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Introduction: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo‐geneic hematopoiesis stem cell transplantation (allo‐HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. Methods: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF‐normal (CSF−) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. Results: Compared to those in the CSF‐negative group, the conventional cytology positive and MFC+ groups had comparable 8‐year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia‐free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. Conclusion: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients. [ABSTRACT FROM AUTHOR]

Objective: Chronological age (CAge), biological age (BAge), and accelerated age (AAge) are all important for aging‐related diseases. CAge is a known risk factor for benign prostatic hyperplasia (BPH); However, the evidence of association of BAge and AAge with BPH is limited. This study aimed to evaluate the association of CAge, Bage, and AAge with BPH in a large prospective cohort. Method: A total of 135,933 males without BPH at enrolment were extracted from the UK biobank. We calculated three BAge measures (Klemera–Doubal method, KDM; PhenoAge; homeostatic dysregulation, HD) based on 16 biomarkers. Additionally, we calculated KDM‐BAge and PhenoAge‐BAge measures based on the Levine method. The KDM‐AAge and PhenoAge‐AAge were assessed by the difference between CAge and BAge and were standardized (mean = 0 and standard deviation [SD] = 1). Cox proportional hazard models were applied to assess the associations of CAge, Bage, and AAge with incident BPH risk. Results: During a median follow‐up of 13.150 years, 11,811 (8.690%) incident BPH were identified. Advanced CAge and BAge measures were associated with an increased risk of BPH, showing threshold effects at a later age (all P for nonlinearity <0.001). Nonlinear relationships between AAge measures and risk of BPH were also found for KDM‐AAge (P = 0.041) and PhenoAge‐AAge (P = 0.020). Compared to the balance comparison group (−1 SD < AAge < 1 SD), the accelerated aging group (AAge > 2 SD) had a significantly elevated BPH risk with hazard ratio (HR) of 1.115 (95% CI, 1.000–1.223) for KDM‐AAge and 1.180 (95% CI, 1.068–1.303) for PhenoAge‐AAge, respectively. For PhenoAge‐AAge, subgroup analysis of the accelerated aging group showed an increased HR of 1.904 (95% CI, 1.374–2.639) in males with CAge <50 years and 1.233 (95% CI, 1.088–1.397) in those having testosterone levels <12 nmol/L. Moreover, AAge‐associated risk of BPH was independent of and additive to genetic risk. Conclusions: Biological aging is an independent and modifiable risk factor for BPH. We suggest performing active health interventions to slow biological aging, which will help mitigate the progression of prostate aging and further reduce the burden of BPH. [ABSTRACT FROM AUTHOR]

Background: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. Methods: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single‐cell RNA‐sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single‐cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. Results: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone‐lysine N‐methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto‐oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. Conclusions: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti‐inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. Highlights: Single‐cell RNA‐sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands.PA cells show a pervasive increase in gene expression linked to KMT2A upregulation.KMT2A‐mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2.PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis. [ABSTRACT FROM AUTHOR]

Background and Aims: Accurate preoperative prediction of microvascular invasion (MVI) and recurrence‐free survival (RFS) is vital for personalised hepatocellular carcinoma (HCC) management. We developed a multitask deep learning model to predict MVI and RFS using preoperative MRI scans. Methods: Utilising a retrospective dataset of 725 HCC patients from seven institutions, we developed and validated a multitask deep learning model focused on predicting MVI and RFS. The model employs a transformer architecture to extract critical features from preoperative MRI scans. It was trained on a set of 234 patients and internally validated on a set of 58 patients. External validation was performed using three independent sets (n = 212, 111, 110). Results: The multitask deep learning model yielded high MVI prediction accuracy, with AUC values of 0.918 for the training set and 0.800 for the internal test set. In external test sets, AUC values were 0.837, 0.815 and 0.800. Radiologists' sensitivity and inter‐rater agreement for MVI prediction improved significantly when integrated with the model. For RFS, the model achieved C‐index values of 0.763 in the training set and ranged between 0.628 and 0.728 in external test sets. Notably, PA‐TACE improved RFS only in patients predicted to have high MVI risk and low survival scores (p <.001). Conclusions: Our deep learning model allows accurate MVI and survival prediction in HCC patients. Prospective studies are warranted to assess the clinical utility of this model in guiding personalised treatment in conjunction with clinical criteria. [ABSTRACT FROM AUTHOR]

Numerous synaptic devices have been explored for the next generation of energy‐efficient computing techniques. Among them, optoelectronic synaptic devices based on semiconductor/ferroelectric heterostructures have received a lot of attention lately due to their amazing parallelism, efficiency, and fault tolerance properties. However, polarizing the ferroelectric layer or gating the dielectric layer is necessary to achieve tunable synaptic functions, which generally causes an increase in energy consumption and complex manufacturing processes. Here, a simple and efficient method is demonstrated to develop a tunable optoelectronic synaptic device based on a single ferroelectric semiconductor, BiFeO3‐BaTiO3 (BF‐BT). Multi‐essential synaptic functions including short‐term plasticity, paired‐pulse facilitation, and long‐term plasticity are all satisfactorily replicated by the memristor device. More significantly, light‐controllable synaptic behaviors are realized by altering the ferroelectric polarization state of BF‐BT. Synaptic devices' relaxation characteristics enable simulation of the effects of positive/negative emotions on learning and forgetting processes. This study highlights the potential of the ferroelectric semiconductor memristor in constructing the efficient optoelectronic synapses for future neuromorphic electronics with the ability to learn and sense optical information. [ABSTRACT FROM AUTHOR]

