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Abstract In this work, the rapid and efficient preparation of isolated galloyl glucoside tautomer free radical inhibitors was investigated using Saxifraga tangutica as a raw material. Four highly polar galloyl glucoside tautomers, 3-O-galloyl-α-d-glucose ⇌ 3-O-galloyl-β-d-glucose (Fr2-1-1), 2-O-galloyl-α-d-glucose ⇌ 2-O-galloyl-β-d-glucose (Fr2-1-2/2-1-3), 1-O-galloyl-β-d-glucose (Fr2-2-1), and 6-O-galloyl-α-d-glucose ⇌ 6-O-galloyl-β-d-glucose (Fr2-3-1/Fr2-3-2), were obtained via two-step medium-pressure liquid chromatography (with solid loading instead of conventional liquid injection) and one-step high-performance chromatography coupled with on-line RPLC-DPPH techniques for targeted isolation. This separation integration technique not only increases sample intake and reduces time cost but also visualizes each step of targeted separation. All four compounds were isolated from the plant for the first time. In vitro antioxidant activity assays by DPPH (1,1‑diphenyl-2-picrylhydrazyl) revealed that Fr2-1-2/Fr2-1-3 (IC50: 5.52 ± 0.32 μM), Fr2-2-1 (IC50: 7.22 ± 0.57 μM), and Fr2-3–1/Fr2-3-2 (IC50: 7.36 ± 0.25 μM) had superior free radical scavenging abilities and that both were superior to that of quercetin (IC50: 18.61 ± 3.55 μM). Oxidative stress assays revealed that Fr2-1-2/Fr2-1-3 significantly inhibited oxidative stress damage in H2O2-induced HepG2 cells, decreased the level of ROS (P

Abstract Background Tuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with a challenging diagnosis due to inadequate detection methods. This study evaluated current clinical detection methods and their applicability. Methods A cohort of 514 CNS infection patients from 2018 to 2020 was studied. Data on general demographics, Cerebrospinal Fluid (CSF) analysis, epidemiology, and clinical outcomes were collected. TBM patients were identified, and the sensitivities of mmetagenomic next-generation sequencing (NGS), GeneXpert, and microbial culture were compared. Kappa statistic assessed the consistency between methods. Results Among the patients involved, TBM (29%) and neurosyphilis (25%) were the two most prevalent CNS infections. CSF analysis indicated that 76% of patients had leukocytosis, suggesting a potential CNS inflammation. In TBM cases, 92.5% had elevated CSF protein and leukocyte counts. Moreover, the percentage of positive mNGS results was 55.6%. GeneXpert and MTB cultures alone had lower sensitivity, but combined use resulted in a 53.4% positive rate. Conclusions This study highlights the high sensitivity of mNGS, comparable to GeneXpert and MTB culture. The combined methods are cost-effective and straightforward, and can partially substitute for mNGS, offering valuable alternatives for TBM diagnosis and providing insights into multiple diagnostic strategies in clinical practice.

Abstract Implantable peripheral nerve electrodes are crucial for monitoring health and alleviating symptoms of chronic diseases. Advanced compliant electrodes have been developed because of their biomechanical compatibility. However, these mechanically tissue‐like electrodes suffer from unmanageable operating forces, leading to high risks of nerve injury and fragile electrode‐tissue interfaces. Here, a peripheral nerve electrode is developed that simultaneously fulfills the criteria of body temperature softening and tissue‐like modulus (less than 0.8 MPa at 37 °C) after implantation. The central core is altered from the tri‐arm crosslinker to the star‐branched monomer to kill two birds (close the translation temperature to 37 °C and decrease the modulus after implantation) with one stone. Furthermore, the decreased interfacial impedance (325.1 ± 46.9 Ω at 1 kHz) and increased charge storage capacity (111.2 ± 5.8 mC cm−2) are achieved by an in situ electrografted conductive polymer on the strain‐insensitive conductive network of Au nanotubes. The electrodes are readily wrapped around nerves and applied for long‐term stimulation in vivo with minimal inflammation. Neuromodulation experiments demonstrate their potential clinical utility, including vagus nerve stimulation in rats to suppress seizures and alleviation of cardiac remodeling in a canine model of myocardial infarction.

Berberine is an isoquinoline alkaloid, which has demonstrated significant therapeutic potential in the treatment of various diseases, including tumors, acute and chronic infections, autoimmune disorders, and diabetes. Studies have demonstrated that berberine exhibits polypharmacological effects, including antibacterial, anti-inflammatory, antioxidant, and hypoglycemic activities. To further elucidate the multifaceted pharmacological mechanisms of berberine, we reviewed 7 targets of berberine identified through co-crystal structure analysis, including filamentous temperature-sensitive protein Z (FtsZ), QacR, BmrR, phospholipase A2 (PLA2), RamR, NIMA-related kinase 7 (NEK7), and mesenchymal-epithelial transition (MET). Through target fishing, molecular docking, and surface plasmon resonance (SPR) analyses, combined with cellular and molecular experiments, we further identified 6 targets of berberine. These findings provide a comprehensive summary of berberine’s direct molecular targets, offering a theoretical foundation for further exploration of its diverse pharmacological activities.

BackgroundSmoking is a risk factor for a wide range of diseases. Previous research has confirmed over 30 Smoking-Associated Diseases in diverse systems. There is limited research exploring the correlation among multiple diseases, with an absence of comprehensive investigations. Few studies concentrate on diseases exhibiting a negative correlation with smoking, wherein smokers demonstrate a lower prevalence.ObjectiveThis study aimed to detect the correlation between smoking and other diseases using data from National Health and Nutrition Examination Surveys (NHANES) and construct a Smoking-Diseases Correlation Database (SDCD). The second aim is to obtain an extensive screening test for diseases that may be linked to smoking.Methods39,126 subjects’ data from the NHANES 2013–2018 dataset were extracted. The baseline information, difference in blood routine and blood chemistry indicators between smokers and non-smokers, and diseases’ correlation with smoking in four different models were analyzed by R. The data and statistics were aggregated into an online SDCD.ResultsOur study reported 46 Smoking-Associated Diseases (SAD), including 29 Smoking Positively Associated Diseases (SPAD) and 17 Smoking Negatively Associated Diseases (SNAD). The SDCD of 422 diseases was constructed and can be accessed at https://chatgptmodel.shinyapps.io/sdcd/.ConclusionOur findings revealed 46 SADs including 29 SPADs and 17 SNADs. We aggregated the statistics and developed online SDCD, advancing our understanding of the correlation between smoking and diseases.

