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Vibrio parahaemolyticus (V. parahaemolyticus) is a major food-borne pathogen which causes human gastroenteritis. Since the characteristics of V. parahaemolyticus remain unknown, 220 isolates selected from clinical and environmental samples in Dapeng of Shenzhen were tested for the presence of two hemolysin-expressing genes tdh and trh. Among 27 clinical isolates, 26 carrired the tdh gene, and the other one carried both tdh and trh genes, however neither genes were detected in environmental isolates. Meanwhile, antimicrobial susceptibility profiles revealed the isolates with high frequency of resistance to ampicillin (77.73%) and colistin (71.82%) and medium to streptomycin (57.27%). Genetically, by whole genome sequencing (WGS), comparative genomics studies was performed on isolates from various districts and GenBank. Data analysis showed that antimicrobial resistance genes (ARGs) blaCARB, tet(34) and tet(35) were harbored in all genomes and other ARGs was absent in the genomes of 27 clinical isolates. Besides, little regional difference was observed. As for virulence factors, MAM7, T3SS1, T3SS1 secret effector, T3SS2, T3SS2 secret effector, and VpadF were carried by most isolates. Two isolates from other districts were tdh gene positive which clustered with clinical isolates from Dapeng in the same clade, indicating close genetic distance. This study revealed the widely distribution of V. parahaemolyticus in Shenzhen and the diverse ARGs and virulence genes it carried. Furthermore, pathways that pathogen disseminated through were discussed.

Abstract MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1. MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1β, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE.

Abstract With the rapid development of nuclear energy, problems with uranium supply chain and nuclear waste accumulation have motivated researchers to improve uranium separation methods. Here we show a paradigm for such goal based on the in-situ formation of π-f conjugated two-dimensional uranium-organic framework. After screening five π-conjugated organic ligands, we find that 1,3,5-triformylphloroglucinol would be the best one to construct uranium-organic framework, thus resulting in 100% uranium removal from both high and low concentration with the residual concentration far below the WHO drinking water standard (15 ppb), and 97% uranium capture from natural seawater (3.3 ppb) with a record uptake efficiency of 0.64 mg·g−1·d−1. We also find that 1,3,5-triformylphloroglucinol can overcome the ion-interference issue such as the presence of massive interference ions or a 21-ions mixed solution. Our finds confirm the superiority of our separation approach over established ones, and will provide a fundamental molecule design for separation upon metal-organic framework chemistry.

Abstract The field of environmental DNA (eDNA) has rapidly advanced in recent years, providing a non‐invasive and time‐saving method for assessing biodiversity. The First International Environmental DNA (eDNA) Workshop in Hong Kong was held from 16 to 27 October 2023 and provided early career professionals with hands‐on training and collaboration opportunities in eDNA research. With support from The Croucher Foundation Limited (Hong Kong), the workshop covered all stages of an eDNA‐based research project, including study design, field sampling, eDNA extraction, library preparation, bioinformatics, statistical data analysis, and ethics in scientific research. Participants gained insights into the principles and practical applications of eDNA technology, emphasizing the importance of careful experimental design and data interpretation. The workshop also highlighted the need for standardized protocols, comprehensive and local DNA reference databases, and careful selection of primer sets to overcome current issues and limitations. Workshop participants expressed enthusiasm for the potential of eDNA metabarcoding as a valuable tool for ecological monitoring, biodiversity assessment, and conservation decision‐making. The future of eDNA research looks promising overall, with continued advancements in technology, collaboration among researchers, and the integration of eDNA into large‐scale ecological monitoring. Future iterations of the Hong Kong International eDNA workshop will continue to provide hands‐on training and collaboration opportunities for early career professionals interested in eDNA research, focusing on addressing current limitations and challenges in the field.