Background and Aims: To assess patient comfort, wound healing, and scarring at the 6‐month follow‐up of split‐skin graft donor sites treated with Ba‐Hao burn ointment (BHBO) gauze, a compound preparation of traditional Chinese medicine since 1970s, compared with petrolatum gauze. Methods: Thirty patients admitted to the Department of Burns of the First Affiliated Hospital of Anhui Medical University between September 2021 and September 2022 participated in this randomized, prospective, self‐control clinical study. After harvesting the split skin, donor sites were divided into two parts along the midline. BHBO gauze was applied to half of the donor wounds, and petrolatum gauze was applied to the other half. The wound healing time, pain scores on the postoperative Days 3, 6, and 9, and Vancouver Scar Scale (VSS) score at the 6‐month follow‐up were assessed. Results: The wound healing time was significantly shorter in the BHBO group than in the control group (10.07 ± 1.48 days vs. 11.50 ± 1.74 days, p < 0.001). On postoperative Days 3 and 6, the pain scores quantified by visual analog scores were significantly lower in the BHBO group than in the control group (5.33 ± 1.54 and 4.17 ± 1.51, respectively vs. 7.57 ± 1.41 and 5.20 ± 1.47, respectively). The difference in the visual analog scale score on postoperative Day 9 between the groups was not significant (p > 0.05). Microbiological assessment revealed the absence of bacterial contamination in both groups. At the 6‐month follow up, the VSS score was significantly lower in the BHBO group (6.67 ± 1.92) than in the control group (9.57 ± 1.55). Conclusion: BHBO resulted in faster donor‐site healing, reduced postoperative pain, and improved scar quality at the 6‐month follow‐up than petrolatum gauze alone. Key points: Explore the different clinical effect of Ba‐Hao burn ointment (BHBO) and petrolatum gauzes in donor site.BHBO can shorten donor site wound healing time and dull pain.BHBO can improve scare quality. [ABSTRACT FROM AUTHOR]

Objectives: CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor‐infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown. Methods: A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD‐1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC‐infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC‐infiltrating T cells was investigated by inhibiting CD39 enzymatic activity. Results: In comparison with CD4+ T cells from the non‐tumor tissues, significantly more GC‐infiltrating CD4+ T cells expressed CD39. Most GC‐infiltrating CD39+CD4+ T cells exhibited CD45RA−CCR7− effector–memory phenotype expressing more exhaustion‐associated inhibitory molecules and transcription factors and produced less TNF‐α, IFN‐γ and cytolytic molecules than their CD39−CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF‐α and IFN‐γ production. Finally, increased percentages of GC‐infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival. Conclusion: Our study demonstrates that CD39 expression defines GC‐infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of perampanel (PER) monotherapy (MT) or add‐on therapy (AT) in Chinese children with epilepsy, as well as to evaluate the data from routine therapeutic drug monitoring (TDM) of PER for these pediatric patients. Methods: This retrospective and observational study was carried out on children with epilepsy (n = 340) from 2020 to 2022 at the Children's Hospital of Nanjing Medical University. Outcome measures were the responder rate (50% or greater seizure reduction), long‐term efficacy, and tolerability (number and types of adverse events) in MT and AT groups. Concentrations of plasma PER obtained from these patients, if available, were analyzed too. Results: A total of 279 patients achieved at least 3 months of therapy, and 58.1% responded to PER therapy. 53 of the responders were seizure‐free (32.7%). The retention rate dropped from 88.0% at 3 months to 40.6% at 12 months after treatment. Patients with MT achieved better seizure control than those with AT (P < 0.001). Intriguingly, PER exerted a very weak effect on patients who took more than 2 ASMs or were diagnosed with drug‐resistant epilepsy. There were no significant differences in tolerability between the two groups. In addition, 179 patients were routinely monitored for PER, and the trough concentrations (C0) for these patients ranged from 30.0 to 992.0 ng/mL. However, no significant difference in C0 was observed between responders and nonresponders (333 ng/mL vs 325.5 ng/mL, P = 0.264). Significance: This study provides effectiveness and safety data on Chinese children with epilepsy treated with PER either as MT or as AT. The efficacy of patients receiving MT was much better than cases administered with more than 2 ASMs or diagnosed with drug‐resistant epilepsy. In addition, no association was found between the plasma PER concentration and efficacy or safety. Plain Language Summary: The study reports the effects of perampanel on seizures and adverse effects in Chinese patients with epilepsy younger than 18 years. Seizures decreased in 58.1% of patients (responders); in a third of these responders, seizures stopped. After treatment was started, 88% of patients were still on perampanel at 3 months and 40.6% at 12 months. People who were treated with perampanel only were more likely to respond than those who received perampanel and other antiseizure treatments, although perampanel was tolerated equally well in these groups. Plasma perampanel concentration did not predict seizure response or adverse effects. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦs in regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age‐paired patients with lower‐risk MDS (N = 15), higher‐risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro‐inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher‐risk MDS compared to lower‐risk MDS. BM MФs from patients with higher‐risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower‐risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower‐risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher‐risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower‐risk MDS. Gene Ontology enrichment comparing BM MΦs from lower‐risk MDS and higher‐risk MDS for genes was involved in hematopoiesis‐ and immunity‐related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS. [ABSTRACT FROM AUTHOR]

This study investigates the influence of donor‐specific anti‐HLA antibodies (DSA) levels on primary poor graft function (PGF) and graft rejection (GR) after haploidentical stem cell transplantation (haplo‐SCT) with rituximab desensitization. A total of 155 DSA‐positive haplo‐SCT candidates with mean fluorescence intensity (MFI) between 2000 and 10,000 were enrolled in this prospective clinical trial. Receiver operating characteristic (ROC) curves determined the optimal DSA MFI cutoff for identifying high‐risk patients. Patients were categorized into two groups: DSA low‐level group (2000 ≤ DSA MFI < 5000, Group A) and high‐level group (5000 ≤ DSA MFI ≤ 10,000, Group B). The incidence of primary PGF was 6.5% (2.6%–10.3%), while GR incidence was 0.6% (0.0%–1.9%). Group A had significantly lower primary PGF rates than Group B (2.3% [0.0%–5.7%] vs. 12.9% [4.8%–21.0%], p = 0.017). Only one patient in Group B experienced GR. High DSA levels (5000 ≤ MFI ≤ 10,000) were identified as the sole independent risk factor for primary PGF and GR after haplo‐SCT with rituximab desensitization (HR = 7.282, 95% CI 1.517–34.953, p = 0.013). The 4‐year cumulative incidence of relapse, non‐relapse mortality, disease‐free survival, and overall survival were 14.7% (11.6%–17.8%), 16.3% (13.1%–19.4%), 69.0% (65.9%–76.2%), and 70.6% (66.4%–74.8%), respectively. DSA levels have an impact on efficiency of rituximab desensitization, and a DSA MFI threshold is provided for predicting primary PGF and GR. [ABSTRACT FROM AUTHOR]

