Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

Trapping and reversing neuromuscular blocking agent by anionic pillar[5]arenes: Understanding the structure-affinity-reversal effects.

Selective relaxant binding agents (SRBA) have great potential in clinical surgeries for the precise reversal of neuromuscular blockades. Understanding the relationship between the structure-affinity-reversal effects of SRBA and neuromuscular blockade is crucial for the design of new SRBAs, which has rarely been explored. Seven anionic pillar[5]arenes (AP5As) with different aliphatic chains and anionic groups at both edges were designed. Their binding affinities to the neuromuscular blocking agent decamonium bromide (DMBr) were investigated using 1H NMR, isothermal titration calorimetry (ITC), and theoretical calculations. The results indicate that the capture of DMBr by AP5As is primarily driven by electrostatic interactions, ion-dipole interactions and C-H‧‧‧π interactions. The optimal size matching between the carboxylate AP5As and DMBr was ∼0.80. The binding affinity increased with an increase in the charge quantity of AP5As. Further animal experiments indicated that the reversal efficiency increased with increasing binding affinity for carboxylate or phosphonate AP5As. However, phosphonate AP5As exhibited lower reversal efficiencies than carboxylate AP5As, despite having stronger affinities with DMBr. By understanding the structure-affinity-reversal relationships, this study provides valuable insights into the design of innovative SRBAs for reversing neuromuscular blockade.

Spotlight on the vertical migration of aged microplastics in coastal waters.

Coastal waters are complex and dynamic areas with unique environmental attributes that complicate the vertical migration of microplastics (MPs). The MPs that enter coastal waters from diverse sources, including terrestrial, riverine, oceanic, and shoreline inputs undergo various aging pathways. In this study, the variations in the physiochemical characteristics of MPs undergoing various aging pathways and their vertical migration under dynamic conditions subjected to the effects of different MP characteristics and coastal environmental features were comprehensively explored. Opposite effects of aging on the vertical migration of hydrophobic and hydrophilic MPs were observed, with aging appearing to promote the dispersion of hydrophobic MPs but enhance the vertical migration of hydrophilic ones. The positive role of salinity and the negative role of humic acid (HA) concentrations on MP vertical migration were identified, and the mechanisms driving these effects were analyzed. Notably, intense turbulence not only promoted the floating of positively buoyant MPs but also reversed the migration direction of negatively buoyant MPs from downward to upward. Aging-induced changes in MP characteristics had a limited effect on MP vertical migration. The inherent characteristics of MPs and the surrounding environmental features, however, played major roles in their vertical migration dynamics. ENVIRONMENTAL IMPLICATION: Microplastics (MPs) have emerged as a significant global environmental concern and the coastal zones are the hotspots for MP pollution due to their high population density. This study comprehensively investigated the variations in the physiochemical characteristics of MPs undergoing various aging pathways. Their vertical migration patterns under dynamic conditions subjected to the effects of different MP characteristics and coastal environmental features were revealed. The roles of turbulence and MP density in their migration were identified. The findings of this study have important implications for understanding the transport and determining the ecological risks of MPs in coastal waters.

Glioma-targeted oxaliplatin/ferritin clathrate reversing the immunosuppressive microenvironment through hijacking Fe2+ and boosting Fenton reaction.

Glioma is easy to develop resistance to temozolomide (TMZ). TMZ-resistant glioma secretes interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), recruiting regulatory T cell (Treg) and inhibiting the activity of T cells and natural killer cell (NK cell), subsequently forming an immunosuppressive microenvironment. Oxaliplatin (OXA) greatly inhibits the proliferation of TMZ-resistant glioma cells, but the ability of OXA to cross blood-brain barrier (BBB) is weak. Thus, the therapeutic effect of OXA on glioma is not satisfactory. Transferrin receptor 1 (TfR1) is highly expressed in brain capillary endothelial cells and TMZ-resistant glioma cells. In this study, OXA was loaded into ferritin (Fn) to prepare glioma-targeted oxaliplatin/ferritin clathrate OXA@Fn. OXA@Fn efficiently crossed BBB and was actively taken up by TMZ-resistant glioma cells via TfR1. Then, OXA increased the intracellular H2O2 level and induced the apoptosis of TMZ-resistant glioma cells. Meanwhile, Fn increased Fe2+ level in TMZ-resistant glioma cells. In addition, the expression of ferroportin 1 was significantly reduced, resulting in Fe2+ to be locked up inside the TMZ-resistant glioma cells. This subsequently enhanced the Fenton reaction and boosted the ferroptosis of TMZ-resistant glioma cells. Consequently, T cell mediated anti-tumor immune response was strongly induced, and the immunosuppressive microenvironment was significantly reversed in TMZ-resistant glioma tissue. Ultimately, the growth and invasion of TMZ-resistant glioma was inhibited by OXA@Fn. OXA@Fn shows great potential in the treatment of TMZ-resistant glioma and prospect in clinical transformation.

