencephalogram (EEG). Methods A total of 17 SPs and 17 healthy controls (HCs) were included in this study. We measured the EEG activity, whereas they performed the AX‐continuous performance test which consisted of the preparatory phase and the response phase. The MATRICS Consensus Cognitive Battery (MCCB) was used for cognitive function, and the Positive and Negative Syndrome Scale (PANSS) was used for clinical symptom assessment. A univariate linear regression model was used to explore the relationships among behavioral index, event‐related potentials (ERPs), rhythmic oscillation power, and score of MCCB and PANSS. Results A significant difference was found in response accuracy and reaction time (RT) during the preparatory phase between patients and HCs (p

ABSTRACTAsparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P = .017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR: 1.009, 95% CI:0.370–2.752, P = .986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase.

In a low-Earth orbit (LEO) satellite network, the satellite operation speed is high, the operation cycle is short, and intersatellite links change dynamically. To sense the intersatellite link state in time and select the correct route for an intelligent routing decision, a dendritic network-based intelligent-aware routing algorithm for LEO satellites is proposed in this paper. This algorithm divides the intersatellite link routing of an LEO satellite network into situation-aware, quality-aware, and routing-decision stages and establishes a routing policy framework with real-time correction capability from the source node to the destination. This approach overcomes the problems of the limited selection of routing paths from fixed labels of existing deep learning-based routing algorithms and the long convergence time of reinforcement learning-based routing algorithms.In the intersatellite link situational awareness stage, the intersatellite visibility of the entire LEO satellite network is periodically obtained by analyzing the constraint conditions of the intersatellite link establishment. In the intersatellite link quality perception stage, the final output of the probabilistic forwarding matrix based on the ant colony algorithm is used as the label of the training set, and the corresponding intersatellite link quality is evaluated using the probability value of the current node by selecting the next hop node. By changing the weight coefficients in the path cost function under different load states, more effective training set label data can be collected, which can be consequently used to improve the performance of the trained dendritic network. Moreover, the training set can be optimized in real-time through semi-supervised learning. The trained dendritic network is used to analyze and process the link state parameters, perceive the comprehensive service quality of the link, and output the evaluation value matrix of the next hop routing. It is also used to automatically adjust the weight of the global satellite network link. Meanwhile, the traditional Dijkstra algorithm is optimized to realize the quality perception of the intersatellite link. In the routing decision stage, the reciprocal of the evaluation value matrix is used as the adjacency matrix to pass the shortest-path algorithm. Then, the initial routing path between the source and destination nodes is obtained. Finally, the initial path is corrected via periodic monitoring to cope with the failure of the satellite node. The simulation results show that the routing algorithm based on the dendritic network has low computational complexity and fast convergence. The algorithm can determine the status of the intersatellite link establishment in time, assess the quality of the intersatellite link in real-time, and automatically avoid congested satellite nodes. Accordingly, its end-to-end path delay, delay jitter, and packet loss rate are lower than those of the traditional heuristic routing algorithm and Dijkstra routing algorithm.

ObjectiveThis paper observes the efficacy of chemotherapy combined with CD19 and CD20 monoclonal antibodies in clearing minimal residual disease (MRD) and bridging transplantation for refractory acute B-lymphoblastic leukemia (B-ALL) in children and reviews the literature.MethodsA 4-year-old boy diagnosed with B-ALL in our hospital was treated with the SCCLG-ALL-2016 protocol. MRD and gene quantification decreased after induction but remained persistently positive, with poor efficacy. After this patient received three cycles of consolidation chemotherapy combined with blinatumomab and rituximab, MRD and fusion gene quantification became negative, and he received allogeneic hematopoietic stem cell transplantation (allo-HSCT).ResultsDuring the use of monoclonal antibodies, neurotoxicity, CRS, or other side effects did not occur. Before transplantation, MRD became negative, and the bone marrow had been in complete remission since transplantation (13 months).ConclusionChemotherapy combined with blinatumomab for refractory B-ALL in children can bring a better remission rate for patients and is a means of bridging transplantation. Nevertheless, sequential CD20 monoclonal antibody therapy is the first report , and no adverse effects were observed in our case. It is well tolerated and can be used as one of the treatments for refractory B-ALL.

Ensemble learning, online learning and deep learning are very effective and versatile in a wide spectrum of problem domains, such as feature extraction, multi-class classification and retrieval. In this paper, combining the ideas of ensemble learning, online learning and deep learning, we propose a novel deep learning method called deep error-correcting output codes (DeepECOCs). DeepECOCs are composed of multiple layers of the ECOC module, which combines several incremental support vector machines (incremental SVMs) as base classifiers. In this novel deep architecture, each ECOC module can be considered as two successive layers of the network, while the incremental SVMs can be viewed as weighted links between two successive layers. In the pre-training procedure, supervisory information, i.e., class labels, can be used during the network initialization. The incremental SVMs lead this procedure to be very efficient, especially for large-scale applications. We have conducted extensive experiments to compare DeepECOCs with traditional ECOC, feature learning and deep learning algorithms. The results demonstrate that DeepECOCs perform, not only better than existing ECOC and feature learning algorithms, but also related to deep learning ones in most cases.