Background: Arthrofibrosis (AF) is a fibrotic joint disease resulting from excessive collagen production and fibrous scar formation after total knee arthroplasty (TKA). This devastating complication may cause consistent pain and dramatically reduction of functionality. Unfortunately, the conservative treatments to prevent the AF in the early stage are largely unknown due to the lack of specific biomarkers and reliable therapeutic targets. Methods: In this study, we extracted1782 fibrosis related genes (FRGs) from 373,461published literature based on the large natural language processing models (ChatGPT) and intersected with the 2750 differential expressed genes (DEGs) from mRNA microarray (GSE135854). A total of 311 potential AF biomarker genes (PABGs) were obtained and functional analysis were performed including gene ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Subsequently, we accomplished validation in AF animal models with immobilization of the unilateral knee joints of 16 rabbits for 1-week, 2-weeks, 3-weeks and 4-weeks. Finally, we tested the biomarkers in a retrospective cohort enrolled 35 AF patients and 35 control group patients. Results: We identified G-protein-coupled receptor 17 (GPR17) as a reliable therapeutic biomarker for AF diagnosis with higher AUC (0.819) in the ROC curve. A total of 21 potential drugs targeted to GPR17 were screened. Among them, pranlukast and montelukast have achieved therapeutic effect in animal models. In addition, we established an online AF database for data integration (https://chenxi2023.shinyapps.io/afdbv1). Conclusions: These results unveiling therapeutic biomarkers for AF diagnosis, and provide potential drugs for clinical treatment. The translational potential of this article: Our study demonstrated that GPR17 holds significant promise as a potential biomarker and therapeutic target for arthrofibrosis. Moreover, pranlukast and montelukast targeted to GPR17 that could be instrumental in the treatment of AF.

IntroductionBacillus velezensis occurs extensively in the soil environment. It produces a range of antimicrobial compounds that play an important role in the field of biological control. However, during the actual application process it is often affected by factors such as the medium formulation and fermentation conditions, and therefore biocontrol measures often do not achieve their expected outcomes.MethodsIn this study, the B. velezensis BHZ-29 strain was used as the research object. The carbon and nitrogen sources, and inorganic salts that affect the number of viable bacteria and antibacterial potency of B. velezensis BHZ-29, were screened by a single factor test. A Plackett–Burman design experiment was conducted to determine the significant factors affecting the number of viable bacteria and antibacterial potency, and a Box–Behnken design experiment was used to obtain the optimal growth of B. velezensis BHZ-29. The medium formula that produced the highest number of viable bacteria and most antibacterial substances was determined. The initial pH, temperature, amount of inoculant, liquid volume, shaking speed, and culture time were determined by a single factor test. The factors that had a significant influence on the number of viable bacteria of B. velezensis BHZ-29 were selected by an orthogonal test. A Box–Behnken design experiment was conducted to obtain the optimal fermentation conditions, and highest number of viable bacteria and antibacterial titer.ResultsMolasses, peptone, and magnesium sulfate had significant effects on the viable count and antibacterial titer of B. velezensis BHZ-29. The viable count of B. velezensis BHZ-29 increased from 7.83 × 109 to 2.17 × 1010 CFU/mL, and the antibacterial titer increased from 111.67 to 153.13 mm/mL when the optimal media were used. The optimal fermentation conditions for B. velezensis BHZ-29 were as follows: temperature 25.57°C, pH 7.23, culture time 95.90 h, rotation speed 160 rpm, amount of inoculant 2%, and liquid volume 100 ml. After the optimization of fermentation conditions, the number of viable bacteria increased to 3.39 × 1010 CFU/mL, and the bacteriostatic titer increased to 158.85 mm/ml.The plant height and leaf number of cotton plants treated with BHZ-29 fermentation broth were higher than those of cotton inoculated with Verticillium dahliae. The number of bacteria was 1.15 × 107 CFU/g, and the number of fungi was 1.60 × 105 spores/g. The disease index of the cotton seedlings treated with the optimized fermentation broth was 2.2, and a control effect of 93.8% was achieved. B. velezensis BHZ-29 could reduce the disease index of cotton Verticillium wilt and had a controlling effect on the disease. The best effect was achieved in the treatment group with an inoculation concentration of 2 × 108 CFU/ml, the disease index was 14.50, and a control effect of 84.18% was achieved.DiscussionThe fermentation process parameters of the number of viable bacteria and antibacterial titer by strain B. velezensis BHZ-29 were optimized to lay a foundation for the practical production and application of strain B. velezensis BHZ-29 in agriculture.

Abstract Background/Objective Bereaved family surrogates from intensive care units (ICU) are at risk of comorbid anxiety, depression, and post-traumatic stress disorder (PTSD), but the temporal reciprocal relationships among them have only been examined once among veterans. This study aimed to longitudinally investigate these never-before-examined temporal reciprocal relationships for ICU family members over their first two bereavement years. Methods In this prospective, longitudinal, observational study, symptoms of anxiety, depression, and PTSD were assessed among 321 family surrogates of ICU decedents from 2 academically affiliated hospitals in Taiwan by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale, and the Impact of Event Scale-Revised, respectively at 1, 3, 6, 13, 18, and 24 months postloss. Cross-lagged panel modeling was conducted to longitudinally examine the temporal reciprocal relationships among anxiety, depression, and PTSD. Results Examined psychological-distress levels were markedly stable over the first 2 bereavement years: autoregressive coefficients for symptoms of anxiety, depression, and PTSD were 0.585–0.770, 0.546–0.780, and 0.440–0.780, respectively. Cross-lag coefficients showed depressive symptoms predicted PTSD symptoms in the first bereavement year, whereas PTSD symptoms predicted depressive symptoms in the second bereavement year. Anxiety symptoms predicted symptoms of depression and PTSD at 13 and 24 months postloss, whereas depressive symptoms predicted anxiety symptoms at 3 and 6 months postloss while PTSD symptoms predicted anxiety symptoms during the second bereavement year. Conclusions Different patterns of temporal relationships among symptoms of anxiety, depression, and PTSD over the first 2 bereavement years present important opportunities to target symptoms of specific psychological distress at different points during bereavement to prevent the onset, exacerbation, or maintenance of subsequent psychological distress.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