Unveiling the Vertical Migration of Microplastics with Suspended Particulate Matter in the Estuarine Environment: Roles of Salinity, Particle Properties, and Hydrodynamics.

The estuary is an energetic area connecting the inland, river, and ocean. The migration of microplastics (MPs) in this highly complex area is tied to the entire ecosystem. In this study, the effects of cohesive SPM (clay) and noncohesive SPM (sand) on the vertical migration of positively buoyant MPs, polyethylene (PE), and negatively buoyant MPs, polytetrafluoroethylene (PTFE), in the estuarine environment under hydrodynamic disturbances were investigated. The settling of positively buoyant MPs was more reliant on the cohesive SPM compared to the settling of negatively buoyant MPs. Moreover, MPs interacting with the SPM mixture at a clay-to-sand ratio of 1:9 settled more efficiently than those interacting with clay alone. A significant positive correlation was observed between MP settling percentage and the salinity level. MP settling percentage was significantly negatively correlated with fluid shear stress for both types of MPs, meanwhile, negatively buoyant MPs were able to resist greater hydraulic disturbances. In the low-energy mixing state, for both types of MPs, the settling percentage reached about 50% in only 10 min. The resuspension process of MPs under hydrodynamic disturbances was also uncovered. Additionally, the migration and potential sites of MPs were described in the context of prevalent environmental phenomena in estuaries.

The Global Prevalence of Methicillin-Resistant Staphylococcus Aureus in Patients with Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis.

Objective: Diabetic foot ulcer (DFU) frequently leads to infections, with infected DFUs being a common cause of amputation. Infection by methicillin-resistant Staphylococcus aureus (MRSA) notably increases the necessity for amputation and surgical debridement in affected individuals. Consequently, determining the prevalence and trends of MRSA in patients with DFU is of critical importance. This study aimed to assess the global prevalence and to identify trends in the occurrence of MRSA in tissue or wound swab samples from DFU patients. Methods: We conducted a comprehensive literature search across PubMed, Embase, Scopus, and Ovid, spanning from the inception of these databases to July 2023, imposing no language restrictions. The inclusion criteria required that the studies report on 30 or more patients with DFU. Additionally, we categorized our analysis based on geographic region, publication date, and the economic status of the patient's domicile. Our primary endpoint was to ascertain the prevalence of MRSA in DFUs. This systematic review has been registered at (https://www.crd.york.ac.uk/prospero/), with the identifier CRD 42023444360. Results: Our analysis encompassed 40 studies involving 12,924 patients across 20 countries. We found that the overall prevalence of MRSA in DFU was 17% (95% Confidence Interval [CI] 0.14-0.20). Regional prevalence varied significantly: in South America, it was 61% (95% CI 0.46-0.76), in North America 20% (95% CI 0.12-0.27), in Europe 19% (95% CI 0.14-0.25), in Africa 13% (95% CI 0.06-0.20), and in other subgroups 11% (95% CI 0.08-0.15). The prevalence of MRSA in DFUs also differed according to the economic status of the countries: 19% (95% CI 0.15-0.23) in high-income countries, 24% (95% CI 0.1-0.37) in upper-middle-income countries, 11% (95% CI 0.07-0.15) in lower-middle-income countries, and 20% (95% CI 0.13-0.27) in low-income countries. Notably, there has been a decline in MRSA prevalence, from 25% before 2010 to 9% thereafter. Conclusion: This meta-analysis reveals a decreasing yet still significant global prevalence of MRSA in DFUs. This trend has important implications for antimicrobial resistance and underscores the need for developing targeted programs focusing on infection prevention and exploring alternative therapeutic strategies.

Efficacy of Acupuncture for Chronic Spontaneous Urticaria : A Randomized Controlled Trial.