A modified slotted microstrip patch sensor antenna has been developed for sensitivity enhancement to measure the moisture content of leaves. The design incorporates a rectangular slot positioned above the feed of a rectangular patch antenna. The antenna achieves resonant frequency at a lower range than the operating frequency of a traditional patch antenna without slot while maintaining a miniaturized form factor. To evaluate the sensitivity of the proposed modified slotted patch antenna, the variation in the resonant frequency and the reflection coefficient (S11) is observed with the sample under test (SUT), i.e., leaf is placed above the patch. A comparative analysis with regard to sensitivity and shift in frequency is performed between the designed antenna structures. The designed antenna is fabricated on a 0.8 mm F4B substrate in order to resonate within the 2.40–2.80 GHz range under unloaded conditions. The antenna’s sensitivity is tested by performing parametric analysis with respect to the permittivity of the leaf ranging from 20 to 30. The experimental results reveal that the sensitivity of the proposed patch antenna is enhanced by a factor of 1.67 as compared to traditional patch antenna for the four levels of SUT, demonstrating an enhanced sensitivity in detecting the moisture content of leaves.

An innovative IoT-based system utilizing a modified slotted microstrip patch antenna with enhanced coupling is presented for precise measurement of leaf moisture content. The antenna employs a rectangular slot above the feed point with an advanced coupling technique to enhance sensitivity. The antenna, fabricated on a 0.8 mm F4B substrate, is designed to resonate within the 2.40 to 3.0 GHz range under unloaded conditions. A parametric analysis focusing on leaf permittivity ranging from 20 to 30 is conducted to determine the antennas’ sensitivity. Experimental measurements of the reflection coefficient (S11) with respect to resonant frequency shift are performed with leaf samples as the samples under test (SUT). Experimental results reveal that the proposed patch antenna’s sensitivity is significantly enhanced, ranging from 0.57 to 1.67 times greater than that of traditional patch antennas for the five leaf samples tested. The antenna exhibits a sensitivity of 0.06 GHz and 0.02 GHz for the modified and enhanced coupling designs, respectively. The mean relative error between predicted and measured moisture content values is low at 0.038. The findings highlight the antenna’s increased sensitivity in detecting leaf moisture content and illustrate the potential of the proposed IoT-based system for real-time agricultural monitoring, marking an advancement in precision farming practices. The study validates the microstrip patch antenna’s capability as a moisture sensor through detailed sensitivity analysis, frequency shift measurements, and regression modeling.

Abstract A disorder of cholesterol homeostasis is one of the main initiating factors in the progression of atherosclerosis (AS). Metabolism and removal of excess cholesterol facilitates the prevention of foam cell formation. However, the failure of treatment with drugs (e.g. methotrexate, MTX) to effectively regulate progression of disease may be related to the limited drug bioavailability and rapid clearance by immune system. Thus, based on the inflammatory lesion “recruitment” properties of macrophages, MTX nanoparticles (MTX NPs) camouflaged with macrophage membranes (MM@MTX NPs) were constructed for the target to AS plaques. MM@MTX NPs exhibited a uniform hydrodynamic size around ~ 360 nm and controlled drug release properties (~ 72% at 12 h). After the macrophage membranes (MM) functionalized “homing” target delivery to AS plaques, MM@MTX NPs improved the solubility of cholesterol by the functionalized β-cyclodextrin (β-CD) component and significantly elevate cholesterol efflux by the loaded MTX mediated the increased expression levels of ABCA1, SR-B1, CYP27A1, resulting in efficiently inhibiting the formation of foam cells. Furthermore, MM@MTX NPs could significantly reduce the area of plaque, aortic plaque and cholesterol crystals deposition in ApoE−/− mice and exhibited biocompatibility. It is suggested that MM@MTX NPs were a safe and efficient therapeutic platform for AS. Graphical Abstract

Abstract Multifunctional nanomedicines have been used in atherosclerosis theranostics. Herein, phosphatidylserine‐specific peptide CLIKKPF‐functionalized carbon‐dots nanozymes (pep‐CDs) are reported for specific and efficient noninvasive theranostic of atherosclerosis. Surprisingly, pep‐CDs are discovered to not only inherit the inherent properties of carbon dots (CDs), including deep‐red fluorescence emission, photoacoustic response, and superoxide dismutase‐like antioxidant, and anti‐inflammatory activities but also possess the ability to target recognition on foam cells and target localization on plaques due to the specific interaction of CLIKKPF with phosphatidylserine on the membrane outer surface of foam cells. Furthermore, the target localization effect of pep‐CDs vastly promotes the efficient accumulation of CDs in plaque, thus maximizing AS theranostic of CDs. Interestingly, pep‐CDs could be developed to image plaque for monitoring atherosclerosis pathological progression in real‐time resulting from the different content of foam cells. This work on the one hand proposes a simple and feasible strategy to construct theranostic nanoplatform employing only a single functional unit (i.e., multifunctional CDs) to simplify the fabrication procedure, on the other hand, highlights the advantages of the active target auxiliary mode for atherosclerosis theranostic applications.