IntroductionArsenic trioxide (ATO) is a promising anticancer drug for hematological malignancy. Given the dramatic efficacy of acute promyelocytic leukemia (APL), ATO has been utilized in other types of cancers, including solid tumors. Unfortunately, the results were not comparable with the effects on APL, and the resistance mechanism has not been clarified yet. This study intends to identify relevant genes and pathways affecting ATO drug sensitivity through genome-wide CRISPR-Cas9 knockdown screening to provide a panoramic view for further study of ATO targets and improved clinical outcomes.MethodsA genome-wide CRISPR-Cas9 knockdown screening system was constructed for ATO screening. The screening results were processed with MAGeCK, and the results were subjected to pathway enrichment analysis using WebGestalt and KOBAS. We also performed protein-protein interaction (PPI) network analysis using String and Cytoscape, followed by expression profiling and survival curve analysis of critical genes. Virtual screening was used to recognize drugs that may interact with the hub gene.ResultsWe applied enrichment analysis and identified vital ATO-related pathways such as metabolism, chemokines and cytokines production and signaling, and immune system responses. In addition, we identified KEAP1 as the top gene relating to ATO resistance. We found that KEAP1 expression was higher in the pan-cancer, including ALL, than in normal tissue. Patients with acute myeloid leukemia (AML) with higher KEAP1 expression had worse overall survival (OS). A virtual screen showed that etoposide and eltrombopag could bind to KEAP1 and potentially interact with ATO.DiscussionATO is a multi-target anticancer drug, and the key pathways regulating its sensitivity include oxidative stress, metabolism, chemokines and cytokines, and the immune system. KEAP1 is the most critical gene regulating ATO drug sensitivity, which is related to AML prognosis and may bind to some clinical drugs leading to an interaction with ATO. These integrated results provided new insights into the pharmacological mechanism of ATO and potentiate for further applications in cancer treatments.

Introduction: This study investigates risk factors underlying the prognosis of severe aspiration pneumonia (SAP) in intensive care unit (ICU) patients and attempts to provide early prognosis reference for clinical tasks.Methods: Patients diagnosed with SAP and admitted to the ICU of Jinshan Hospital, Fudan University, Shanghai, China, between January 2021 and December 2021 were recruited in this retrospective cohort study. Clinical data on a patient’s general condition, underlying diseases, laboratory indicators, and 90-day outcomes (survival or death) were recorded.Results: Multivariate logistic regression analysis showed that a low platelet count was an independent risk factor affecting the prognosis of death (OR = 6.68, 95% CI:1.10–40.78, β = 1.90, P = 0.040). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of variables; cut-off values were calculated and the area under the curve was 0.7782 [(95% CI:0.686–0.871), p < 0.001] for the prediction of death at 90 days in all patients. The Kaplan-Meier curve used for survival analysis showed that, compared with the normal platelet group, the overall survival rate of patients with low platelet levels was significantly lower, and the difference was statistically significant [HR = 2.11, (95% CI:1.47–3.03), p = 0.0001, z = 4.05, X2 = 14.89]. Cox regression analysis, used to further verify the influence of prognostic risk factors, showed that a concurrent low platelet count was the most important independent risk factor affecting the prognosis of SAP (HR = 2.12 [95% CI:1.12–3.99], X2 = 50.95, p = 0.021).Conclusion: These findings demonstrate an association between SAP mortality and platelet levels on admission. Thus, platelet level at admission may be used as a readily available marker for assessing the prognosis of patients with SAP.

AIM:A total of 1 084 preschool children in 4 kindergartens in Xining City were surveyed on their visual acuity and refraction status to find out abnormal vision and refraction beyond the normal range. METHODS: A cross-sectional survey study. The overall sampling method was used on October 2019, a total of 1 084 preschool children aged 3-6 years were selected from a kindergarten in the east, west, south and north of Xining City. The children were checked for uncorrected distance vision and refractive status was checked by using a refractive screener.RESULTS: The detection rate of abnormal vision in preschool children in Xining City was 12.21%, and the detection rate of abnormal vision increased with the increasing age(χ2lineartrend=94.40, P0.05).CONCLUSION: The abnormal visual acuity of preschool children in Xining City gradually increases with the increasing age; The refractive state is dominated by astigmatism, among which the proportion of mixed astigmatism and pure myopia astigmatism is the highest, followed by pure hyperopic astigmatism and compound hyperopic astigmatism; With the increase of age, the diopter of compound hyperopic astigmatism gradually decreases, which is in line with the law of children's eye refractive development.

Abstract The pathogenesis of lung cancer, the most common cancer, is complex and unclear, leading to limited treatment options and poor prognosis. To provide molecular insights into lung cancer development, we investigated the function and underlying mechanism of SH2B3 in the regulation of lung cancer. We indicated SH2B3 was diminished while TGF-β1 was elevated in lung cancer tissues and cells. Low SH2B3 level was correlated with poor prognosis of lung cancer patients. SH2B3 overexpression suppressed cancer cell anoikis resistance, proliferation, migration, invasion, and EMT, while TGF-β1 promoted those processes via reducing SH2B3. SH2B3 bound to JAK2 and SHP2 to repress JAK2/STAT3 and SHP2/Grb2/PI3K/AKT signaling pathways, respectively, resulting in reduced cancer cell anoikis resistance, proliferation, migration, invasion, and EMT. Overexpression of SH2B3 suppressed lung cancer growth and metastasis in vivo. In conclusion, SH2B3 restrained the development of anoikis resistance and EMT of lung cancer cells via suppressing JAK2/STAT3 and SHP2/Grb2/PI3K/AKT signaling cascades, leading to decreased cancer cell proliferation, migration, and invasion.