BACKGROUND: The effectiveness of acupuncture for patients with chronic spontaneous urticaria (CSU), reported in a few small-scale studies, is not convincing. OBJECTIVE: To investigate whether acupuncture leads to better effects on CSU than sham acupuncture or waitlist control. DESIGN: A multicenter, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR1900022994). SETTING: Three teaching hospitals in China from 27 May 2019 to 30 July 2022. PARTICIPANTS: 330 participants diagnosed with CSU. INTERVENTION: Participants were randomly assigned in a 1:1:1 ratio to receive acupuncture, sham acupuncture, or waitlist control over an 8-week study period (4 weeks for treatment and another 4 weeks for follow-up). MEASUREMENTS: The primary outcome was the mean change from baseline in the Weekly Urticaria Activity Score (UAS7) at week 4. Secondary outcomes included itch severity scores, self-rated improvement, and Dermatology Life Quality Index scores. RESULTS: The mean change in UAS7 (range, 0 to 42) for acupuncture from baseline (mean score, 23.5 [95% CI, 21.8 to 25.2]) to week 4 (mean score, 15.3 [CI, 13.6 to 16.9]) was -8.2 (CI, -9.9 to -6.6). The mean changes in UAS7 for sham acupuncture and waitlist control from baseline (mean scores, 21.9 [CI, 20.2 to 23.6] and 22.1 [CI, 20.4 to 23.8], respectively) to week 4 (mean scores, 17.8 [CI, 16.1 to 19.5] and 20.0 [CI, 18.3 to 21.6], respectively) were -4.1 (CI, -5.8 to -2.4) and -2.2 (CI, -3.8 to -0.5), respectively. The mean differences between acupuncture and sham acupuncture and waitlist control were -4.1 (CI, -6.5 to -1.8) and -6.1 (CI, -8.4 to -3.7), respectively, which did not meet the threshold for minimal clinically important difference. Fifteen participants (13.6%) in the acupuncture group and none in the other groups reported adverse events. Adverse events were mild or transient. LIMITATION: Lack of complete blinding, self-reported outcomes, limited generalizability because antihistamine use was disallowed, and short follow-up period. CONCLUSION: Compared with sham acupuncture and waitlist control, acupuncture produced a greater improvement in UAS7, although the difference from control was not clinically significant. Increased adverse events were mild or transient. PRIMARY FUNDING SOURCE: The National Key R&D Program of China and the Science and Technology Department of Sichuan Province.

Polymer-Initiating Caveolae-Mediated Endocytosis and GSH-Responsive MiR-34a Gene Delivery System for Enhanced Orthotopic Triple Negative Breast Cancer Therapy.

Gene therapy based on miRNAs has broad application prospects in the treatment of tumors. However, due to degradation and ineffective release during intracellular transport, current gene delivery vectors used for miRNAs limited their actual transfection efficiency. This study develops a novel nonviral vector PEI-SPDP-Man (PSM) that can simultaneously target cellular uptake pathways and intracellular responsive release for miR-34a. PSM is synthesized by connected mannitol (Man) to branched polyethylenimine (PEI) using a disulfide bond. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis to reduce the degradation of miR-34a in lysosomes. The disulfide bond is sensed at high concentration of glutathione (GSH) in the tumor cells and miR-34a is released, thereby reducing the expression of Bcl-2 and CD44 to suppress the proliferation and invasion of tumor cells. In vitro and in vivo experiments show that through the targeted cellular uptake and the efficient release of miR-34a, an effective antitumor and antimetastasis profiles for the treatment of orthotopic triple negative breast cancer (TNBC) are achieved. This strategy of controlling intracellular transport pathways by targeting cellular uptake pathways in the gene therapy is an approach that could be developed for highly effective cancer therapy.

Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis.

Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA-Lip-Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA-Lip-Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA-Lip-Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.

Laser-Driven Insulator-Metal Phase Transitions in CsPbI3 Quantum Dots and Influence of Doped Metal Nanowires.

All-inorganic CsPbI3 perovskite quantum dots (QDs) have received extensive attention in developing optoelectronic devices due to their outstanding properties. Here, using time-dependent density functional theory (TDDFT), the optical properties of the three distinct phases (α, γ, and δ) of the CsPbI3 QDs are investigated. Surprisingly, the δ phase structured QDs exhibit stronger optical absorption properties than the α and γ phase QDs when exposed to equivalent laser irradiation. Considering the quantum size effect, size regulation is also performed on the three structures, the results reveal a significant improvement in optical properties as the size increases in the direction of laser irradiation. More interestingly, Ag-hybrid QDs show better optical gain and maintain a laser-driven metallic state. Our results demonstrate the great potential of size adjustment and metal nanowire coupling in improving the optoelectronic properties of QDs and developing efficient photovoltaic devices.