According to the recommendations of literature and standards, the minimum sample size for the friction test of thermoplastics is usually 3–5. While this size is valid for the friction test of neat polymer resins with homogeneous structures, its applicability to short fiber reinforced polymer composites with inhomogeneous structures remains unclear because the uneven distribution of discontinuous fibers or fillers in the matrix leads to the performance of the composites being dispersed. In this work, as a typical example, 100 friction samples made of short carbon fiber reinforced polyetherimide (SCF/PEI) composite with a typical content of 10 vol% SCFs are prepared, and their friction coefficients are measured. The maximum likelihood estimation and goodness of fit methods are employed to assess the fitting degree between the overall friction coefficient results and five mathematical distributions. The results show that the overall friction coefficient data distribution is in good agreement with the Lognormal, Generalized extreme value (GEV), and Burr distributions, respectively. Based on the fitting result, the minimum sample size is analyzed by Monte Carlo Simulation. It shows that the minimum sample size strongly depends on the property dispersion parameter (COV: coefficient of variation). Based on this parameter, the minimum sample size is given. In a practical test, the performance dispersion degree of a composite cannot be known in advance, hence a sample size determination method is proposed to yield a reasonable performance description parameter by applying the results of this work, and this method is validated by the overall test data. Highlights: Proposed a sample size determination method for practical friction tests.The minimum sample size for the friction test is yielded statistically.The minimum sample size strongly depends on a property dispersion parameter. [ABSTRACT FROM AUTHOR]

Summary: Patients who receive allogeneic haematopoietic stem cell transplantation (allo‐HSCT) may develop sepsis, which result in a highly intensive care unit admission rate and mortality. Therefore, short‐term and long‐term prognostic models for sepsis after allo‐HSCT are urgently needed. We enrolled patients receiving allo‐HSCT who developed sepsis after allo‐HSCT at Peking University People's Hospital between 2012 and 2021, including 287 patients who received allo‐HSCT in 2018–2021 in the derivation cohort, and 337 patients in 2012–2017 in the validation cohort. Multivariate logistic regression analysis was used to identify prognostic factors, and these identified factors were incorporated into two scoring models. Seven independent factors (acute graft‐versus‐host disease (GVHD), chronic GVHD (cGVHD), total bilirubin, lactate dehydrogenase (LDH) and organ dysfunction [renal, lung and heart]) were included in the 6‐month prognostic model, and six factors (cGVHD, C‐reactive protein, LDH, organ dysfunction [lung, neurologic and coagulation]) were included in the 14‐day prognostic model. The area under the receiver operating characteristic curves, calibration plots and decision curve analysis demonstrated the robust predictive performance of the models, better than the Sequential Organ Failure Assessment score. Early identification of patients with high risk of 6‐month and 14‐day death may allow clinicians to provide timely treatments and improve the therapeutic effects. [ABSTRACT FROM AUTHOR]

Objective: The drug‐refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy. Methods: This single‐center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non‐responders with VPA polytherapy (NR group) were collected. Non‐targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p‐value <0.05 were regarded as statistically different substances. Results: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well‐established partial least squares‐discriminant analysis (PLS‐DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L‐thyroxine, but with an increased level of glucose and 2‐oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism. Significance: The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high‐priority strategies for DRE management. [ABSTRACT FROM AUTHOR]

P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers. [ABSTRACT FROM AUTHOR]

Objective: To compare the effectiveness of a six‐month home‐based telerehabilitation based on the Internet‐based rehabilitation management system coupled with conventional outpatient care in elderly patients with hip fractures following total hip replacement (THR). Methods: Elderly patients (aged over 65 years) with first hip fractures who underwent THR between March 2018 and September 2018 in Tianjin Hospital were enrolled in this study. Patients were divided into two groups: telerehabilitation group (n = 43) and telephone group (n = 42). A Internet‐based telerehabilitation management system was established and applied on patients in the telerehabilitation group. For patients in the telephone group, the rehabilitation intervention was administered through conventional outpatient care (telephone along with outpatient follow‐up). Data from the Harris hip scale (HHS), functional independence measure (FIM), self‐rating anxiety scale (SAS), and postoperative complications at 1, 3, and 6 months after surgery were collected and compared between the two groups. Results: A total of 85 elderly patients completed the 6‐month follow‐up assessment. Results showed that the HHS score was significantly higher in the telerehabilitation group than in the telephone group at 1 month (66.35 ± 4.63 vs 63.48 ± 4.49), 3 months (76.33 ± 4.52 vs 71.81 ± 3.84), and 6 months (84.23 ± 3.13 vs 77.29 ± 4.95) after surgery (P < 0.001). The FIM score was significantly higher in the telerehabilitation group than in the telephone group at 1 month (89.00 ± 5.63 vs 73.35 ± 8.70), 3 months (100.16 ± 4.56 vs 92.81 ± 5.17), and 6 months (111.70 ± 3.13 vs 98.64 ± 5.12) after surgery (P < 0.001). The SAS score was significantly lower in the telerehabilitation group than in the telephone group at 1 month (42.40 ± 3.07 vs 46.21 ± 3.53), 3 months (36.77 ± 2.26 vs 40.24 ± 1.66), and 6 months (29.26 ± 1.63 vs 33.81 ± 2.62) after surgery (P < 0.001). The overall complication rate was significantly lower in the telerehabilitation group than in the telephone group (14% vs 40.5%) (P < 0.05). Conclusion: Internet‐based rehabilitation management system can not only promote the physical rehabilitation of patients, but also play a positive role in psychological rehabilitation and the prevention of complications, which provides new ideas and methods for clinical rehabilitation. [ABSTRACT FROM AUTHOR]