Most of the dimensionality reduction algorithms assume that data are independent and identically distributed (i.i.d.). In real-world applications, however, sometimes there exist relationships between data. Some relational learning methods have been proposed, but those with discriminative relationship analysis are lacking yet, as important supervisory information is usually ignored. In this paper, we propose a novel and general framework, called relational Fisher analysis (RFA), which successfully integrates relational information into the dimensionality reduction model. For nonlinear data representation learning, we adopt the kernel trick to RFA and propose the kernelized RFA (KRFA). In addition, the convergence of the RFA optimization algorithm is proved theoretically. By leveraging suitable strategies to construct the relational matrix, we conduct extensive experiments to demonstrate the superiority of our RFA and KRFA methods over related approaches.

Abstract Background Knee osteoarthritis (KOA) is a common degenerative disease that causes pain, functional impairment, and reduced quality of life. Resistance training is considered as an effective approach to reduce the risk of muscle weakness in patients with KOA. Blood flow restriction (BFR) with low-load resistance training has better clinical outcomes than low-load resistance training alone. However, the degree of BFR which works more effectively with low-load resistance training has not been determined. The purpose of this study is to evaluate the effectiveness of different degrees of BFR with low-load resistance training in patients with KOA on pain, self-reported function, physical function performance, muscle strength, muscle thickness, and quality of life. Methods This is a study protocol for a randomized, controlled trial with blinded participants. One hundred individuals will be indiscriminately assigned into the following groups: two training groups with a BFR at 40% and 80% limb occlusion pressure (LOP), a training group without BFR, and a health education group. The three intervention groups will perform strength training for the quadriceps muscles twice a week for 12 weeks, while the health education group will attend sessions once a week for 12 weeks. The primary outcome is pain. The secondary outcomes include self-reported function, physical function performance, muscle strength of the knee extensors, muscle mass of the quadriceps, quality of life, and adverse events. Intention-to-treat analysis will be conducted for individuals who withdraw during the trial. Discussion Previous studies have shown that BFR with low-load resistance training is more effective than low-load resistance training alone; however, a high degree of BFR may cause discomfort during training. If a 40% LOP for BFR could produce similar clinical outcomes as an 80% LOP for BFR, resistance training with a low degree of BFR can be chosen for patients with KOA who are unbearable for a high degree of BFR. Trial registration Chinese Clinical Trial Registry ChiCTR2000037859 ( http://www.chictr.org.cn/edit.aspx?pid=59956&htm=4 ). Registered on 2 September 2020

Hyperoside (Hyp), a kind of Chinese herbal medicine, exerts multiple therapeutic effects on many diseases. However, the role and mechanisms of Hyp in vascular pathophysiology in ischemic stroke need to be further established. The study aimed to investigate the role of (large-conductance Ca2+-activated K+) BK channels on the vasoprotection of Hyp against cerebral ischemia and reperfusion (I/R) injury in rats. The concentration gradient of Hyp was pretreated in both the middle cerebral artery occlusion and reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) model of primary vascular smooth muscle cells (VSMCs) in rats. A series of indicators were detected, including neurological deficit score, infarct volume, malondialdehyde (MDA), superoxide dismutase (SOD), cerebral blood flow (CBF), cell viability, membrane potential, and BK channels α- and β1-subunits expression. The results showed that Hyp significantly reduced infarct volume and ameliorated neurological dysfunction in I/R-injured rats. Besides, the effects of I/R-induced reduction of BK channels α- and β1-subunits expression were significantly reversed by Hyp in endothelial-denudated cerebral basilar arteries. Furthermore, the protective effect against I/R-induced increases of MDA and reduction of SOD as well as CBF induced by Hyp was significantly reversed by iberiotoxin (IbTX). In OGD/R-injured VSMCs, downregulated cellular viability and BK channels β1-subunits expression were remarkably reversed by Hyp. However, neither OGD/R nor Hyp affected BK channels α-subunits expression, and Hyp failed to induced hyperpolarization of VSMCs. Moreover, the protective effect against OGD/R-induced reduction of cell viability and SOD level and increases of MDA production induced by Hyp was significantly reversed by IbTX in VSMCs. The study indicates that Hyp has the therapeutic potential to improve vascular outcomes, and the mechanism is associated with suppressing oxidative stress and improving CBF through upregulating BK channels.

Although arsenic trioxide (ATO) shows a strong anti-tumor effect in the treatment of acute promyelocytic leukemia, it does not benefit patients with hepatocellular carcinoma (HCC). Thus, combination therapy is proposed to enhance the efficacy of ATO. Parthenolide (PTL), a natural compound, selectively eradicates cancer cells and cancer stem cells with no toxicity to normal cells. In this study, we chose PTL and ATO in combination and found that nontoxic dosage of PTL and ATO co-treatment can synergistically inhibit the in vitro and in vivo proliferation activity of HCC cells through suppressing stemness and self-renewal ability and inducing mitochondria-dependent apoptosis. More importantly, USP7-HUWE1-p53 pathway is involved in PTL enhancing ATO-induced apoptosis of HCC cell lines. Meanwhile, accompanied by induction of apoptosis, PTL and ATO evoke autophagic activity via inhibiting PI3K/Akt/mTOR pathway, and consciously controlling autophagy can improve the anti-HCC efficacy of a combination of PTL and ATO. In short, our conclusion represents a novel promising approach to the treatment of HCC.