Background. Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are prevalent autoimmune disorders that often co-occur, posing significant treatment challenges. This investigation adopts a multidisciplinary strategy, integrating bioinformatics, network pharmacology, molecular docking, and Mendelian randomization, to elucidate the relationship between AS and IBD and to investigate the potential mechanisms of traditional Chinese medicine formulations, represented by Qiangji Jianpi (QJJP) decoction, in treating these comorbid conditions. Methods. We utilized databases to pinpoint common targets among AS, IBD, and QJJP decoction’s active compounds through intersection analysis. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we mapped a network in Cytoscape, isolating critical targets. Molecular docking with AutoDock validated the affinity between targets and compounds. ROC analysis and dataset validation assessed diagnostic performance, while Gene Set Enrichment Analysis (GSEA) offered pathway insights. Mendelian randomization explored the AS-IBD causal relationship. Results. Screening identified 105 targets for QJJP decoction, 414 for AS, and 2420 for IBD, with 85 overlapping. These targets predominantly participate in organismal responses and DNA transcription factor binding, with a significant cellular presence in the endoplasmic reticulum and vesicle lumen. Molecular docking, facilitated by Cytoscape, confirmed IL1A, IFNG, TGFB1, and EDN1 as critical targets, with IFNG demonstrating diagnostic potential through GEO dataset validation. The integration of GSEA with network pharmacology highlighted the therapeutic significance of the relaxin, osteoclast differentiation, HIF-1, and AGE-RAGE signaling pathways in QJJP decoction’s action. Mendelian randomization analysis indicated a positive causal relationship between IBD and AS, pinpointing rs2193041 as a key SNP influencing IFNG. Conclusion. Based on the principle of “treating different diseases with the same method” in traditional Chinese medicine theory, we explored the intricate mechanisms through which QJJP decoction addresses AS and IBD comorbidity. Our research spotlighted the pivotal role of the IFNG gene. IFNG emerges not only as a key therapeutic target but also assumes significance as a potential diagnostic biomarker through its genetic underpinnings. This investigation establishes a solid base for subsequent experimental inquiries. Our findings introduce novel approaches for incorporating traditional Chinese medicine into the treatment of AS-IBD comorbidity, setting the stage for groundbreaking research directions.

Objectives. The aim of this study was to investigate the impact of nonmotor symptoms (NMS) on the quality of life (QoL) outcome after subthalamic nucleus deep brain stimulation (STN-DBS) at the 1-year follow-up. Methods. Ninety-three patients diagnosed with Parkinson’s disease (PD), who underwent subthalamic nucleus deep brain stimulation (STN-DBS) between April 2020 and August 2021, were included in this study. Demographic information was gathered through a self-designed questionnaire. The severity of both motor and non-motor symptoms, along with the quality of life (QoL), was assessed using the Unified Parkinson’s Disease Rating Scale-III (UPDRS-III), Nonmotor Symptoms Scale (NMSS), and 8-item Parkinson’s Disease Questionnaire (PDQ-8), respectively. Results. Significant differences were observed in the UPDRS-III score, NMSS summary index (SI), and subscores of six domains (sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, and sexual function) between the baseline and the 6- and 12-month follow-ups. The correlation analysis revealed positive correlations between the preoperative NMSS SI and subscores of seven domains (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary) and ΔPDQ-8. Moreover, the preoperative PDQ-8 SI (β = 0.869, P