Oral antiseizure medications are the preferred option for the clinical treatment of epilepsy. Therapeutic drug monitoring has become an important means of achieving individualized treatment of epilepsy. A sensitive, accurate and rapid LC–ESI–MS/MS method was developed and validated for the simultaneous determination of 15 antiseizure medications in human plasma (carbamazepine, gabapentin, pregabalin, phenytoin, zonisamide, oxcarbazepine, tiagabine, lamotrigine, topiramate, phenobarbital, lacosamide, primidone, 10,11‐Dihydro‐10‐hydroxy carbamazepine, ethosuximide, and levetiracetam). The sample preparation procedure was an one‐step protein precipitation with methanol. Mass detection was performed in ionization polarity switching mode (positive–negative–positive) using multiple reaction monitoring mode. A "boot‐shaped" gradient elution program was applied to separate and concentrate those target analytes, resulting in symmetrical peak shapes within 10 min, without endogenous interference. The method showed great linearity over the concentration ranges with acceptable correlation coefficients (0.9966–0.9996). The precision and accuracy values for intra‐ and inter‐assays were within ±15%. Consequently, the method was successfully implemented on pediatric patients undergoing mono‐ or polytherapy for epilepsy and provided timely concentration results to ordering clinicians. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the efficacy and tolerability of perampanel (PER) therapy and to optimize a specific plasma reference range for PER in children. Another major aim was to evaluate the potential determinators of PER concentration. Methods: Concentrations obtained from 80 children were analyzed for routine therapeutic drug monitoring (TDM) between 2021 and 2022. We retrospectively reviewed the clinical data of these patients and assessed the efficacy at 3 months after treatment initiation. Trough concentration‐to‐dose ratio (C0/Dose ratio) of PER was compared among patients on various potential influencing factors. Results: A 3‐month PER therapy produced a ≥50% reduction in seizure frequency in 58.8% of patients. Twelve patients reported at least one adverse effect (AE), mainly dizziness. The monitoring data showed that the median C0 was 325.5 ng/mL. Under maintenance dosages, approximately 75% of the C0 values were 180.0‐610.0 ng/mL. The C0/Dose ratio in patients aged 1 to <4 was significantly lower by twofold than in those aged 4 to ≤12 years (P = 0.001). Enzyme‐inducing ASMs (EIASMs) decreased the C0/Dose ratio of PER by 25.9% (P = 0.165). In addition, seizure frequency reduction in responders was achieved at a median PER C0 value of 357 ng/mL, which was similar to the value of 314 ng/mL found in nonresponders (P = 0.288). No significant difference was found in PER C0 values between patients with and without AEs (P = 0.082). Significance: In this study, PER treatment showed acceptable efficacy and tolerance in Chinese children with epilepsy. Contributing factors like age to variable C0/Dose ratios were identified, and complex PER‐ASMs interactions were observed. Notably, the reference range, that is, 180.0‐610.0 ng/mL, for routine PER monitoring may be more applicable for them. Routine TDM should be considered a positive attempt to manage the effectiveness and safety of PER. [ABSTRACT FROM AUTHOR]

The importance of anti‐HLA antibodies in transplantation settings, such as HLA‐mismatched or haploidentical hematopoietic stem cell transplantation and platelet refractoriness, is widely recognized. In previous reports, it was mentioned that several cut‐off values of donor‐specific anti‐HLA antibodies mean fluorescence intensity (MFI) were related to graft rejection in the environment of HLA mismatched stem cell transplantation and the aim of this study was to investigate the prevalence and risk factors of anti‐HLA antibodies according to those cut‐off values of MFI. A total of 3805 patients with hematologic disease were prospectively enrolled and analyzed. When using MFI of anti‐HLA antibodies ≥500, ≥1000, ≥1500, ≥2000, ≥5000, and ≥ 10,000 as cut‐off values for positivity, the prevalence of class I or II anti‐HLA antibodies ranged from 4.6% to 20.2% in all cases. When the MFI cut‐off value was ≥500 for positivity, multivariate analysis indicated that platelet transfusion, underlying disease, and pregnancy were the most important risk factors for the presence of anti‐HLA antibodies for the total patients. Subgroup analysis according to age, gender, and underlying disease showed that pregnancy was the most important risk factor for the presence of anti‐HLA antibodies. For all patients (n = 3805), when anti‐HLA antibody positivity was defined according to different MFI cut‐off values, including ≥1000, ≥1500, ≥2000, ≥5000, and ≥ 10,000, an association of platelet transfusion and pregnancy with anti‐HLA antibodies was also demonstrated. Our results suggest that pregnancy and platelet transfusion are the main risk factors for the prevalence of anti‐HLA antibodies in haploid allograft candidates, providing evidence for guiding the evaluation of anti‐HLA antibodies and helping donor selection for HLA‐mismatched transplant candidates. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of home‐based telerehabilitation based on the Internet‐based rehabilitation management system on hip function, activities of daily living and somatic integrative ability of elderly postoperative hip fracture patients. Methods: From June 2020 to November 2020, we recruited 58 elderly postoperative hip fracture patients and randomly assigned them to the telephone group (n = 29) and the telerehabilitation group (n = 29). Both groups received routine discharge instructions, and the former received telephone follow‐up after discharge, while the latter received remote rehabilitation based on the Internet‐based rehabilitation management system. The Harris hip score (HHS), functional independence measure (FIM), timed up‐and‐go test (TUG), and short physical performance battery (SPPB) were used to evaluate the patients' hip function, activities of daily living, and overall somatic ability. Results: There was no significant difference between the baseline data of the two groups before the intervention (P > 0.05); no matter after hip replacement or internal fixation, the HHS score and FIM score of both groups increased gradually with the postoperative time, and the scores in the telerehabilitation group were higher than those in the telephone group at 1 and 3 months after the intervention, and the difference was significant (P < 0.05); for patients after hip replacement, the TUG and SPPB scores in the telerehabilitation group were better than those in the telephone group at 3 months after the intervention, and the difference was significant (P < 0.05). Conclusions: The Internet‐based rehabilitation management system applied to postoperative home rehabilitation of elderly hip fracture patients can improve the functional recovery of the hip joint and enhance the ability to perform activities of daily living and somatic integration to a certain extent. This seems to provide an effective option for conducting home rehabilitation. [ABSTRACT FROM AUTHOR]