The classification of electroencephalogram (EEG) motor imagery signals has emerged as a prominent research focus within the realm of brain-computer interfaces. Nevertheless, the conventional, limited categories (typically just two or four) offered by brain-computer interfaces fail to provide an extensive array of control modes. To address this challenge, we propose the Time-Spatial Parallel Network (TSPNet) for recognizing six distinct categories of upper limb motor imagery. Within TSPNet, temporal and spatial features are extracted separately, with the time dimension feature extractor and spatial dimension feature extractor performing their respective functions. Following this, the Time-Spatial Parallel Feature Extractor is employed to decouple the connection between temporal and spatial features, thus diminishing feature redundancy. The Time-Spatial Parallel Feature Extractor deploys a gating mechanism to optimize weight distribution and parallelize time-spatial features. Additionally, we introduce a feature visualization algorithm based on signal occlusion frequency to facilitate a qualitative analysis of TSPNet. In a six-category scenario, TSPNet achieved an accuracy of 49.1% ± 0.043 on our dataset and 49.7% ± 0.029 on a public dataset. Experimental results conclusively establish that TSPNet outperforms other deep learning methods in classifying data from these two datasets. Moreover, visualization results vividly illustrate that our proposed framework can generate distinctive classifier patterns for multiple categories of upper limb motor imagery, discerned through signals of varying frequencies. These findings underscore that, in comparison to other deep learning methods, TSPNet excels in intention recognition, which bears immense significance for non-invasive brain-computer interfaces.

The limited number of brain-computer interface based on motor imagery (MI-BCI) instruction sets for different movements of single limbs makes it difficult to meet practical application requirements. Therefore, designing a single-limb, multi-category motor imagery (MI) paradigm and effectively decoding it is one of the important research directions in the future development of MI-BCI. Furthermore, one of the major challenges in MI-BCI is the difficulty of classifying brain activity across different individuals. In this article, the transfer data learning network (TDLNet) is proposed to achieve the cross-subject intention recognition for multiclass upper limb motor imagery. In TDLNet, the Transfer Data Module (TDM) is used to process cross-subject electroencephalogram (EEG) signals in groups and then fuse cross-subject channel features through two one-dimensional convolutions. The Residual Attention Mechanism Module (RAMM) assigns weights to each EEG signal channel and dynamically focuses on the EEG signal channels most relevant to a specific task. Additionally, a feature visualization algorithm based on occlusion signal frequency is proposed to qualitatively analyze the proposed TDLNet. The experimental results show that TDLNet achieves the best classification results on two datasets compared to CNN-based reference methods and transfer learning method. In the 6-class scenario, TDLNet obtained an accuracy of 65%±0.05 on the UML6 dataset and 63%±0.06 on the GRAZ dataset. The visualization results demonstrate that the proposed framework can produce distinct classifier patterns for multiple categories of upper limb motor imagery through signals of different frequencies. The ULM6 dataset is available at https://dx.doi.org/10.21227/8qw6-f578.

Summary: Arthrofibrosis (AF) is a debilitating complication that occurs after trauma or surgery, leading to functional impairment and surgical failures worldwide. This study aimed to uncover the underlying mechanism of AF. A total of 141 patients were enrolled, and synovial samples were collected from both patients and animal models at different time points. Single-cell RNA-sequencing (scRNA-seq) and bulk tissue RNA sequencing (bulk-seq) were employed to profile the distinct synovial microenvironment. This study revealed changes in cell proportions during AF pathogenesis and identified Engrailed-1 (EN1) as a key transcription factor strongly associated with disease severity and clinical prognosis. Additionally, the researchers discovered a specific type of synovial fibroblast called DKK3-SLF, which played a critical role in driving AF development. These findings shed light on the composition and heterogeneity of the synovial microenvironment in AF, offering potential avenues for identifying therapeutic targets and developing clinical treatments for AF and other fibrotic diseases.

Atopic dermatitis (AD) is one of the most common, relapsing, chronic inflammatory skin disease, being regarded as a global health issue. Recent studies have shown that Th2 cell-mediated type 2 immunity plays a central role in AD. The type 2 inflammatory cytokines such as IL-4, IL-13, IL-22, IL-31, IL-17 and IL-5 mediate the pathogenesis of AD. A variety of antibody drugs targeting these cytokines have been developed to treat AD in clinics. Notably, several antibody drugs have exhibited high efficacy in treating atopic dermatitis in previous studies, demonstrating that they could be therapeutic methods for AD patients. Herein, we reviewed the clinical trials of antibody drugs in the treatment of AD, which provides a useful guideline for clinicians to treat patients with AD in clinics.

Abstract Background Bereaved ICU family surrogates are at risk of comorbid prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression. Knowledge about temporal relationships between PGD, PTSD, and depression is limited by a lack of relevant studies and diverse or inappropriate assessment time frames given the duration criterion for PGD. We aimed to determine the temporal reciprocal relationships between PGD, PTSD, and depressive symptoms among ICU decedents’ family surrogates during their first 2 bereavement years with an assessment time frame reflecting the PGD duration criterion. Methods This prospective, longitudinal, observational study examined PGD, PTSD, and depressive symptoms among 303 family surrogates of ICU decedents from two academic hospitals using 11 items of the Prolonged Grief Disorder-13, the Impact of Event Scale—Revised, and the depression subscale of the Hospital Anxiety and Depression Scale, respectively, at 6, 13, 18, and 24 months post-loss. Cross-lagged panel modeling was conducted: autoregressive coefficients indicate variable stability, and cross-lagged coefficients indicate the strength of reciprocal relationships among variables between time points. Results Symptoms (autoregressive coefficients) of PGD (0.570–0.673), PTSD (0.375–0.687), and depression (0.591–0.655) were stable over time. Cross-lagged standardized coefficients showed that depressive symptoms measured at 6 months post-loss predicted subsequent symptoms of PGD (0.146) and PTSD (0.208) at 13 months post-loss. PGD symptoms did not predict depressive symptoms. PTSD symptoms predicted subsequent depressive symptoms in the second bereavement year (0.175–0.278). PGD symptoms consistently predicted subsequent PTSD symptoms in the first 2 bereavement years (0.180–0.263), whereas PTSD symptoms predicted subsequent PGD symptoms in the second bereavement year only (0.190–0.214). PGD and PTSD symptoms are bidirectionally related in the second bereavement year. Conclusions PGD, PTSD, and depressive symptoms can persist for 2 bereavement years. Higher PGD symptoms at 6 months post-loss contributed to the exacerbation of PTSD symptoms over time, whereas long-lasting PTSD symptoms were associated with prolonged depression and PGD symptoms beyond the first bereavement year. Identification and alleviation of depression and PGD symptoms as early as 6 months post-loss enables bereaved surrogates to grieve effectively and avoid the evolution of those symptoms into long-lasting PGD, PTSD, and depression.