PurposeTo evaluate a noval bilateral asymmetric single-rivet occluder with reserved interatrial septal puncture area for treating patent foramen ovale (PFO).Materials and methodsThe study established a pig model of patent foramen ovale (PFO) by puncturing the oval fossa and then performing high-pressure balloon dilation. A specially designed bilateral asymmetric occluder for the reserved interatrial septal puncture area was then. used to close the PFO through catheter-based intervention. The pigs were kept for 3 months before undergoing a second catheter-based intervention, involving interatrial septal puncture using a newly developed occluder in the reserved interatrial septal puncture area. During 6 months, the experimental pigs underwent assessment using digital subtraction angiography (DSA), echocardiography, and histological evaluation.ResultsA patent foramen ovale (PFO) model was successfully established in 6 pigs using the puncture atrial septum high-pressure balloon dilation method. The diameter of the unclosed PFO was measured (3.56 ± 0.25 mm). Using the newly developed occluder device, all 6 pigs with unclosed PFO underwent successful catheter-based closure surgeries, with intraoperative and postoperative transesophageal echocardiography showing excellent device positioning and complete closure without residual shunting. After 3 months of implantation, the catheter-based interatrial septal puncture was performed through the reserved interatrial septal puncture area, and all procedures were successful. Immediately following euthanasia, a histological examination revealed intact and undamaged occluder devices with visible puncture holes in the reserved interatrial septal puncture area. No fracture of the nitinol wire was observed, and the surface of the occluder device showed coverage of endothelial and connective tissues. Utilizing a bilateral asymmetric single-rivet occluder device implanted through the reserved interatrial septal puncture area has proven effective in closing PFO. After implantation, the occluder device allows subsequent interatrial septal puncture procedures through the reserved area.ConclusionThe novel occluder device demonstrated excellent closure performance, biocompatibility, and puncturability in the experiment. This indicates the feasibility of conducting further catheter-based interventions on the interatrial septum.

Benzo[a]pyrene (BaP) is ubiquitously present in the aquatic environment and has been identified as a bone toxicant. Previous studies have demonstrated that ancestral BaP exposure can cause transgenerational bone deformities in fish. Transgenerational effects are thought to be caused by heritable epigenetic changes, such as DNA methylation, histone modification, and non-coding RNAs. To investigate the role of DNA methylation in BaP-induced transgenerational skeletal deformities and the related transcriptomic changes in deformed vertebrae, we examined the vertebrae of male F1 and F3 medaka fish using high-throughput RNA sequencing (RNA-seq) and whole-genome bisulphite sequencing (WGBS). The histological results revealed that osteoblast numbers at the vertebral bone decreased in the BaP-derived F1 and F3 adult males in comparison with the control group. Differentially methylated genes (DMGs) associated with osteoblastogenesis (F1 and F3), chondrogenesis (F1 and F3), and osteoclastogenesis (F3) were identified. However, RNA-seq data did not support the role of DNA methylation in the regulation of genes involved in skeletogenesis since there was very little correlation between the level of differential methylation and gene expression profiles related to skeletogenesis. Although DNA methylation plays a major role in the epigenetic regulation of gene expression, the dysregulation of vertebral gene expression patterns observed in the current study is most likely to be mediated by histone modification and miRNAs. Notably, RNA-seq and WGBS data indicated that genes related to nervous system development are more sensitive to ancestral BaP exposure, indicating a more complex transgenerational phenotype in response to ancestral BaP exposure.

Abstract Background Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections. Methods Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2′,7′-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-β-d-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real‑time reverse transcription‑polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson’s trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo. Results Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P

CYP1A is the most commonly used biomarker and transgenic fish which carrying a cyp1a promoter to drive a reporter gene can be used as reliable way to monitor dioxin/dioxin-like compounds (DLCs) in the environment. Here, we cloned the cyp1a promoter of Gambusia affinis and this promoter showed stronger transcriptional activity than that of zebrafish. Then, a Tg(GAcyp1a:eGFP/Luc) transgenic zebrafish line was first constructed with the G. affinis cyp1a promoter driving eGFP expression using meganuclease I-SceI mediated transgenesis technology. The Tg(GAcyp1a:eGFP/Luc) larvae at 72 h post-fertilization (hpf) were tested by exposing to TCDD for 72 h, and induced GFP was mainly expressed in the liver with low background. The Tg(GAcyp1a:eGFP/Luc) zebrafish showed high sensitivity (limit of detection of 0.322 ng/L TCDD and 0.7 TEQ-ng/L PCDD/Fs) and specificity (insensitive to responses to PAHs and PCBs). In addition, the transgenic line showed a low detection concentration of the DLCs contaminated environmental samples (as low as 1.8 TEQ-ng/L), and the eGFP fluorescence intensity and the chemical-TEQ values were closely correlated. In conclusion, a sensitively and specifically transgenic zebrafish line was established to convenient and effective to detect DLCs in the environment.