Abstract Background Considering the high morbidity and mortality of lung cancer and the high incidence of pulmonary nodules, clearly distinguishing benign from malignant lung nodules at an early stage is of great significance. However, determining the kind of lung nodule which is more prone to lung cancer remains a problem worldwide. Methods A total of 480 patients with pulmonary nodule data were collected from Shandong, China. We assessed the clinical characteristics and computed tomography (CT) imaging features among pulmonary nodules in patients who had undergone video‐assisted thoracoscopic surgery (VATS) lobectomy from 2013 to 2018. Preliminary selection of features was based on a statistical analysis using SPSS. We used WEKA to assess the machine learning models using its multiple algorithms and selected the best decision tree model using its optimization algorithm. Results The combination of decision tree and logistics regression optimized the decision tree without affecting its AUC. The decision tree structure showed that lobulation was the most important feature, followed by spiculation, vessel convergence sign, nodule type, satellite nodule, nodule size and age of patient. Conclusions Our study shows that decision tree analyses can be applied to screen individuals for early lung cancer with CT. Our decision tree provides a new way to help clinicians establish a logical diagnosis by a stepwise progression method, but still needs to be validated for prospective trials in a larger patient population.

ObjectivesThe prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children’s Leukemia Group (SCCLG).MethodsA total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction.ResultsThe frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P

Helicobacter pylori (H. pylori)-derived vacuolating cytotoxin A (VacA) causes damage to various organelles, including mitochondria, and induces autophagy and cell death. However, it is unknown whether VacA-induced mitochondrial damage can develop into mitophagy. In this study, we found that H. pylori, H. pylori culture filtrate (HPCF), and VacA could activate autophagy in a gastric epithelial cell line (GES-1). VacA-caused mitochondrial depolarization retards the import of PINK1 into the damaged mitochondria and evokes mitophagy. And, among mass spectrometry (LC-MS/MS) identified 25 mitochondrial proteins bound with VacA, Tom20, Tom40, and Tom70, TOM complexes responsible for PINK1 import, were further identified as having the ability to bind VacA in vitro using pull-down assay, co-immunoprecipitation, and protein–protein docking. Additionally, we found that the cell membrane protein STOM and the mitochondrial inner membrane protein PGAM5 also interacted with VacA. These findings suggest that VacA captured by STOM forms endosomes to enter cells and target mitochondria. Then, VacA is transported into the mitochondrial membrane space through the TOM complexes, and PGAM5 aids in inserting VacA into the inner mitochondrial membrane to destroy the membrane potential, which promotes PINK1 accumulation and Parkin recruitment to induce mitophagy. This study helps us understand VacA entering mitochondria to induce the mitophagy process.

ObjectiveEven though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL.MethodChildren with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children’s leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram.ResultThe parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan–Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated.ConclusionThe nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

AIM: To observe the effect of AGGF1 on the proliferation, migration and tube formation of retinal endothelial cells in diabetic retinal tissue and high glucose conditions.METHODS: C57BL/6J mice were randomly divided into the control group and diabetic retinopathy(DR)model group. The cultured rhesus monkey choroido-retinal endothelial cells(RF/6A cells)were randomly divided into the control group(cultured in low-glucose environment)and the high-glucose group(cultured in medium with 25mmol/L D-glucose), and the AGGF1 protein expression in the cells was detected by immunofluorescence assay. RF/6A cells were then divided into the control group and AGGF1 treatment group, and cell proliferation, migration and tube formation was detected by CCK-8, Transwell and Matrigel, respectively.RESULTS: AGGF1 protein was expressed in all layers of the retinas and in vascular endothelial cells. The expression of AGGF1 in the retinas of DR group(0.17±0.05)was significantly higher than that of the control group(0.07±0.02)(PPPPPPPPCONCLUSION: The expression of AGGF1 protein was significantly increased in diabetic retinal tissues and retinal vascular endothelial cells induced by high glucose. AGGF1 can promote the proliferation, migration and tube formation of retinal vascular endothelial cells, suggesting that AGGF1 may be involved in retinal neovascularization of DR.

AIM: To summarize quantitatively the prospective association between physical activity and age-related cataract (ARC) risk. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for all relevant follow up studies until July 2019. Multivariable-adjusted relative risks (RRs) and corresponding 95% confidence intervals (CIs) from individual studies were used to calculate the overall summary estimates. The dose-response relationship was assessed using generalized least-squares trend estimation. RESULTS: Six prospective cohort studies, involving 19 173 cases in 6.2-12.1y follow up of 171 620 participants, were included in the analysis. Increased physical activity was significantly associated with reduced risk of ARC by 10% (RR: 0.90; 95%CI: 0.81, 0.99, P=0.04). Stratified analysis by assessment method for physical activity suggest that studies using metabolic equivalent (MET) per day tended to report a slightly stronger association with ARC (RR: 0.85; 95%CI: 0.81, 0.90, P