BackgroundThe immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial in maintaining a delicate balance between protective effects and harmful pathological reactions that drive the progression of coronavirus disease 2019 (COVID-19). T cells play a significant role in adaptive antiviral immune responses, making it valuable to investigate the heterogeneity and diversity of SARS-CoV-2-specific T cell responses in COVID-19 patients with varying disease severity.MethodsIn this study, we employed high-throughput T cell receptor (TCR) β repertoire sequencing to analyze TCR profiles in the peripheral blood of 192 patients with COVID-19, including those with moderate, severe, or critical symptoms, and compared them with 81 healthy controls. We specifically focused on SARS-CoV-2-associated TCR clonotypes.ResultsWe observed a decrease in the diversity of TCR clonotypes in COVID-19 patients compared to healthy controls. However, the overall abundance of dominant clones increased with disease severity. Additionally, we identified significant differences in the genomic rearrangement of variable (V), joining (J), and VJ pairings between the patient groups. Furthermore, the SARS-CoV-2-associated TCRs we identified enabled accurate differentiation between COVID-19 patients and healthy controls (AUC > 0.98) and distinguished those with moderate symptoms from those with more severe forms of the disease (AUC > 0.8). These findings suggest that TCR repertoires can serve as informative biomarkers for monitoring COVID-19 progression.ConclusionsOur study provides valuable insights into TCR repertoire signatures that can be utilized to assess host immunity to COVID-19. These findings have important implications for the use of TCR β repertoires in monitoring disease development and indicating disease severity.

Abstract Background/objective Bereaved ICU family surrogates’ psychological distress, e.g., anxiety, depression, and post-traumatic stress disorder (PTSD), is usually examined independently, despite the well-recognized comorbidity of these symptoms. Furthermore, the few studies exploring impact of psychological distress on development of prolonged grief disorder (PGD) did not consider the dynamic impact of symptom evolution. We identified surrogates’ distinct patterns/states of comorbid psychological distress and their evolution over the first 3 months of bereavement and evaluated their associations with PGD at 6-month postloss. Methods A longitudinal observational study was conducted on 319 bereaved surrogates. Symptoms of anxiety, depression, PTSD, and PGD were measured by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised scale, and the PGD-13, respectively. Distinct psychological-distress states and their evolution were examined by latent transition analysis. Association between psychological-distress states and PGD symptoms was examined by logistic regression. Results Three distinct comorbid psychological-distress states (prevalence) were initially identified: no distress (56.3%), severe-depressive/borderline-anxiety distress (30.5%), and severe-anxiety/depressive/PTSD distress (13.3%). Except for those in the stable no-distress state, surrogates tended to regress to states of less psychological distress at the subsequent assessment. The proportion of participants in each psychological-distress state changed to no distress (76.8%), severe-depressive/borderline-anxiety distress (18.6%), and severe-anxiety/depressive/PTSD distress (4.6%) at 3-month postloss. Surrogates in the severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD-distress state at 3-month postloss were more likely to develop PGD at 6-month postloss (OR [95%] = 14.58 [1.48, 143.54] and 104.50 [10.45, 1044.66], respectively). Conclusions A minority of family surrogates of ICU decedents suffered comorbid severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD symptoms during early bereavement, but they were more likely to progress into PGD at 6-month postloss.

Oral microbes play a critical role in maintaining oral homeostasis. Microbial dysbiosis promotes disease pathogenesis through several mechanisms. Recent studies have revealed that microbial imbalance and sustained inflammation are involved in disease progression. The adverse interaction triggered by a host immune response to microorganisms can lead to oral and systemic diseases. Here, we reviewed how oral microbes communicate with hosts during the development of local and distant inflammation. Elucidation of these processes may reveal future directions in this field and the potential targets of novel biological therapies for oral and systemic diseases.

BackgroundThere is a paucity of data about VAs clustered at the vicinity of the basal septum of the ventricle. We aimed to report and characterize the clinical and electrophysiological features of basal septum VAs and explore the systematic ablation approach.MethodsA consecutive series of 51 patients who had their VAs successfully ablated at the basal septum of the ventricle was enrolled in this study. The basal septum was defined as the area 2 cm away from the septal annulus, the upper boundary was the site of the left or right His-Purkinje system, and the lower boundary was the borderline that separated away from the septum. RFCA was performed based on detailed activation mapping or pace mapping. Patients who underwent VA ablation from other areas of the tricuspid annulus (TA) and mitral annulus (MA) during the same period were enrolled as the control group.ResultsThe patients with basal septum VAs were significantly older (p < 0.01) and had more comorbidities (hypertension and coronary artery disease) (p < 0.01). Meanwhile, the precordial R wave transition was significantly different in right side, left side and intramural foci group (p < 0.001). Acute procedural success was achieved in 44 patients (86.3%) in the study group and in 63 patients (95.5%) in the control group. After a median of 12 (6–36) months of follow-up, compared with VA recurrence in the control group (2 cases), 11 patients with basal septum VAs had recurrences (p = 0.002), while a delayed cure was observed in 3 in intramural foci group.ConclusionBased on the unique anatomical and electrophysiological characteristics, a systematic approach for VAs originating from the basal septal area is warranted. Moreover, the follow-up data seemed to show a relative high recurrence rate for basal septal VAs during a period of time.