Neurocomputations on dual-brain signals underlie interpersonal prediction during a natural conversation.

Prediction on the partner's speech plays a key role in a smooth conversation. However, previous studies on this issue have been majorly conducted at the single-brain rather than dual-brain level, leaving the interpersonal prediction hypothesis untested. To fill this gap, this study combined a neurocomputational modeling approach with a natural conversation paradigm in which two salespersons persuaded a customer to buy their product with their haemodynamic signals being collected using functional near-infrared spectroscopy hyperscanning. First, the results showed a cognitive hierarchy in a natural conversation, with the lower-level process (i.e., pragmatic representation of the persuasion) in the salesperson interacting with the higher-level process (i.e., value representation of the product) in the customer. Next, we found that the right dorsal lateral prefrontal cortex (rdlPFC) and temporoparietal junction (rTPJ) were associated with the representation of the product's value in the customer, while the right inferior frontal cortex (rIFC) was associated with the representation of the pragmatic processes in the salesperson. Finally, neurocomputational modeling results supported the prediction of the salesperson's lower-level brain activity based on the customer's higher-level brain activity. Moreover, the updating weight of the prediction model based on the neural computation between the rIFC of the salesperson and the rTPJ of the customer was closely associated with the interaction context, whereas that based on the rIFC-rdlPFC was not. In summary, these findings provide initial support for the interpersonal prediction hypothesis at the dual-brain level and reveal a hierarchy for the interpersonal prediction process.

Integrated analysis of high­throughput sequencing reveals the regulatory potential of hsa_circ_0035431 in HNSCC.

Circular RNAs (circRNAs) are molecular sponges that are involved in regulation of multiple types of cancer. The present study aimed to screen and explore the key circRNA/microRNA (miRNA or miR)/mRNA interactions in head and neck squamous cell carcinoma (HNSCC) using bioinformatics. A total of six pairs of cancerous and adjacent healthy tissue were obtained from patients with HNSCC and genome-wide transcriptional sequencing was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on differentially expressed genes (DEGs). Moreover, expression levels of DEGs were verified in HNSCC cells and tissues using reverse transcription-quantitative (RT-q)PCR. A molecular regulatory network consisting of three circRNAs, seven miRNAs and seven mRNAs was constructed, resulting in identification of two signaling axes, hsa_circ_0035431/hsa-miR-940/fucosyltransferase 6 (FUT6) and hsa_circ_0035431/hsa-miR-940/cingulin-like 1 (CGNL1). FUT6 and CGNL1 were downregulated in HNSCC compared with adjacent healthy tissue and the expression levels of these genes were associated with tumor stage. Low FUT6 and CGNL1 expression levels were associated with lower overall survival rate and progression-free intervals in HNSCC. RT-qPCR demonstrated that hsa_circ_0035431, FUT6 and CGNL1 were downregulated in HNSCC cells and tissue and hsa-miR-940 was upregulated. Notably, these results were consistent with those obtained using high-throughput sequencing. In conclusion, hsa_circ_0035431 may participate in regulation of FUT6 and CGNL1 expression by sponging hsa-miR-940, thus, impacting the occurrence, development and prognosis of HNSCC.

Chinese Herbal Medicine for the Treatment of Adult Viral Myocarditis: An Overview of Systematic Reviews and Meta-analyses of Randomized Controlled Trials.