Abstract Background Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. Buyang Huanwu Tang (BYHWT), a classical traditional Chinese medicine formula, has been widely utilized for the treatment of PF in China. This present study aimed to explore the mechanism of BYHWT in the treatment of PF in vitro. Methods TGF-β1 stimulated human alveolar epithelial A549 cells were used as in vitro model for PF. Post the treatment of BYHWT, cell viability was measured by MTT assay, and cell morphology was observed under microscope. The epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, Vimentin) and collagen I (Col I) were detected by western blot, immunofluorescence staining and real-time quantitative polymerase chain reaction. With the co-administration of activators (IGF-1, SC79) and inhibitors (LY294002, MK2206), the effect of BYHWT on PI3K/Akt pathway was analyzed by western blot. Results BYHWT inhibited cell growth, and prevented cell morphology changed from epithelial to fibroblasts in TGF-β1 induced A549 cells. BYHWT decreased Vimentin and Col I, while increased E-cadherin at both protein and mRNA levels. Moreover, phosphorylation of PI3K (p-PI3K) and phosphorylation of Akt (p-Akt) were significantly down-regulated by BYHWT in TGF-β1 stimulated A549 cells. Conclusion These results indicate that BYHWT suppressed TGF-β1-induced collagen accumulation and EMT of A549 cells by inhibiting the PI3K/Akt signaling pathway. These findings suggest that BYHWT may have potential for the treatment of PF.

As a classic and well-performed deep convolutional neural network, DenseNet links every layer to each of its preceding layers via skip connections. However, the dense connectivity of the links leads to much redundance, consuming lots of computational resources. In this paper, to automatically prune redundant skip connections in DenseNet, we introduce a novel reinforcement learning method called automatic DenseNet sparsification (ADS). In ADS, we use adjacent matrix to represent dense connections in DenseNet, and design an agent using recurrent neural networks (RNNs) to sparsify the matrix, i. e. removing redundant skip connections in DenseNet. The validation accuracies of the sparsified DenseNets are used as rewards to update the agent, which promotes the agent to generate sparsified DenseNets with high performance. Extensive experiments demonstrate the effectiveness of ADS: The performance of the sparsified DenseNet surpasses not only the original DenseNet but related models; Moreover, the sparsified DenseNet has strong transferability when it is applied to new tasks. More importantly, ADS is very efficient. For the compression of a 40-layer DenseNet, it takes less than 1 day on a single GPU.

Neuropsychiatric disorders represent a set of severe and complex mental illnesses, and the exact etiologies of which are unknown. It has been well documented that impairments in the early development of the brain contribute to the pathogenesis of many neuropsychiatric disorders. Currently, the diagnosis of neuropsychiatric disorders largely relies on subjective cognitive assessment, because there are no widely accepted biochemical or genetic biomarkers for diagnosing mental illness. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNA (ncRNA) with a closed-loop structure. In recent years, there have been tremendous advances in our understanding of the expression profiles and biological roles of circRNAs. In the brain, circRNAs are particularly enriched and are expressed more abundantly in contrast to linear counterpart transcripts. They are highly active at neuronal synapses. These features make circRNAs uniquely crucial for understanding brain health, disease, and neuropsychiatric disorders. This review focuses on the role of circRNAs in early brain development and other brain-related processes that have been associated with the development of neuropsychiatric disorders. In addition, we discuss the potential for blood or cerebrospinal fluid circRNAs to be used as novel biomarkers in the early diagnosis of neuropsychiatric disorders. The findings reviewed here may provide new insight into the pathological mechanisms underlying the onset and progression of neuropsychiatric disorders.

Introduction. The diagnosis of pulmonary infection and the identification of pathogens are still clinical challenges in immunocompromised patients. Metagenomic next-generation sequencing (mNGS) has emerged as a promising infection diagnostic technique. However, its diagnostic value in immunocompromised patients needs further exploration. Purposes. This study was to evaluate the diagnostic value of mNGS compared with comprehensive conventional pathogen tests (CTs) in the etiology of pneumonia in immunocompromised patients and immunocompetent patients. Methods. We retrospectively reviewed 53 patients who were diagnosed with pneumonia from May 2019 to June 2021. There were 32 immunocompromised patients and 21 immunocompetent patients with pneumonia who received both mNGS and CTs. The diagnostic performance was compared between mNGS and CTs in immunocompromised patients, using the composite diagnosis as the reference standard. And, the diagnostic value of mNGS for mixed infections was further analyzed. Results. Compared to immunocompetent patients, the most commonly pathogens, followed by Cytomegalovirus, Pneumocystis jirovecii and Klebsiella pneumoniae in immunocompromised patients. Furthermore, more mixed infections were diagnosed, and bacterial-fungal-virus coinfection was the most frequent combination (43.8%). mNGS can detect more types of pathogenic microorganisms than CTs in both groups (78.1% vs. 62.5%, P=0.016and 57.1% vs. 42.9%, P=0.048). The overall diagnostic positive rate of mNGS for pathogens was higher in immunocompromised patients (P=0.002). In immunocompromised patients, a comparable diagnostic accuracy of mNGS and CTs was found for bacterial, fungal, and viral infections and coinfection. mNGS had a much higher sensitivity for bacterial infections (92.9% vs. 50%, P