Abstract Background/Objective Death in intensive care units (ICUs) may increase bereaved family members’ risk for posttraumatic stress disorder (PTSD). However, posttraumatic stress-related symptoms (hereafter as PTSD symptoms) and their precipitating factors were seldom examined among bereaved family members and primarily focused on associations between PTSD symptoms and patient/family characteristics. We aimed to investigate the course and predictors of clinically significant PTSD symptoms among family members of deceased ICU patients by focusing on modifiable quality indicators for end-of-life ICU care. Method In this longitudinal observational study, 319 family members of deceased ICU patients were consecutively recruited from medical ICUs from two Taiwanese medical centers. PTSD symptoms were assessed at 1, 3, 6, and 13 months post-loss using the Impact of Event Scale-Revised (IES-R). Family satisfaction with end-of-life care in ICUs was assessed at 1 month post-loss. End-of-life care received in ICUs was documented over the patient’s ICU stay. Predictors for developing clinically significant PTSD symptoms (IES-R score ≥ 33) were identified by multivariate logistic regression with generalized estimating equation modeling. Results The prevalence of clinically significant PTSD symptoms decreased significantly over time (from 11.0% at 1 month to 1.6% at 13 months post-loss). Longer ICU stays (adjusted odds ratio [95% confidence interval] = 1.036 [1.006, 1.066]), financial insufficiency (3.166 [1.159, 8.647]), and reported use of pain medications (3.408 [1.230, 9.441]) by family members were associated with a higher likelihood of clinically significant PTSD symptoms among family members during bereavement. Stronger perceived social support (0.937 [0.911, 0.965]) and having a Do-Not-Resuscitate (DNR) order issued before the patient’s death (0.073 [0.011, 0.490]) were associated with a lower likelihood of clinically significant PTSD symptoms. No significant association was observed for family members’ satisfaction with end-of-life care (0.988 [0.944, 1.034]) or decision-making in ICUs (0.980 [0.944, 1.018]). Conclusions The likelihood of clinically significant PTSD symptoms among family members decreased significantly over the first bereavement year and was lower when a DNR order was issued before death. Enhancing social support and facilitating a DNR order may reduce the trauma of ICU death of a beloved for family members at risk for developing clinically significant PTSD symptoms.

Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3+ CD4+ HPGDS+ CRTH2+ CD161high ST2high CD49dhigh CD27low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.

Coronavirus disease 2019 (COVID-19) was caused by a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 utilizes human angiotensin converting enzyme 2 (hACE2) as the cellular receptor of its spike glycoprotein (SP) to gain entry into cells. Consequently, we focused on the potential of repurposing clinically available drugs to block the binding of SARS-CoV-2 to hACE2 by utilizing a novel artificial-intelligence drug screening approach. Based on the structure of S-RBD and hACE2, the pharmacophore of SARS-CoV-2-receptor-binding-domain (S-RBD) -hACE2 interface was generated and used to screen a library of FDA-approved drugs. A total of 20 drugs were retrieved as S-RBD-hACE2 inhibitors, of which 16 drugs were identified to bind to S-RBD or hACE2. Notably, tannic acid was validated to interfere with the binding of S-RBD to hACE2, thereby inhibited pseudotyped SARS-CoV-2 entry. Experiments involving competitive inhibition revealed that tannic acid competes with S-RBD and hACE2, whereas molecular docking proved that tannic acid interacts with the essential residues of S-RBD and hACE2. Based on the known antiviral activity and our findings, tannic acid might serve as a promising candidate for preventing and treating SARS-CoV-2 infection.

This study investigated the effects of berberine (BBR) on pancreatic cancer (PC) lung metastasis and explored the underlying mechanisms, using a BALB/C-nu/nu nude mouse model injected with PC cells (AsPC-1). Intragastric administration of BBR dose-dependently improves survival of mice intravenously injected with AsPC-1 cells, and reduces lung metastasis. Especially, BBR significantly reduces lung infiltration of circulating tumor cells (CTCs) 24 h after AsPC-1 cells injection. In vitro, tumor cells (TCs) trigger endothelial barrier disruption and promote trans-endothelial migration of CFSE-labeled TCs. BBR treatment effectively ameliorates TC-induced endothelial disruption, an effect that is diminished by inhibiting transforming growth factor-β receptor 1 (TGFBR1). Blocking TGFBR1 blunts the anti-metastatic effect of BBR in vivo. Mechanistically, BBR binds to the intercellular portion of TGFBR1, suppresses its enzyme activities, and protects endothelial barrier disruption by TCs which express higher levels of TGF-β1. Hence, BBR might be a promising drug for reducing PC lung metastasis in clinical practice.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a threat to the health of the global population. As the result of a global effort in the determination of origin, structure, and pathogenesis of SARS-CoV-2 and its variants, particularly such the variant of concern as Delta Variant and Omicron Variant, the understanding of SARS-CoV-2 are deepening and the development of vaccines against SARS-CoV-2 are ongoing. Currently, AstraZeneca-Vaxzevria/SII-Covishield vaccine, Janssen-Ad26.COV2.S vaccine, Moderna-mRNA-1273 vaccine, Pfizer BioNTech-Comirnaty vaccine and Sinovac-CoronaVac vaccine have been listed as WHO Emergency Use Listing (EUL) Qualified Vaccines by WHO. Because of the antigen escape caused by the mutation in variants, the effectiveness of vaccines, which are currently the main means of prevention and treatment, has been affected by varying degrees. Herein, we review the current status of mutations of SARS-CoV-2 variants, the different approaches used in the development of COVID-19 vaccines, and COVID-19 vaccine effectiveness against SARS-CoV-2 variants.

Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.

Coronavirus disease 2019 (COVID-19) continuously progresses despite the application of a variety of vaccines. Therefore, it is still imperative to find effective ways for treating COVID-19. Recent studies indicate that NRP1, an important receptor of the natural peptide tuftsin (released from IgG), facilitates SARS-CoV-2 infection. Here, we found 91 overlapping genes between tuftsin targets and COVID-19-associated genes. We have demonstrated that tuftsin could also target ACE2 and exert some immune-related functions. Molecular docking results revealed that tustin could combine with ACE2 and NRP1 in stable structures, and their interacted regions cover the binding surfaces of S1-protein with the two receptors. Using surface plasmon resonance (SPR) analysis, we confirmed that tuftsin can bind ACE2 and NRP1 directly. Importantly, using SPR-based competition assay we have shown here that tuftsin effectively prevented the binding of SARS-CoV-2 S1-protein to ACE2. Collectively, these data suggest that tuftsin is an attractive therapeutic candidate against COVID-19 and can be considered for translational as well as clinical studies.

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.