HLA‐DPB1*05:01:21 differs from HLA‐DPB1*05:01:01:01 by one nucleotide in exon 3. [ABSTRACT FROM AUTHOR]

Introduction: Widespread use of antibiotics has led to an increase in bacterial multiple drug resistance, thereby searching for natural antimicrobial agents from plants becomes an effective and alternative approach. In the present study, we selected six foodborne bacteria to evaluate the antibacterial activities of 12 medicinal plants ethyl acetate (EA) extracts. Objective: This study aims to search for natural antibiotic substitutes from plant extracts. The antibacterial components were further discussed through chemometric and mass spectroscopic analyses. Methodology: Agar well diffusion and the microdilution methods were used to test the antibacterial activity. Total phenolic content (TPC) and total flavonoid content (TFC) were used to judge the active phytochemicals. To further characterise the potential antibacterial components, an ultra‐performance liquid chromatography‐quadrupole‐time of flight‐mass spectrometry (UPLC‐Q‐TOF‐MS) coupled with Pearson correlation and feature‐based molecular network (FBMN) were proposed. Results: Most of the plant extracts possessed antibacterial activity against Bacillus subtilis and Salmonella typhi. Toona sinensis shoots and Firmiana simplex barks showed high inhibitory activities against Staphylococcus aureus, Shigella dysenteriae, and Escherichia coli strains with minimum inhibitory concentrations (MICs) of 1.56, 0.78, and 0.39 mg/mL, respectively. Salmonella typhi was highly sensitive to Firmiana simplex barks with an inhibitory diameter up to 21.67 ± 0.95 mm, and MIC at 0.78 mg/mL. Moreover, Toona sinensis shoots and Firmiana simplex barks had the highest TPCs. Conclusion: Our results indicated that Toona sinensis shoots, Koelreuteria paniculate seeds, and Firmiana simplex barks could be supplied as potential sources of antimicrobial agents. Furthermore, 36 potential bioactive compounds were identified mainly as polyphenols, glycosides, and terpenoids. We selected six foodborne bacteria to evaluate the antibacterial activities of 12 medicinal plant originated ethyl‐acetate. Most of the plant extracts possessed antibacterial activity against Bacillus subtilis and Salmonella typhi. Toona sinensis shoots and Firmiana simplex barks showed high inhibitory activities against Staphylococcus aureus, Shigella dysenteriae, and Escherichia coli strains with MICs at 1.56, 0.78, and 0.39 mg/mL, respectively. Salmonella typhi was highly sensitive to Firmiana simplex barks with inhibitory diameter up to 21.67 ± 0.95 mm, and MICs at 0.78 mg/mL. [ABSTRACT FROM AUTHOR]

Summary: Haploidentical allogeneic haematopoietic stem cell transplantation (haplo‐HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo‐HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n = 288) and a validation (n = 144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) score were independent risk factors for worse treatment‐related mortality (TRM) in the final multivariable model. The haplo‐HSCT scoring system was developed by these three parameters. Three‐year TRM after haplo‐HSCT were 6% [95% confidence interval (CI), 1–21%], 21% (95% CI, 7–40%), and 47% (95% CI, 20–70%) for the low‐, intermediate‐, and high‐risk group, respectively (P < 0·0001). In the validation cohort, the haplo‐HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate‐risk [hazard ratio (HR) 2·45, 95% CI, 0·92–6·53] and high‐risk (HR 11·74, 95% CI, 3·07–44·89) compared with the low‐risk group (P = 0·001). In conclusion, the haplo‐HSCT scoring system could effectively predict TRM after transplantation. [ABSTRACT FROM AUTHOR]

Background: Docetaxel (DTX) exhibits antitumor effects against breast cancer by stabilizing microtubules and increasing the accumulation of reactive oxygen species (ROS). DTX extravasation during infusion often causes skin injury. The present study aimed to investigate the effects and mechanisms of icaritin (ICT) on DTX‐induced skin injury. Methods: The effects of ICT on the viability and apoptosis of HaCaT cells were measured by SRB assay and flow cytometry, respectively. Endogenous LC3 puncta and microtubules were determined by immunofluorescence. The number of mitochondria was measured by MitoTracker orange staining. ROS were determined by dihydroethidium staining. The expression of markers of ROS and autophagy were measured by western blotting. Chloroquine, compound D, and tamoxifen were employed as the inhibitor for autophagy and AMPK, estrogen receptors (ERs) modulator, respectively. Results: DTX inhibited the viability and decreased apoptosis of HaCaT cells, which can be rescued by ICT. ICT decreased microtubule bundles, increased the number of mitochondria, and attenuated ROS of HaCaT cells induced by DTX. ICT blocks autophagy and the autophagic flux. Compound C or tamoxifen diminished the protection effects of ICT on DTX‐treated HaCaT cells. Conclusion: ICT alleviates DTX‐induced skin injury by suppressing ROS, reducing microtubule bundles, and blocking autophagy via ERs. Our study indicated that ICT may be a potential candidate for DTX‐induced skin injury. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess β-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-β was computed by Homeostasis Model Assessment model to evaluate β-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β-cell function. [ABSTRACT FROM AUTHOR]