Vascular endothelial polarity induced by blood flow plays crucial roles in the development of atherosclerosis. Loss of endothelial polarity leads to an increase in permeability and leukocyte recruitment, which are crucial hallmarks of atherosclerotic initiation. Endothelial cells exhibit a morphological adaptation to hemodynamic shear stress and possesses planar cell polarity to the direction of blood flow. However, the mechanism of how hemodynamic shear stress regulates endothelial planar cell polarity has not been firmly established. Here, we found that TET1s, a short isoform of Tet methylcytosine dioxygenase 1, was a mediator in the regulation of the planar cell polarity in endothelial cells in response to hemodynamic shear stress. In the process, low expression of TET1s induced by oscillatory shear stress led to the endothelial planar polarity damage through inhibition of F-actin polymerization. TET1s can regulate demethylation level of the sFRP-1 promoter to alter the expression of sFRP-1, which affects the interaction of sFRP-1/Fzd4 and F-actin polymerization. Our study revealed the mechanism of how TET1s mediates endothelial planar cell polarity in response to hemodynamic shear stress and provides a new insight for the prevention of atherosclerosis.

The bio-inertness of titanium (Ti) and accompanying severe inflammation can extremely inhibit the coupled osteogenesis-angiogenesis regulation and result in an undesirable osseointegration of peri-implant during the implantation process. Herein, three types of TiO2 nanotubes (TNT) were prepared on native Ti substrate using an anodic oxidation approach, including TNT with a diameter of 30 nm (TNT-30), 70 nm (TNT-70), or 110 nm (TNT-110). Among the four substrates, TNT-70 was the most prominent to induce the differentiation of macrophages to the pro-healing M2 phenotype via significant down-regulation of pro-inflammation genes (CD86, iNOS, CD11c) and cytokines (TNF-α, IL-6), as well as up-regulation of anti-inflammation genes (CD206, Arg-1, IL-10) and cytokines (TGF-β, IL-10). Furthermore, TNT-70 could stimulate the osteogenic potential of mesenchymal stem cells (MSCs) and the angiogenic ability of human umbilical vein endothelial cells (HUVECs) via multiple paracrine signaling. In vivo experiments suggested that TNT-70 significantly relieved early inflammatory response around the implant, facilitated coupled osteogenesis and angiogenesis, and effectively promoted the osseointegration of peri-implant. This study provided a reference for fabricating surface topography on Ti implant for improving osseointegration and relieving associated excessive inflammatory response.

Erythromycin (ERY) is a typical macrolide antibiotic with large production and extensive use on a global scale. Detection of ERY in both freshwaters and coaster seawaters, as well as relatively high ecotoxicity of ERY have been documented. Notably, hormesis has been reported on several freshwater algae under ERY stress, where growth was promoted at relatively lower exposures but inhibited at higher treatment levels. On the contrary, there is limited information of ERY toxicity in marine algae, hampering the risk assessment on ERY in the coaster waters. The presence of hormesis may challenge the current concept of dose-response adopted in chemical risk assessment. Whether and how exposure to ERY can induce dose-dependent toxicity in marine algae remain virtually unknown, especially at environmentally relevant concentrations. The present study used a model marine diatom Thalassiosira weissflogii (T. weissflogii) to reveal its toxicological responses to ERY at different biological levels and decipher the underlying mechanisms. Assessment of multiple apical endpoints shows an evident growth promotion following ERY exposure at an environmentally relevant concentration (1 µg/L), associated with increased contents reactive oxygen species (ROS) and chlorophyll-a (Chl-a), activated signaling pathways related to ribosome biosynthesis and translation, and production of total soluble protein. By contrast, growth inhibition in the 750 and 2500 µg/L treatments was attributed to reduced viability, increased ROS formation, reduced content of total soluble protein, inhibited photosynthesis, and perturbed signaling pathways involved in xenobiotic metabolism, ribosome, metabolism of amino acid, and nitrogen metabolism. Measurements of multiple apical endpoints coupled with de novo transcriptomics analysis applied in the present study, a systems biology approach, can generate detailed mechanistic information of chemical toxicity including dose-response and species sensitivity difference used in environmental risk assessment.