The plant microbiome is a key determinant of health and productivity. However, it is still difficult to understand the structural composition of the bacterial and fungal microbiomes of diseased and healthy plants, especially the spatial dynamics and phylogenies of endophytic and rhizosphere microbial communities. We studied the differentiation and variability in the rhizosphere and endosphere microbiomes of healthy and diseased cotton from north and south of the Tianshan Mountains using the methods of PCR-based high-throughput sequencing and real-time quantitative PCR. The endophytic and rhizosphere bacterial abundances in the diseased plants were greater than those of healthy plants. The numbers of endophytic and rhizosphere fungi associated with diseased plants were greater than those associated healthy plants (p < 0.05). Endophytic and rhizosphere bacteria did not share common OTUs. The dominant rhizosphere bacteria were Proteobacteria (29.70%), Acidobacteria (23.14%), Gemmatimonadetes (15.17%), Actinobacteria (8.31%), Chloroflexi (7.99%), and Bacteroidetes (5.15%). The dominant rhizosphere fungi were Ascomycota (83.52%), Mortierellomycota (7.67%), Basidiomycota (2.13%), Chytridiomycota (0.39%), and Olpidiomycota (0.08%). The distribution of dominant bacteria in different cotton rhizosphere soils and roots differed, with the dominant bacteria Pseudomonas (15.54%) and Pantoea (9.19%), and the dominant fungi Alternaria (16.15%) and Cephalotrichum (9.10%) being present in the greatest numbers. At sampling points in different ecological regions, the total numbers of cotton endophytic and rhizosphere microbiome OTUs from southern to northern Xinjiang showed an increasing trend. There were significant differences in the composition and diversity of rhizosphere microbes and endophytes during the entire cotton growth period and in representative ecological regions (p < 0.01), whereas rhizosphere microbes and endophytes showed no significant differences among the four growth periods and in representative ecological regions. RB41, H16, Nitrospira, and Sphingomonas play important roles in the microbial ecology of cotton rhizosphere soil. Pseudomonas accounted for a large proportion of the microbes in the cotton rhizosphere soil. This study provides an in-depth understanding of the complex microbial composition and diversity associated with cotton north and south of the Tianshan Mountains.

Hippophae rhamnoides L. is a deciduous shrub that contains many unique bioactive substances. This sea buckthorn possesses anticancer, antioxidant, anti-inflammatory, and cardiovascular protective properties. Herein, the effects of phenylpropyl compounds extracted from H. rhamnoides L. on doxorubicin (Dox)-induced cardiotoxicity were evaluated in zebrafish. Cardiac injury in zebrafish was induced using 35 μM Dox for 96 h, and 30 μM phenylpropanoid compounds were used as the protective treatment. The cardioprotective effects and mechanisms of the four phenylpropanoids were investigated using microscopy, behavioral analysis, acridine orange staining, western blotting, flow cytometry, and real-time quantitative polymerase chain reaction. The extracted phenylpropanoids could significantly relieve Dox-induced cardiac injury in zebrafish and inhibit cardiomyocyte apoptosis. The mechanisms of action were mainly related to the stability of mitochondrial biogenesis and function maintained by phenylpropanoids in zebrafish. To our knowledge, this is the first report on the protective effect of sea buckthorn against myocardial injury in zebrafish. Our findings provide support for the further research and development of sea buckthorn and its components.

Transcription factor DP family member 3 (TFDP3) is a cancer-testis antigen, mainly expressed in normal testis and multiple cancers. TFDP3 gene (Gene ID: 51270) is located on the chromosome X and shares a high degree of sequence homology with TFDP1 and TFDP2, which can form heterodimers with E2F family members and enhance DNA-binding activity of E2Fs. In contrast to TFDP1 and TFDP2, TFDP3 downregulates E2F-mediated transcriptional activation. During DNA damage response in cancer cells, TFDP3 is induced and can inhibit E2F1-mediated apoptosis. Moreover, TFDP3 is involved in cell autophagy and epithelial-mesenchymal transition. Regarding cancer therapy opportunity, the transduction of dendritic cells with recombinant adenovirus-encoding TFDP3 can activate autologous cytotoxic T lymphocytes to target hepatoma cells. Here, we review the characterization of TFDP3, with an emphasis on the biological function and molecular mechanism. A better understanding of TFDP3 will provide new insights into the pathological mechanisms and therapeutic strategies for cancers.

Polychlorinated biphenyls (PCBs) tend to accumulate in adipose tissue and induce toxicity due to their high lipophilicity and persistence. Tuna play an important role in the ocean food web and human diet. PCBs can damage the growth of tuna directly and have some adverse effects on human indirectly. This review aims to provide geographic variations, bioaccumulation factors and the toxic effects of PCBs in tuna. PCB levels found were varied significantly among the different regions and it showed a trend of offshore greater than pelagic, with the northern hemisphere higher than the southern hemisphere. The highest PCB concentration of tuna was in FAO area 37. Nearly all of the specimens presented similar domain configuration, while their concentrations varied significantly. PCB congeners and concentrations in tuna were affected by a vast of factors, such as geographical distribution, tissue types, trophic level and growth stage, gender, tuna species and physical and chemical properties of PCBs. They can damage reproductive, neurologic and development systems. This review gives a systematic insight into PCBs in tuna and highlights the more attention should be paid to the long-term changes of PCBs in tuna and oceans. There is also a need to strengthen the assessment of PCB impacts on tuna ecology.

The space target capturing task using the spacecraft-manipulator system (SMS) has special significance in on-orbit servicing due to its theoretical challenges and practical value. The contact force between the end effector (gripper) and the target exerted by the tumbling motion of the space target destabilizes the spacecraft base. A full-dimensional controllable damping mechanism (FDCDM) with a cross-axis structure was designed to buffer the transient impact force on the end joint. The introduction of a damping mechanism gives the space robot a variable stiffness and damping system, and a stiffness estimation algorithm is proposed to calibrate the system stiffness, as stiffness cannot be measured directly. The full-dimensional controllable damping mechanism (FDCDM) with a cross-axis structure is equivalent to a four-DOF tandem joint, and the whole-body dynamic model of the SMS endowed with a full-dimensional controllable damping mechanism (FDCDM) was established using the Kane equation. Then, an unknown input observer (UIO)-based identification theory is proposed to precisely estimate the internal flexibility torque and the corresponding joint stiffness. A model-based neural learning algorithm is proposed to update the variable parameter matrix of the observer. The simulation experiment results demonstrate that the flexibility torque and joint stiffness could be accurately estimated within the expected error, illustrating the feasibility and effectiveness of the proposed method.