Objectives: The aim of our study was to determine possible predictors and clinical course of mixed chimerism (MC) in aplastic anemia after transplantation. Methods: A total of 207 transplants were obtained from haploidentical donors (HID) using busulfan (Bu), cyclophosphamide (Cy), and anti‐thymocyte globulin (ATG) regimens, and 69 transplants from matched related donors (MRD) and 29 transplants from unrelated donors (URD) using Cy/ATG regimens were obtained. Results: Incidences of MC were 1.93 ± 0.01%, 20.29 ± 0.01%, and 35.71 ± 0.01% in HID, MRD, and URD transplantation (p <.001). In multivariate analysis, incidence of MC was significantly higher in patients without adding Bu in conditioning (p <.001) and receiving a lower number of CD3 + cells in graft (p =.042). MC was associated with significantly lower II‐IV aGvHD (3.70% vs. 27.7%, p =.007), but higher secondary graft rejection rates (14.8% vs. 0.4%, p <.001) and poorer overall survival (72.7 ± 8.9% vs. 89.6 ± 2.0%, p =.011) than those of donor chimerism cohort. Conclusions: Mixed chimerism was an unsettling status even in non‐malignancy. Haploidentical transplantation with more intense regimen by adding Bu to Cy and ATG was associated with reduced MC following HSCT for SAA. An intensified regimen should be explored in matched related or unrelated donors. [ABSTRACT FROM AUTHOR]

BACKGROUND Herbicide safeners mitigate crop damage without reducing herbicide efficacy. Here, the protective effects of phenoxyacetyl oxazolidine derivatives as potential safeners were evaluated with a view toward reducing injury caused by sulfonylurea herbicide nicosulfuron to sensitive maize varieties. RESULTS: Growth indices demonstrated that the bioactivity of compound 9 (N‐phenoxyacety‐2‐methyl‐2,4‐diethyl‐1,3‐oxazolidine) was superior to that of R‐28725 and all other compounds tested. Compound 9 induced endogenous glutathione and upregulated glutathione‐S‐transferase (GST) in maize. Thus, it could enhance maize tolerance to nicosulfuron. Compared with the untreated water control group, the maximum reaction rate of GST was increased by 37.62%, while the maximum velocity of GST was decreased by 61.93% after treatment with compound 9. Acetolactate synthase relative activity was significantly enhanced in the case of treatment with compound 9, indicating the excellent protective effects of compound 9 against nicosulfuron in maize. CONCLUSIONS: The present work demonstrates that phenoxyacetyl oxazolidine derivatives are potentially efficacious as herbicide safeners and merit further investigation. [ABSTRACT FROM AUTHOR]

Background: Plasmid construction of small fragments of interest (such as insertion of small fragment marker genes, expression of shRNA, siRNA, etc) is the basis of many biomolecular experiments. Here, we describe a method to clone short DNA into vectors by polymerase chain reaction (PCR), named one‐step PCR cloning. Our method uses PCR to amplify the entire circular plasmid. The PCR was performed by the primers containing the gene of short DNA with overlapping sequences between 10–15 bp. The PCR products were then transformed into E. coli and cyclized by homologous recombination in vivo. Methods: The pEGFP‐N1‐HA plasmid was constructed by one‐step PCR and transformation. Cells were transfected with pEGFP‐N1‐HA and pEGFP‐N1 plasmid using TurboFect transfection reagent. Protein expression was detected by western blotting and the HA‐GFP fusion protein was detected by confocal microscopy. Results: The pEGFP‐N1‐HA plasmid was successfully constructed and HA expression in cells. Conclusions: Free from the limitations of restriction enzyme sites and omitting the ligation process, our method offers a flexible and economical option of plasmid construction. Key points: Significant findings of the study: A method to clone short DNA into plasmids was found. What this study adds: Our study provides a flexible and economical option to clone short DNA into plasmids. [ABSTRACT FROM AUTHOR]

Young donors are associated with a lower cumulative incidence of acute graft‐vs‐host disease (aGVHD) after allogenic haematopoietic stem cell transplantation (allo‐HSCT) than old donors. Although grafts are harvested from healthy donors, it is unclear whether donor age is associated with aGVHD occurrence owing to its effect on cell compositions in grafts. Moreover, the differences in monocyte subsets in grafts between young and old donors and the association between monocyte subsets in bone marrow (BM) grafts and aGVHD remain to be elucidated. In the current study, non‐classical monocytes and the CD4+/CD8+ T cell ratio were remarkably decreased in BM grafts in donors <30 years old. Multivariate analysis further revealed that the level of non‐classical monocytes in BM grafts (≥0.31 × 106/kg) was an independent risk factor for the occurrence of II‐IV aGVHD. In summary, our data indicate that non‐classical monocytes in BM grafts may help identify patients at high risk for aGVHD after allo‐HSCT. Although further validation is required, our results suggest that the low level of non‐classical monocytes and a low ratio of CD4+/CD8+ T cell in BM grafts may be correlated with the lower incidence of aGVHD in young donors. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a novel type of highly contagious pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Despite the strong efforts taken to control the epidemic, hundreds of thousands of people were infected worldwide by 11 March, and the situation was characterized as a pandemic by the World Health Organization. Pregnant women are more susceptible to viral infection due to immune and anatomic alteration, though hospital visits may increase the chance of infection, the lack of medical care during pregnancy may do more harm. Hence, a well‐managed system that allows pregnant women to access maternal health care with minimum exposure risk is desired during the outbreak. Here, we present the managing processes of three pregnant women who had fever during hospitalization in the gynecology or obstetrics department, and then, we further summarize and demonstrate our maternal health care management strategies including antenatal care planning, patient triage based on the risk level, admission control, and measures counteracting emergencies and newly discovered high‐risk cases at in‐patient department. In the meantime, we will explain the alterations we have done throughout different stages of the epidemic and also review relative articles in both Chinese and English to compare our strategies with those of other areas. Although tens of COVID‐19 cases were confirmed in our hospital, no nosocomial infection has occurred and none of the pregnant women registered in our hospital was reported to be infected. Highlights: Demonstration of three cases of pregnant women who developed a fever during hospitalization. [ABSTRACT FROM AUTHOR]