Background: The activation of subcutaneous mast cells (MCs) helps to trigger the analgesic effect induced by acupuncture (AP), a traditional oriental therapy, that has been gradually accepted worldwide. This work aimed to reveal whether the serotonin (5-hydroxytryptamine, 5-HT) released from MCs plays an important role in this process, which has a controversial effect in the mechanism of pain. Methods: In vivo tests, a 20-min session of AP was applied at Zusanli acupuncture point (acupoint) of acute ankle arthritis rats. Pain thresholds of the injured hindpaw were assessed to reflect the pain state, and the targeting substances in the interstitial space of the treated acupoint were sampled by microdialysis. In vitro experiments, exogenous 5-HT (exo-5-HT) was introduced to mediate adenosine triphosphate (ATP) release from cultured MCs. Results: Needling promoted 5-HT accumulation at the Zusanli acupoint, which was prevented by sodium cromolyn. AP’s analgesic effect was suppressed by the inhibition of 5-HT receptors at the acupoint, especially 5-HT1A subtype. In vitro tests, mechanical perturbation mimicking needling stimulation induced MCs to release 5-HT. 1 μM and 10 μM of exo-5-HT facilitated ATP release, which was restrained by blocking of 5-HT1 receptors rather than 5-HT3 receptors. As 5-HT, ATP and adenosine were also transiently accumulated in the treated acupoint during needling. Promoting ATP hydrolysis or activation adenosine A1 receptors duplicated AP analgesic effect. Finally, the inhibition of ATP receptors by suramin or pyridoxal phosphate-6-azo tetrasodium salt hydrate (PPADS) prevented AP analgesic effect. Conclusions: Our results suggest that MC-associated 5-HT release at acupoints contributes to AP analgesia, and the mediation of ATP secretion through 5-HT1A receptors might be the underlying mechanism at play. ATP could facilitate adenosine production or the propagation of needling signals.

Abstract Background Knee osteoarthritis (KOA) is one of the most common bone and joint diseases. As one of the main non-drug therapies, acupuncture is widely used to treat KOA, although the evidence for its efficacy is inconclusive. The objective of this pilot trial is to clarify the clinical efficacy and safety of fire acupuncture in the treatment of mild to moderate KOA and to provide high-quality data for further research. Methods/design This study is a prospective randomized controlled pilot trial in which 120 patients with mild to moderate KOA will be randomly allocated in equal proportions to a fire acupuncture group or a general acupuncture group. They will receive acupuncture for six sessions over 2 weeks. The primary end point is success rate, which will be calculated based on the change from baseline of the pain and function scores in the Western Ontario and McMaster Universities Osteoarthritis Index at 4 weeks. Secondary end points include the proportion of patients achieving clinical improvement based on: (1) the OMERACT-OARSI responder criteria, (2) levels of matrix metalloproteinase 3, interleukin 1β, and tumor necrosis factor α in blood, and (3) a subjective efficacy evaluation from patients. Trial registration Chinese Clinical Trial Registry, ChiCTR1800019162. Registered on 29 October 2018.

PurposeTo analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value.MethodA total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers.ResultsIn total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age

Abstract Background China has the world’s largest aging population and the number of empty-nest older adults is on the rise. In comparison to the aging population in general, empty-nest older adults have a lower level of subjective well-being and poorer mental health status due to a lack of emotional support from their children. The aim of this study is to conduct an empirical study to evaluate the efficacy of the ‘Path-oriented Psychological Self-help Intervention’ (P-oPSI) led by nurses on the mental health of empty-nest older adults in the community, to provide a scientific foundation for improving their quality of life. Methods A Quasi-Experimental controlled intervention study was conducted from 2015 to 2017. A total of 76 empty-nest older adults from 2 districts were recruited using a convenience sampling and assigned to 2 groups based on their residential communities in the city of Chifeng in the Inner Mongolia Autonomous Region, China. The wait list control group participated in a mental health lecture to gain knowledge and learn techniques of mental health promotion. The intervention group additionally received 1 month of training in a nurse-led ‘P-oPSI’ for a month. Both groups were followed-up for 3 months. Mental health status, coping styles, and psychological self-help ability of the participating empty nest older adults were assessed at the baseline, 1 month, and 3-months follow up, respectively. Two-way analysis of variance and a simple effect test were used to analyse the differences of the two groups. Results The P-oPSI yielded a greater benefit for the mental health status, coping styles, and psychological self-help ability of the participants in the intervention group. Combined with a simple effect test, the scores of the mental health status, positive coping style, and psychological self-help ability of those in the intervention group significantly increased at 1 month after the baseline (F mental health status = 7.59, F positive coping style = 7.24, F psychological self-help ability = 7.07); and the sustainable effect of this program lasted for 3 months after the intervention (F mental health status = 13.24, F positive coping style = 10.42, F psychological self-help ability = 10.45), which reached statistical significance (P

In recent years, deep neural networks (DNNs) have been widely applied in many areas, such as computer vision and pattern recognition. However, we observe that most of the DNNs include redundant layers. Hence, in this paper, we introduce a novel method named incremental layers resection (ILR) to resect the redundant layers in DNNs, while preserving their learning performances. ILR uses a multistage learning strategy to incrementally resect the inconsequential layers. In each stage, it preserves the data representations learned by the original network, while connecting the two nearby layers of each resected one. Particularly, based on a teacher-student knowledge transfer framework, we have designed the layer-level learning and overall learning procedures to enforce the resected network performing similarly with the original one. Extensive experiments demonstrate that, compared to the original networks, the compressed ones by ILR need only about half of the storage space and have higher inference speed. More importantly, they even deliver higher classification accuracy than the original networks.