PURPOSE: Viral myocarditis (VMC) is a life-threatening disease that can affect all ages and genders, with middle-aged adults being particularly susceptible. Numerous systematic reviews have been conducted to investigate the efficacy and safety of Chinese herbal medicine (CHM) in treating adult viral myocarditis (AVM). The objective of this study was to conduct a comprehensive overview of systematic reviews and meta-analyses of randomized controlled trials (RCTs) regarding the efficacy and safety of CHM for AVM. METHODS: A comprehensive systematic search was conducted across 8 electronic databases from their inception to June 23, 2022, augmented by manual searches of the gray literature. Systematic reviews were independently selected and data extracted in accordance with predetermined criteria by 2 reviewers. Included systematic reviews were assessed for methodologic and reporting quality using Assessing the Methodological Quality of Systematic Reviews 2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The quality of evidence relating to outcome measures was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. Recalculation of effect sizes and subsequent determination of 95% CIs were conducted with either a fixed-effects or random-effects model. FINDINGS: The current overview of systematic reviews included a total of 6 systematic reviews, which reported on 67 RCTs with a participant pool of 5611 individuals. The findings of our study indicate that the combination of CHM and Western medications had positive effects on the effective rate, cure rate, ECG recovery, atrial premature contraction/premature ventricular contraction, left ventricular ejection fraction, myocardial enzymes, and improvement of clinical symptoms for AVM. The adverse drug reactions in the combination therapy group were generally less than or lighter than that in the Western medication group (relative risk = 0.79; 95% CI, 0.44-1.40; P > 0.05, I2 = 0). IMPLICATIONS: Our research results provide evidence that combining CHM with Western medicine could offer potential benefits for patients with AVM. However, the number of studies included in our review is limited and the methodologic quality of these studies is modest. Therefore, there are potential uncertainties regarding the conclusion that CHM with Western medication may benefit patients with AVM. We call for more large-scale, high-quality studies with standardized designs to further verify and support our findings. This would promote a better understanding of the efficacy and safety profile of CHM and provide reliable reference evidence for clinical practice and policy making. Moreover, future research should explore optimal drug combinations, examine therapeutic doses and durations of CHM combination therapy, and evaluate its long-term efficacy and safety.

Runx1 Deficiency Promotes M2 Macrophage Polarization Through Enhancing STAT6 Phosphorylation.

Our previous study had demonstrated that Runx1 promoted LPS-induced macrophage inflammatory response, however, the role of Runx1 in M2 macrophage polarization still remains largely unknown. This study was conducted to investigate the role of Runx1 in IL-4/IL-13-induced M2 macrophage polarization and its potential regulatory mechanism. We found that exposure of macrophages to IL-4/IL-13 induced a remarkable increasement in Runx1 expression level. Specifically, we established genetically modified mice lacking Runx1 in myeloid cells, including macrophages. RNA-Seq was performed to identify differentially expressed genes (DEGs) between Runx1 knockout and WT control bone marrow-derived macrophages (BMDMs). We identified 686 DEGs, including many genes which were highly expressed in M2 macrophage. In addition, bioinformatics analysis indicated that these DEGs were significantly enriched in extracellular matrix-related processes. Moreover, RT-qPCR analysis showed that there was an obvious upregulation in the relative expression levels of M2 marker genes, including Arg1, Ym1, Fizz1, CD71, Mmp9, and Tgm2, in Runx1 knockout macrophages, as compared to WT controls. Consistently, similar results were obtained in the protein and enzymatic activity levels of Arg1. Finally, we found that the STAT6 phosphorylation level was significantly enhanced in Runx1 knockout macrophages, and the STAT6 inhibitor AS1517499 partly reduced the upregulated effect of Runx1 deficiency on the M2 macrophage polarization. Taken together, Runx1 deficiency facilitates IL-4/IL-13-induced M2 macrophage polarization through enhancing STAT6 phosphorylation.

Acupuncture for Patients with Chronic Spontaneous Urticaria: A Randomized, Sham-Controlled Pilot Trial.

OBJECTIVE: To determine the feasibility of conducting a full-scale randomized controlled trial (RCT) and investigate the basic information and safety of acupuncture for patients with chronic spontaneous urticaria (CSU). METHODS: A total of 80 participants with CSU from July 2018 to July 2019 were randomly assigned to receive active acupuncture (n=41) on a fixed prescription of acupoints or sham acupuncture (n=39) with superficial acupuncture on non-acupuncture points through the completely randomized design. Patients in both groups received 5 sessions per week for 2 weeks, and participants were followed for a further 2 weeks. Feasibility was assessed by recruitment and randomization rates, retention of participants, treatment protocol adherence, and the incidence of adverse events (AEs). The clinical primary outcome was the changes from baseline weekly urticaria activity scores (UAS7) after treatment at 2 weeks. Secondary outcomes included the Visual Analogue Scale (VAS) score of itching intensity, Dermatology Life Quality Index (DLQI), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA). RESULTS: A total of 80 participants were enrolled. The recruitment rate of 24.02%, randomization rate of 100%, a loss rate of 6.25%, and no obvious AEs were observed in either group. The decrease from baseline in the mean UAS7 total score at week 2 in the active acupuncture group was -8.63 (95%CI, -11.78 to -5.49) and -6.21 (95%CI, -9.43 to -2.98) in the sham acupuncture group for a between-group difference of -2.42 (95% CI, -6.93 to 2.07). The change in the DLQI, VAS of itching intensity, HAMA, and HAMD were a slightly better improvement trend in the active acupuncture group than the sham acupuncture group, but the between-group difference was not significant. CONCLUSIONS: Active acupuncture had a better improvement trend in alleviating symptoms, improving quality of life and regulating the mood of anxiety and depression in patients with CSU than sham acupuncture. (Registration Nos. AMCTR-ICR-18000190 and ChiCTR2100054776).