Our patient presented with severe hyperkeratosis and palmoplantar hyperhidrosis, with no perioral or perianal skin symptoms, no elbows or knees involvement, whose clinical characteristics differ from other reported patients with mutation of c.256G>A. A patient from Korea[10] was reported with compound heterozygous mutation in I SLURP-1 i : a missense mutation of c.256G>A (p.G86R) and a nonsense mutation of c.286C>T (p.R86X). As MDM patients with mutation of c.256G>A (p.G86R) presented various clinical manifestations, the association between the mutation of c.256G>A in I SLURP-1 i and phenotype severity of MDM is not significant. [Extracted from the article]

Dy3+‐doped Y3Al5O12 phosphors were prepared at a relatively low temperature using molten salt synthesis. The phase of the prepared Dy3+‐doped Y3Al5O12 phosphors was confirmed using X‐ray powder diffraction. Results indicated that Dy3+ doping did not change the Y3Al5O12 phase. Following excitation at 352 nm, emission spectra of the Dy3+‐doped Y3Al5O12 phosphors consisted of blue, yellow, and red emission bands. The influence of Dy3+ concentration and excitation wavelength on emission was investigated. The ratio of yellow light to blue light varied with change in Dy3+ doping concentration, due to changes in the structure around Dy3+. Emission intensities also changed when the excitation wavelength was changed. This variation is luminescence generated a system for tunable white light for Dy3+‐doped Y3Al5O12 phosphors. [ABSTRACT FROM AUTHOR]

This retrospective multicenter cohort study aimed to compare the outcome of haploidentical hematopoietic stem cell transplantation (HID‐HSCT) with matched sibling donor (MSD) and unrelated donor (URD) transplantation in severe aplastic anemia (SAA) patients 40 years of age and older. With a median follow‐up time of 17.6 months, 85 consecutive patients were enrolled in the study, and the median patient age was 45 years (40, 58). The cumulative engraftment rates of neutrophil and platelet were 98.8 ± 0.0% and 92.9 ± 0.1%. The cumulative incidences of Grade 2‐4 acute graft‐versus‐host disease (aGvHD) and chronic graft‐versus‐host disease (cGvHD) at 3 years were 14.1 ± 0.1% and 17.3 ± 0.2%. The 3‐year estimated overall survival (OS) and failure‐free survival (FFS) were 91.2 ± 3.2% and 89.7 ± 3.5%. In multivariate analysis, the only factor associated with inferior survival was an ECOG score ≥2. HID‐HSCT was associated with a higher incidence of GvHD, but the difference of 3‐year estimated OS between HID group and the other two cohorts was not significant (86.7 ± 6.4% for HID vs 92.1% ± 4.4% for MSD and 100% for URD, P =.481). HID‐HSCT might be a feasible alternative option for selected SAA patients aged 40 years and older without a matched donor. [ABSTRACT FROM AUTHOR]

Background and Aim: Considering the large size of the potential population and limitations of common detection methods, covert hepatic encephalopathy (CHE) is difficult to screen for routinely. The present study aims to explore EncephalApp Stroop Test as a smartphone‐based CHE screening tool in China. Methods: A multicenter, single‐visit study was carried out. The cutoff of the Chinese EncephalApp translation was determined by using Chinese standardized psychometric hepatic encephalopathy score (PHES) in cirrhotic patients as the gold standard. Indicators reflecting time required and number of tests on subtask on (naming the color of pound signs) and off (naming the color of the word in discordant coloring) were recorded, with the feedback from investigators and patients. Results: One hundred forty‐four patients were included; 58 (40.28%) patients were diagnosed with CHE by PHES. The cutoff of > 97.34 s for off time and > 186.63 s for on time + off time had the maximum area under the curve values (0.77) in all patients. Furthermore, with the cutoff of 186.63 s, on time + off time has the highest sensitivity (0.86). However, the specificity was unsatisfactory (0.59). Age and alcoholic hepatitis (odds ratio = 1.05 and 3.12, both P < 0.05) were positively correlated with the risk of CHE. The experience with electronic devices and education duration were negatively correlated (odds ratio = 0.21 and 0.92, both P < 0.05). Compared with PHES, EncephalApp represented 38% time saving. Furthermore, it was superior to PHES regarding accessibility, convenience, and acceptability by administrators (all P < 0.05). Conclusions: The EncephalApp Stroop Test is an efficient screening tool for CHE in Chinese cirrhotic patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non-muscular myosin heavy chain IIA (NMMHC IIA) plays a key role in tissue factor expression and venous thrombosis. Natural products might inhibit thrombosis through effects on NMMHC IIA. Here, we have shown that a natural saponin, D39, from Liriope muscari exerted anti-thrombotic activity in vivo, by targeting NMMHC IIA.Experimental Approach: Expression and activity of tissue factor in endothelial cells were analysed in vitro by Western blot and simplified chromogenic assays. Interactions between D39 and NMMHC IIA were assessed by serial affinity chromatography and molecular docking analysis. D39-dependent interactions between NMMHC IIA and TNF receptor 2 (TNFR2) were measured by immunofluorescence, co-immunoprecipitation and proximity ligation assays. Anti-thrombotic activity of D39 in vivo was evaluated with a model of inferior vena cava ligation injury in mice.Key Results: D39 inhibited tissue factor expression and procoagulant activities in HUVECs and decreased thrombus weight in inferior vena cava-ligated mice dose-dependently. Serial affinity chromatography and molecular docking analysis suggested that D39 bound to NMMHC IIA. In HEK293T cells, D39 inhibited tissue factor expression evoked by NMMHC IIA overexpression. This effect was blocked by NMMHC IIA knockdown in HUVECs. D39 inhibited dissociation of NMMHC IIA from TNFR2, which subsequently modulated the Akt/GSK3β-NF-κB signalling pathways.Conclusions and Implications: D39 inhibited tissue factor expression and thrombus formation by modulating the Akt/GSK3β and NF-κB signalling pathways through NMMHC IIA. We identified a new natural product that targeted NMMHC IIA, as a potential treatment for thrombotic disorders and other vasculopathies. [ABSTRACT FROM AUTHOR]