Background: Neural precursor cell-expressed developmentally downregulated 4 (NEDD4) polymorphisms and childhood trauma (CT) are associated with schizophrenia. However, whether NEDD4 interacts with CT on symptoms of schizophrenia remains unknown. This study aimed to investigate the gene–environment interaction effect.Methods: We recruited 289 schizophrenia patients and 487 controls and genotyped rs2303579, rs3088077, rs7162435, rs11550869, and rs62043855 in their NEDD4 gene.Results: We found significant differences in the rs2303579 and rs3088077 between the two groups. Patients with the rs2303579 CC genotype had higher scores compared with other genotype (P = 0.026) in the test of positive schizophrenia syndrome scores, whereas patients with the rs3088077 TT (P = 0.037) and rs7162435 CC genotypes (P = 0.009) had higher scores compared with the other genotypes in the test of excitement factor. Patients with a family history of psychosis (FH+) reported higher negative scores (P = 0.012) than those without. Patients exposed to physical abuse (PA) reported a lower language learning and memory score (P = 0.017) and working memory score (P = 0.047) than those not. Patients exposed to sexual abuse (SA) reported a lower reasoning and problem-solving skills score (P = 0.025); those exposed to emotional neglect (EN) reported a lower social cognition score (P = 0.044); and those exposed to physical neglect reported a lower social cognition score (P = 0.036) but higher visual learning and memory score (P = 0.032). Rs3088077 could interact with EN to increase risk for schizophrenia. Optimal model rs62043855 × EA, rs3088077 × rs7162435 × rs11550869 × SA × EN and rs2303579 × rs7162435 × rs11550869 × rs62043855 × EA × PA could explain positive symptom, excitement symptom and working memory, respectively, in FH+ group.Conclusion: The study highlighted that the combined interaction of NEDD4 and CT may be associated with symptoms of schizophrenia especially for those with FH+.

This review summarizes experimental evidence indicating that subcutaneous mast cells are involved in the trigger mechanism of analgesia induced by acupuncture, a traditional oriental therapy, which has gradually become accepted worldwide. The results are essentially based on work from our laboratories. Skin mast cells are present at a high density in acupuncture points where fine needles are inserted and manipulated during acupuncture intervention. Mast cells are sensitive to mechanical stimulation because they express multiple types of mechanosensitive channels, including TRPV1, TRPV2, TRPV4, receptors and chloride channels. Acupuncture manipulation generates force and torque that indirectly activate the mast cells via the collagen network. Subsequently, various mediators, for example, histamine, serotonin, adenosine triphosphate and adenosine, are released from activated mast cells to the interstitial space; they or their downstream products activate the corresponding receptors situated at local nerve terminals of sensory neurons in peripheral ganglia. The analgesic effects are thought to be generated via the reduced electrical activities of the primary sensory neurons. Alternatively, these neurons project such signals to pain-relevant regions in spinal cord and/or higher centers of the brain.

AIM: To evaluate the efficacy and safety of vitrectomy with internal limiting membrane (ILM) peeling for diabetic macular edema (DME). METHODS: The PubMed, Embase, Web of Science, Cochrane, SionMed, ClinicalTrials.gov, CNKI databases and Wanfang databases, published until Oct. 2017, were searched to identify studies comparing the clinical outcomes following vitrectomy with and without ILM peeling, for treating DME. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for vitrectomy with and without ILM peeling with regard to best corrected visual acuity (BCVA), central macular thickness (CMT), and complication incidents. RESULTS: A total of 14 studies involving 857 eyes were included of which three studies were Chinese and the rests were English literatures. Meta-analysis indicated that compared with vitrectomy alone, vitrectomy with ILM peeling could improve BCVA more obviously (OR=1.66, 95%CI: 1.12-2.46, P=0.01) and had higher rate of CMT reduction (OR=3.89, 95%CI: 1.37-11.11, P=0.01). There were significant statistical differences between the two surgical methods for both BCVA and CMT (P