It is increasingly aware that gut microbiota is closely associated with atherosclerosis. However, which and how specific gut bacteria regulate the progression of atherosclerosis is still poorly understood. In this study, modified linear discriminant analysis was performed in comparing the gut microbiota structures of atherosclerotic and non-atherosclerotic mice, and Desulfovibrio desulfuricans (D. desulfuricans) was found to be associated with atherosclerosis. D. desulfuricans-treated Apoe−/− mice showed significantly aggravated atherosclerosis. The proatherogenic effect of D. desulfuricans was attributed to its ability to increase intestinal permeability and subsequent raise in the transit of lipopolysaccharide (LPS) from the intestine to the bloodstream. Excessive LPS in the blood can elicit local and systemic inflammation and activate Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling of endothelial cells. TAK-242, a specific inhibitor of TLR4, can ameliorate the development of D. desulfuricans-induced atherosclerosis by blocking the LPS-induced activation of TLR4/NF-κB signaling.

Objective: Sorafenib and lenvatinib have been recommended as standard tyro sine kinase inhibitors (TKIs) for progressive radioiodine-refractory differentiated thyroid carcinoma (RR-DTC). However, their efficacy remains limited with unresolved drug resistance. Therefore, we conceived this open-label study based on real-world evidence to investigate the efficacy and safety of apatinib in patients wi th progressive RR-DTC. Methods: Off-label use of apatinib as either initial treatment or salvage treatment for sorafenib resistance was investigated. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included objective r esponse rate (ORR), overall survival (OS), and safety. Results: For all 28 enrolled patients, the median PFS was 15.1 months, w ith an ORR of 69.6%. The median OS was not reached at the data cut-off. In det ail, the median PFS of 17.3 months and the ORR of 75% were determined in patients with TKI-naive RR-DTC (initial treatment group, n = 14). And, in patients with first-line sorafenib-resistant RR-DTC (salvage treatment group, n = 14), a median PFS of 12.0 months was reached, with an ORR of 45.5%. In the salvage treatment group, the media n OS from the start of apatinib administration was 20.6 months, reaching 89.1 month s from sorafenib treatment initiation. Adverse events at grade 3 or higher occur red in 64.3% of all subjects treated with apatinib. Conclusions: This study demonstrated that apatinib shows promise against RR- DTC with tolerable toxicity, representing a novel initial treatment for progressive RR-DTC and effective salvage treatment for RR-DTC resistant to sorafenib.

The authors report high-efficiency emission depletion through a surface migration emission depletion mechanism, which takes advantage of the effects of surface quenching and energy migration in nanocrystals. They demonstrate super-resolution microscopy with very low depletion saturation intensities.

In recent years, higher requirements have been placed on the response characteristics of X-ray detectors in the field of medical diagnostic imaging. Due to this, high sensitivity, high attenuation coefficient and low cost detection materials need to be developed. In this paper, the geometric model of a detector was established by Geant4 code. The absorption efficiency and mass attenuation coefficient of MAPbBr3 crystals were calculated in the energy range of 30 keV to 100 keV. Compared with the mass attenuation coefficient of the NIST database, the deviation was within 1.39%. The signal charge number and detection sensitivity of the X-ray interaction with the MAPbBr3 crystal ware calculated. Compared with the CdTe crystal and α-Se, the MAPbBr3 crystal still had a larger detection sensitivity under a smaller applied electric field, which was approximately 9 times higher than that of α-Se. This result indicated that the detection sensitivity could be greatly improved by using a high atomic number and high charge mobility-lifetime product. Based on the simulation results, the 2 mm thick MAPbBr3 crystal exhibited the highest detection sensitivity at 60 keV X-rays, which was in agreement with the experimental results.