Summary: Aims: The G‐protein‐coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear. Methods: In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)‐ and letrozole (LET)‐treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERβ, and SRC‐1, selected synaptic proteins, mTORC2 signals (Rictor and p‐AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC‐1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A‐443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory. Results: The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC‐1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC‐1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15‐induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4. Conclusions: Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC‐1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus‐based, E2‐related memory impairments. [ABSTRACT FROM AUTHOR]

Bistability (coexistence of two stable steady states in a dynamical system) is a key mechanism of cellular decision‐making and has been observed in many biochemical reaction networks such as mitogen‐activated protein kinase (MAPK) signaling pathways. Theoretical studies have shown that bistability can arise in a single two‐site MAPK phosphorylation and dephosphorylation cycle. However, the bistable behavior mostly relies on the kinetic mechanisms and parameters of this two‐site modification. In exploring the system‐level properties of MAPK regulation, most models to date focus on two limiting reaction regimes, distributive and processive, and are characterized by high levels of parametric uncertainty. Here, we developed a combined kinetic method which applies a continuous spectrophotometric enzyme‐coupled assay incorporated with the viscosity approach, to perform detailed kinetic analyses of p38α MAPK dual phosphorylation by MKK6. Almost all kinetic rate constants for the first and second phosphorylation steps in p38α activation have been quantitatively determined, supporting that the phosphorylation occurs randomly in the first step, albeit preferring the tyrosine residue. The release rates of monophosphorylated p38α from MKK6, either as the product in the first modification or as the substrate in the second step, were comparable to the respective adjacent phosphoryl transfer steps. These results indicated that dual phosphorylation of p38α by MKK6 involves a random, partially processive mechanism. Based on the experimentally determined models and parameters, dynamics of the p38α‐MKK6‐MKP5 system were explored, demonstrating for the first time that bistability can arise with this model at biologically feasible parameter values. Enzymes: p38α (EC 2.7.11.24); MKK6 (EC 2.7.12.2). Almost all kinetic rate constants for the first and second phosphorylation steps in p38α activation have been quantitatively determined. Dynamics of the p38α‐MKK6‐MKP5 system were explored based on these experimentally determined models and parameters, demonstrating for the first time that bistability (coexistence of two stable steady states in a dynamical system) can arise with this model at biologically feasible parameter values. [ABSTRACT FROM AUTHOR]

The three‐component reaction of quinoline, dimethyl acetylenedicarboxylate and 2‐arylidene‐1,3‐indanediones or 5‐arylidene‐N,N'‐dimethylbarbituric acids in acetonitrile at room temperature afforded polysubstituted spiro[indene‐2,4′‐pyrido[1,2‐a]quinolines] or spiro[pyrido[1,2‐a]quinoline‐4,5′‐pyrimidines] in high yields and with high diastereoselectivity. However, the similar reaction of dimethyl acetylenedicarboxylate with 2‐arylidene‐1,3‐indanediones in the presence of 4‐Dimethylaminopyridine (DMAP) gave unexpected dihydroindeno[1,2‐b]pyrene derivatives in satisfactory yields. This three‐component reaction containing quinoline might be the most sustainable reaction without release any waste. The three‐component reaction of quinoline, dimethyl acetylenedicarboxylate and 2‐arylidene‐1,3‐indanediones or 5‐arylidene‐N,N'‐dimethylbarbituric acids in acetonitrile afforded spiro[indene‐2,4′‐pyrido[1,2‐a]quinolines] or spiro[pyrido[1,2‐a]quinoline‐4,5′‐pyrimidines] in high yields and with high diastereoselectivity. The similar reaction with DMAP gave dihydroindeno[1,2‐b]pyrenes in satisfactory yields. [ABSTRACT FROM AUTHOR]

Carbohydrate antigen 19‐9 (CA19‐9) fails to demonstrate the predictive value for early detection pancreatic ductal adenocarcinoma (PDAC). Glypican‐1 (GPC1+) exosomes may serve as a noninvasive diagnostic tool to detect early stages of PDAC. Therefore, it is necessary to explore the serum GPC1 levels and determine whether serum GPC1 serves as a novel biomarker for PDAC patients. Blood samples were collected from 156 patients with PDAC, 199 non‐cancer controls, and 240 patients with other cancers. Serological levels of GPC1 were examined by enzyme‐linked immunosorbent assay (ELISA). Finally, a 5‐year follow‐up was monitored to evaluate the correlation between serum GPC1 levels and overall survival in 156 patients with PDAC. The results suggested that levels of serum GPC1 and CA19‐9 were higher in PDAC patients than that of controls (P < 0.05). Serum GPC1 levels in PDAC were different from those in gallbladder carcinoma (P < 0.001), colorectal carcinoma (P < 0.001), gastric carcinoma (P < 0.001), and prostate cancer (P < 0.001), but not hepatocellular carcinoma (P = 0.395) and cholangiocarcinoma (P = 0.724). Receiver operating characteristic curve (ROC) analysis showed that serum CA19‐9 was significantly better than serum GPC1 in distinguishing PDAC patients from the controls (AUC, 95% CI: 0.908, 0.868‐0.947 vs 0.795, 0.749‐0.841, respectively). The serum GPC1 cannot be used as a serum diagnostic biomarker for PDAC patients. The level of serum GPC1 decreased 2 days after surgery (P = 0.001), which were not different from serum GPC1 levels in healthy control (P = 0.381). The overall survival rate was shorter in patients with high levels of serum GPC1 compared to those with low levels of serum GPC1 (log‐rank = 5.16, P = 0.023). Taken together, the results indicate that high levels of serum GPC1 predict poor prognosis in PDAC patients. Serum GPC1 may be a prognosis factor for PDAC patients. Our study provided evidence that high levels of serum GPC1 correspond to poor prognosis in pancreatic ductal adenocarcinoma patients. [ABSTRACT FROM AUTHOR]