Objective To compare the difference of the rate of cholesterol crystals in thrombi obtained from patients of acute ischemic stroke with different etiologies and the effect of thrombi containing cholesterol crystals on vascular recanalization. Methods A total of 92 patients with acute ischemic stroke caused by intracranial large vascular occlusion underwent endovascular treatment, such as catheter suction, thrombectomy, balloon dilatation and stent implantation. Histopathological examinations of the retrieved thrombi were performed. Results Of 92 cases, 81 cases (88.04%) achieved recanalization [Thrombolysis in Cerebral Infarction (TICI) ≥ 2b]. Thrombi were retrieved in 66 cases (71.74%) and 63 cases (68.48%)performed pathological examinations, among whom 26 cases (41.27%) were atherothrombosis (AT), 24 cases (38.10%) were cardioembolism (CE), 2 (3.17%) were stroke of other determined etiology (SOD) and 11 cases (17.46%) were stroke of undetermined etiology (SUD). Among 26 AT cases, 18 cases (69.23%) accepted endovascular treatment and 8 cases (30.77% ) accepted bridging therapy. One case (3.85% ) underwent catheter suction, and 25 cases (96.15%) underwent thrombectomy, including thrombectomy alone in 9 cases (34.62% ), thrombectomy combined with balloon dilatation in 3 cases (11.54% ), thrombectomy combined with stent implantation in 3 cases (11.54% ), thrombectomy combined with balloon dilatation and stent implantation in 10 cases (38.46%), respectively. Cholesterol crystals were detected in 4 cases (15.38%). There was no significant difference in the number of thrombectomy between thrombi with cholesterol crystals and those without cholesterol crystals [2.50 (2.00, 3.00) times vs. 2 (2, 2) times; Z = ? 1.155, P = 0.248]. Among 37 non ? AT cases, 26 cases (70.27% ) accepted endovascular treatment and 11 cases (29.73%) accepted bridging therapy. All of them underwent thrombectomy, including thrombectomy alone in 34 cases (91.89%), thrombectomy combined with balloon dilatation in one case (2.70%), thrombectomy combined with stent implantation in 2 cases (5.41% ), respectively. There was statistically significant difference in the rate of cholesterol crystals between AT cases and non?AT cases [15.38% (4/26) vs. 0/37， Fisher's exact probability: P = 0.025]. There was no significant difference in the rate of cholesterol crystals between patients with and without recanalization [3.77% (2/53) vs. 2/10, Fisher's exact probability: P = 0.115]. Conclusions Although the rate of cholesterol crystals in thrombi of acute ischemic stroke patients is relatively low, it is specific for diagnosing AT. Besides, cholesterol crystals has no relationship with vascular recanalization. DOI: 10.3969/j.issn.1672-6731.2018.05.011

Abstract Background Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis. Methods First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls in analysis of the platelet desialylation levels (study I). Next, we conducted an open-label randomized controlled trial (RCT) in which the patients who had severe sepsis with thrombocytopenia (platelet counts ≤50 × 109/L) were randomly assigned to receive antimicrobial therapy alone (control group) or antimicrobial therapy plus oseltamivir (oseltamivir group) in a 1:1 ratio (study II). The primary outcomes were platelet desialylation level at study entry, overall platelet response rate within 14 days post-randomization, and all-cause mortality within 28 days post-randomization. Secondary outcomes included platelet recovery time, the occurrence of bleeding events, and the amount of platelets transfused within 14 days post-randomization. Results The platelet desialylation levels increased significantly in the 127 septic patients with thrombocytopenia compared to the 134 patients without thrombocytopenia. A platelet response was achieved in 45 of the 54 patients in the oseltamivir group (83.3%) compared with 34 of the 52 patients in the control group (65.4%; P = 0.045). The median platelet recovery time was 5 days (interquartile range 4–6) in the oseltamivir group compared with 7 days (interquartile range 5–10) in the control group (P = 0.003). The amount of platelets transfused decreased significantly in the oseltamivir group compared to the control group (P = 0.044). There was no difference in the overall 28-day mortality regardless of whether oseltamivir was used. The Sequential Organ Failure Assessment score and platelet recovery time were independent indicators of oseltamivir therapy. The main reason for all of the mortalities was multiple-organ failure. Conclusions Thrombocytopenia was associated with increased platelet desialylation in septic patients. The addition of oseltamivir could significantly increase the platelet response rate, shorten platelet recovery time, and reduce platelet transfusion. Trial registration Chinese Clinical Trial Registry, ChiCTR-IPR-16008542 .

Abstract Background Milk is a complex liquid that provides nutrition to newborns. Recent reports demonstrated that milk is enriched in maternal-derived exosomes that are involved in fetal physiological and pathological conditions by transmission of exosomal mRNAs, miRNAs and proteins. Until now, there is no such research relevant to exosomal mRNAs and proteins in porcine milk, therefore, we have attempted to investigate porcine milk exosomal mRNAs and proteins using RNA-sequencing and proteomic analysis. Results A total of 16,304 (13,895 known and 2, 409 novel mRNAs) mRNAs and 639 (571 known, 66 candidate and 2 putative proteins) proteins were identified. GO and KEGG annotation indicated that most proteins were located in the cytoplasm and participated in many immunity and disease-related pathways, and some mRNAs were closely related to metabolisms, degradation and signaling pathways. Interestingly, 19 categories of proteins were tissue-specific and detected in placenta, liver, milk, plasma and mammary. COG analysis divided the identified mRNAs and proteins into 6 and 23 categories, respectively, 18 mRNAs and 10 proteins appeared to be involved in cell cycle control, cell division and chromosome partitioning. Additionally, 14 selected mRNAs were identified by qPCR, meanwhile, 10 proteins related to immunity and cell proliferation were detected by Western blot. Conclusions These results provide the first insight into porcine milk exosomal mRNA and proteins, and will facilitate further research into the physiological significance of milk exosomes for infants.

Three coordination polymers, [Cd(L)2(H2O)2]n (1), [Zn(L)2(H2O)2]n (2) and [Mn(L)2]n (3) were prepared by reacting 5-(3-pyridyl)-1,3,4-oxadiazole-2-thioacetic acid (HL) with corresponding metal acetate in DMF/CH3CN medium under solvothermal condition. The isolated complexes were characterized by elemental analysis and infrared spectroscopy. The X-ray crystallographic analysis revealed double strand structure of 1 and 2, and 3D framework of 3. The different structures of these complexes indicate that the configuration of the ligand and the reaction condition play a key role in self-assemble of complexes 1–3. Furthermore, photoluminescent properties of 1 and 2 were also studied in the solid state.