Compliant capture of the space non-cooperative targets is a key technology in on-orbit services. A great challenge is that the multi-dimensional contact force generated by the tumbling space target can destabilize the spacecraft-manipulator system (SMS), which may eventually cause failure of the capture task. A full-dimensional controllable damping mechanism (FDCDM) with gyroscopic structure is introduced into the joint of the SMS to buffer the multi-dimensional contact forces during capture. The six-dimensional damping force outputs by the FDCDM can be equivalent to the actuator outputs in the end joint, which could form a coordinated control system with the torque of base flywheel and active joints. The whole-body dynamic model of SMS with FDCDM is established using the Kane method. Furthermore, a backstepping non-singular sliding mode control is proposed to optimize the momentum distribution and impact absorption. The characteristics of collision process for the above SMS-FDCDM system is analyzed in the ADAMS workspace, and the experiments performed in MATLAB demonstrate that the full-dimensional damping mechanism and coordinated control can greatly reduce the vibration caused by the impact force, and the attitude of SMS is quickly stabilized after capture, which proves the feasibility of its application in non-cooperative target capturing tasks.

Background: Arthrofibrosis is a debilitating complication after total knee arthroplasty (TKA) which becomes a considerable burden for both patients and clinical practitioners. Our study aimed to identify novel biomarkers and therapeutic targets for drug discovery. Methods: Potential biomarker genes were identified based on bioinformatic analysis. Twelve male New Zealand white rabbits underwent surgical fixation of unilateral knees to mimics the joint immobilization of the clinical scenario after TKA surgery. Macroscopic assessment, hydroxyproline content determination, and histological analysis of tissue were performed separately after 3-days, 1-week, 2-weeks, and 4-weeks of fixation. We also enrolled 46 arthrofibrosis patients and 92 controls to test the biomarkers. Clinical information such as sex, age, range of motion (ROM), and visual analogue scale (VAS) was collected by experienced surgeons Findings: Base on bioinformatic analysis, transforming growth factor-beta receptor 1 (TGFBR1) was identified as the potential biomarkers. The level of TGFBR1 was significantly raised in the rabbit synovial tissue after 4-weeks of fixation (p

Developing large-scale flexible display technologies calls for new gate dielectric materials balancing the insulating property and molecular packing of organic semiconductors. Ji et al. synthesize a dielectric copolymer contributing with charge mobility of 5 cm2 V−1 s−1 and low operating voltage of 3 V.

Background/Aims: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. Methods: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson’s trichrome staining to explore the function of S100A4. Results: We found significant increases of S100A4 level and cardiac fibrosis markers, and β-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and β-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited β-catenin signal pathway. Conclusion: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia/wasting syndrome. Cachexia is associated with reduced survival, decreased quality of life, and higher metastasis rates. Here, we demonstrate that fat loss is the earliest feature of PDAC-exosome-induced cachexia. MicroRNA sequencing of exosomal components from normal and cancer-derived exosomes revealed enrichment of miR-16-5p, miR-21-5p, miR-29a-3p, and miR-125b-5p in serum exosomes of mice harboring PDAC and patients with PDAC. Further, miR-16-5p and miR-29a-3p inhibited adipogenesis through decreasing Erlin2 and Cmpk1 expression which downregulates C/EBPβ and PPARγ. Synergistically, miR-29a-3p promotes lipolysis through increasing ATGL expression by suppressing MCT1 expression. Furthermore, PDAC-exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss. Hence, miR-16-5p and miR-29a-3p exosomal miRs are essential for PDAC-induced fat loss. Thus, we unravel that PDAC induces adipose atrophy via exosomal miRs. This knowledge may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia.

During target capturing operation, the changes in the dynamics parameters of a free-floating space manipulator degrade the performance of the base attitude stabilization. This paper presents a new self-learning soft-grasp control algorithm based on the variable stiffness technology. First, the dynamic model of variable stiffness joint space manipulator system is established. Simultaneously, the detailed dynamic analysis of pre-impact and post-impact stages is carried out. Second, a new soft-grasp control strategy utilizing cellular differential evolution algorithm combined opposition-based learning with orthogonal crossover is employed to minimize the base angular momentum. Its principle is to solve the optimal stiffness value of the variable stiffness joint to realize desired buffering. Thereafter, we put forward an adaptive backstepping sliding mode control method to track the actual joint stiffness. Finally, the proposed method is applied to a two-degree of freedom planar free-floating space manipulator and the simulation results verify the effectiveness.

Aiming at the soft contact problem of space docking, a bionic docking mechanism for space target acquisition is proposed to realize the buffering and unloading of six–dimensional spatial collision through flexible rotating and linear components. Using the Kane method, an integrated dynamic equation of the bionic docking mechanism in space docking is established, and the stiffness optimization strategy is carried out based on angular momentum conservation. Based on the particle swarm optimization (PSO), a stiffness optimization scheme was realized. Through the numerical simulation of the bionic docking mechanism in space docking, the stiffness optimization was achieved and the soft contact machine process is verified. Finally, through the docking collision experiments in Adams, the results indicate that the proposed bionic docking mechanism can not only prolong the collision time to win time for space acquisition, but also buffer and unload the six–dimensional spatial collision caused by space target docking.

Particulate matter with an aerodynamic diameter less than 2.5 μM (PM2.5) is one of the major environmental pollutants in China. In this study, we carried out a metabolomics profile study on PM2.5-induced inflammation. PM2.5 from Beijing, China, was collected and given to rats through intra-tracheal instillation in vivo. Acute pulmonary injury were observed by pulmonary function assessment and H.E. staining. The lipid metabolic profile was also altered with increased phospholipid and sphingolipid metabolites in broncho-alveolar lavage fluid (BALF) after PM2.5 instillation. Organic component analysis revealed that benzo[a]pyrene (BaP) is one of the most abundant and toxic components in the PM2.5 collected on the fiber filter. In vitro, BaP was used to treat A549 cells, an alveolar type II cell line. BaP (4 μM, 24 h) induced inflammation in the cells. Metabolomics analysis revealed that BaP (4 μM, 6 h) treatment altered the cellular lipid metabolic profile with increased phospholipid metabolites and reduced sphingolipid metabolites and free fatty acids (FFAs). The proportion of ω–3 polyunsaturated fatty acid (PUFA) was also decreased. Mechanically, BaP (4 μM) increased the phospholipase A2 (PLA2) activity at 4 h as well as the mRNA level of Pla2g2a at 12 h. The pro-inflammatory effect of BaP was reversed by the cytosolic PLA2 (cPLA2) inhibitor and chelator of intracellular Ca2+. This study revealed that BaP, as a component of PM2.5, induces pulmonary injury by activating PLA2 and elevating lysophosphatidylcholine (LPC) in a Ca2+-dependent manner in the alveolar type II cells.