Carvacrol attenuated lipopolysaccharide-induced intestinal injury by down-regulating TLRs gene expression and regulating the gut microbiota in rabbit.

Carvacrol (CAR) is a plant extract that has been reported to enhance antioxidant activity in animals. However, the effect of CAR on the intestinal health of rabbits is poorly understood. Here, we investigated whether CAR exerts protective effects on the intestinal health of rabbits following lipopolysaccharide (LPS) challenge and whether these effects were mediated via the reduction of intestinal inflammation and the regulation of the intestinal flora. Intestinal damage was assessed in LPS-challenged rabbits treated or not with CAR. The serum levels of inflammatory factors were assessed by enzyme-linked immunosorbent assay. Histopathological changes in the ileum and cecum were examined using hematoxylin and eosin staining. The relative gene expression levels of inflammatory factors and tight junction proteins in the rabbit cecum were determined by qRT-PCR. High-throughput sequencing analysis of the microbial 16S rRNA gene was performed using the Illumina NovaSeq Platform. The results showed that CAR can prevent intestinal inflammation and damage as well as mitigate gut dysbiosis in rabbits following LPS challenge. Our study provides a theoretical reference for the application of dietary CAR in rabbit production.

Simplified Evaluation of Shear Stiffness Degradation of Diagonally Cracked Reinforced Concrete Beams.

Shear cracking in concrete box-girder bridges, which could cause excessive deflection during the serviceability limit state, cannot be effectively avoided by code-guided design. While elastic shear deformation only accounts for a small proportion of total deformation for un-cracked reinforced concrete (RC) beams, the magnitude of after-cracking shear deformation becomes comparable to flexural deformation for RC beams. However, there is still a lack of practical models to predict the after-cracking shear deformation of RC beams. First, six thin-webbed I beams were tested to investigate the shear stiffness degradation mechanism and the decrease ratio. Then, a very simple truss strut angle formula, which is the crucial parameter for shear stiffness, was established. Furthermore, a stiffness degradation rule for partially cracked beams was proposed considering the influence of concrete tension stiffening, which is essential for predicting the development process of after-cracking shear deformation. Finally, directly measured shear strains were used to validate the proposed shear stiffness model. The results showed that the shear stiffness drops to about 30~40% of the original stiffness after the first diagonal crack, and the remaining shear stiffness is only about 10% of the original one when the stirrup yields. Increasing the stirrup ratio is a more effective method to control shear stiffness degradation for diagonally cracked RC beams. Also, the proposed shear stiffness model well captures the main features of the shear stiffness degradation, and it provides a relatively accurate prediction of the equivalent shear stiffness at the post-cracking stage.

Small-diameter PCL/PU vascular graft modified with heparin-aspirin compound for preventing the occurrence of acute thrombosis.

The occurrence of acute thrombosis, directly related to platelet aggregation and coagulant system, is a considerable reason for the failure of small-diameter vascular grafts. Heparin is commonly used as a functional molecule for graft modification due to the strong anticoagulant effect. Unfortunately, heparin cannot directly resist the adhesion and aggregation of platelets. Therefore, we have prepared a heparin-aspirin compound by coupling heparin with aspirin, an antiplatelet drug, and covalently grafted it onto the surface of polycaprolactone/polyurethane composite tube. In this way, the graft not only showed a dual function of both anticoagulation and antiplatelet, but also effectively avoided the rapid drug release and excessive toxicity to other organs caused by simple blending the medicine with material matrix. The compound retained the original function of heparin, showing good hydrophilicity and biocompatibility, which could promote the adhesion and proliferation of endothelial cells (ECs) and facilitate the process of tissue regeneration. What's more, the compound showed more effective than heparin in reducing platelet activation and preventing thrombosis. The graft modified by this compound maintained completely unobstructed for one month of implantation, while severe obstruction or stenosis occurred in PCL/PU and PCL/PU-Hep lumen at the first week, verifying the effect of the compound on preventing acute thrombosis. In general, this study proposed a designing method for small-diameter vascular graft which could prevent acute thrombosis and promote intimal construction.