Abstract As a newly identified factor in calcium-activated chloride channel, ANO1 participates in various physiological processes like proliferation and differentiation, and expresses in human cardiac fibroblasts. In this experiment, we investigated the function of ANO1 in cardiac fibrosis after myocardial infraction (MI) with methods of Western blotting, Quantitative real-time PCR (qRT-PCR), metabolic reduction of 3-(4,5-dimethylthiozol-2-yl)-2, 5-diphenyltetrazo-lium bromide (MTT), immunofluorescence and confocal imaging, and Masson’s trichrome staining. The results showed that the expression of ANO1 significantly increased in neonatal rats’ cardiac fibroblasts after hypoxia and in cardiac tissues after MI. After ANO1 over-expression, cardiac fibrosis was reduced in vitro and in vivo. Moreover, the expression of TGF-β and p-smad3 declined after ANO1over-expression in cardiac fiborblasts. In conclusion, ANO1 inhibits cardiac fibrosis after MI via TGF-β/smad3 pathway in rats.

Abstract Proprotein convertase subtilisin/kexin9 monoclonal antibodies (PCSK9-mAb) have been studied intensively to identify their effect in lowering levels of low density lipoprotein cholesterol (LDL-C). However, the applicable target of PCSK9-mAbs remains inconclusive so far. Therefore, this first meta-analysis was carried out to clarify the therapeutic efficacy and safety of PCSK9-mAbs on the potential patients: familial hypercholesterolemia and statin-intolerant patients. All randomized controlled trials that met the search terms were retrieved in multiple databases. Efficacy outcomes included parameter changes from baseline in LDL-C and other lipid levels. Therapeutic safety were evaluated by rates of common adverse events. A total of 15 studies encompassing 4,288 patients with at least 8 weeks duration were selected. Overall, the therapeutic efficacy was achieved with significant reduction in LDL-C, TC, TG, Lp(a), Apo-B versus placebo. The decline in familial hypercholesterolemia patients (−53.28%, 95% CI: −59.88 to −46.68%) was even more obvious than that in statin-intolerant patients (−34.95%, 95% CI: −41.46 to −28.45%). No obvious safety difference was found out in the rates of common and serious adverse events. To conclude, PCSK9-mAb contributes to the decreased level of LDL-C and other lipids in familial hypercholesterolemia and statin-intolerant patients with satisfactory safety and tolerability.

Robots as therapy tools have been researched in intervention for children with autism. During the interaction between robots and autistic children, engagement is an important metric which can be used to express whether robot's behavior is suited to the current context. The evaluation of engagement is a key prerequisite to improve the autonomous ability of robots in intervention. In this paper, we propose a new model to evaluate the engagement of children with autism. The proposed model is developed based on the dynamic Bayesian network, and the parameters of the model are obtained by fuzzy logic and expert elicitation. After determining the input features and the classification of engagement, the topology of the model is established. Afterward, experts' opinions are collected based on linguistic variables. Based on triangular fuzzy number, the parameterization of the model is realized by fuzzification, aggregation, and defuzzification. Finally, the model is validated by experiment. The result demonstrates that proposed model satisfies the actual demands and the result of engagement classification can provide the input condition for the decision making of the robot.

The space-borne manipulator has been playing an important part in docking tasks. Docking collision can easily lead to instability of both the manipulator and floating base. Aiming at the problem of soft capture, a novel soft-contact joint with dual working modes is developed, especially to buffer and unload the spatial collision momentum. Furthermore, considering a series-wound soft-capture manipulator with multi-joints, a generalized modeling method was established by using the Kane approach. Both the benefits of soft-contact joint and the effectiveness of dynamics equations are verified in MATLAB and Adams software by simulations of a two-joint manipulator with eight-DOF. The comparative simulation results showed the advantages of the proposed soft-contact joint in reducing instability from spatial impact.

In order to solve the problem of multi-tag anti-collision in radio frequency identification systems, a multi-tag anti-collision protocol based on 8-ary adaptive pruning query tree is proposed in this article. According to Manchester code, the highest collision bit can be detected. In the process of tag identification, the protocol only locks the target on the three consecutive bits which start from the highest collision bit. The protocol has two tag identification mechanisms, and which one is chosen is determined by the value of collision coefficient. Using the collision information characteristics of the three bits, idle timeslots are evitable, and some collision timeslots are eliminated at the same time. The 8-ary adaptive pruning query tree protocol fully takes into account several important performance indicators such as the number of query timeslots, communication complexity, transmission delay, and throughput. Both theoretical analysis and simulation results show that this protocol performs better than other tree-based anti-collision protocols. The throughput of 8-ary adaptive pruning query tree protocol remains approximately 0.625.

Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine.Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-β1-42 (Aβ1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ1-42 aggregation to delay the pathological process of Alzheimer’s disease.Conclusion: Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer’s disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases.

Phenol-soluble modulins (PSMs) have recently emerged as key virulence determinants, particularly in highly aggressive Staphylococcus aureus isolates. These peptides contribute to the pathogenesis of S. aureus infections, participating in multiple inflammatory responses. Here, we report a new role for S. aureus PSMs in high mobility group box-1 protein (HMGB1) induced inflammation by modulating toll-like receptor (TLR) 4 pathway. Direct ligation of TLR4 with S. aureus PSMα1–α3 and PSMβ1–β2 was identified by surface plasmon resonance. Remarkably, the binding affinity of TLR4 with HMGB1 was attenuated by PSMα1–α3. Further study revealed that PSMα1–α3 directly inhibited HMGB1-induced NF-κB activation and proinflammatory cytokines production in vitro using HEK-Blue hTLR4 cells and THP-1 cells. To analyze the molecular interactions between PSMs and TLR4, blast similarity search was performed and identified that PSMα1 and PSMβ2 were ideal templates for homology modeling. The three-dimensional structures of PSMα2, PSMα4, PSMβ1, and δ-toxin were successfully generated with MODELLER, and further refined using CHARMm. PSMs docking into TLR4 were done using ZDOCK, indicating that PSMα1–α3 compete with HMGB1 for interacting with the surrounding residues (336–477) of TLR4 domain. Our study reveals that S. aureus PSMα1–α3 can act as novel TLR4 antagonists, which account at least in part for the staphylococcal immune evasion. Modulation of this process will lead to new therapeutic strategies against S. aureus infections.