Abstract Background Plantainoside D is widely existed in the herbs and possesses various pharmacological activities, making it possible to co-administrate with other herbs. Its effect on cytochrome P450 enzymes (P450) is a risk factor for inducing adverse drug-drug interactions. To assess the effect of plantainoside D on the activity of major P450 isoenzymes in human liver microsomes. Methods The Cocktail method was conducted in human liver microsomes in the presence of probe substrates. The activity of P450 isoenzymes was evaluated by the production of corresponding metabolites. The concentration-dependent and time-dependent inhibition assays were performed in the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM plantainoside D to characterize the inhibitory effect of plantainoside D. Results Significant inhibition was observed in the activity of CYP1A2, 2D6, and 3A, which was concentration-dependent with the IC50 values of 12.83, 8.39, and 14.66 μM, respectively. The non-competitive manner and competitive manner were observed in the CYP3A inhibition (Ki = 7.16 μM) and CYP1A2 (Ki = 6.26 μM) and 2D6 inhibition (Ki = 4.54 μM), respectively. Additionally, the inhibition of CYP3A was found to be time-dependent with the KI of 1.28 μM−1 and K inact of 0.039 min−1. Conclusions Weak inhibitory effects of plantainoside D on the activity of CYP1A2, 2D6, and 3A were revealed in vitro, implying its potential of inducing interactions with CYP1A2-, 2D6-, and 3A-metabolized drugs. Although further in vivo validations are needed, the feasibility of the Cocktail method in evaluating P450 activity has been verified.

Abstract Studies on clinical features of systemic lupus erythematosus among different age-onset patients are lacking in China. This multicentre study aimed to systemically compare clinical manifestations, comorbidities, organ involvement, and laboratory findings among 797 Chinese juvenile-onset, adult-onset, and late-onset SLE (JSLE, ASLE, and LSLE) patients. They were classified into JSLE, ASLE, and LSLE groups if first diagnosed at < 18, 18–50, and > 50 years old, respectively. Chi-square test and analysis of variance were employed for categorical and continuous variables respectively. In younger-onset patients, the SLE Disease Activity Index 2000 score was significantly higher (JSLE vs. ASLE vs. LSLE = 17.43 ± 9.139 vs. 16.34 ± 8.163 vs. 14.08 ± 6.474, p = 0.031). Mucocutaneous symptoms (79.5% vs. 73.4% vs. 62.0%, p = 0.042), especially malar rash (76.1% vs. 66.1% vs. 53.5%, p = 0.011) occurred more frequently, and proteinuria rate was higher (54.5% vs. 56.3% vs. 36.6%, p = 0.007). In later-onset patients, cardiopulmonary involvement increased (11.4% vs. 24.3% vs. 29.6%, p = 0.012). In ASLE, hypoalbuminemia rate elevated (46.6% vs. 59.9% vs. 47.9%, p = 0.015). Our study demonstrated in a Chinese population that JSLE may be more active and suffer mucocutaneous disorders, while LSLE tended to suffer cardiopulmonary involvement at-onset. These findings may help identify treatment priorities when facing different age-onset SLE patients.

Abstract Both ligustrazine and tangeretin are usually prescribed in the treatment of cardiovascular diseases, which makes their co‐administration possible. The investigation of the interaction between ligustrazine and tangeretin is necessary for the clinical compatibility of their source herbs. This study aimed to investigate the interaction of ligustrazine and tangeretin during their co‐administration. The pharmacokinetics of ligustrazine (15 mg/kg) was investigated in the presence of 50, 100, and 150 mg/kg tangeretin in rats with six of each. A single dose of ligustrazine was set as the control. The effect of tangeretin on the in vitro metabolic stability of ligustrazine was also investigated in rat liver microsomes. Tangeretin significantly reduced the system exposure of ligustrazine under all experimental concentrations. Specifically, tangeretin reduced the AUC (from 48.86 ± 12.57 to 41.02 ± 4.85 (50 mg/kg tangeretin), 31.47 ± 5.26 (100 mg/kg tangeretin), and 27.55 ± 9.60 (150 mg/kg) μg/mL × h), MRT (from 7.05 ± 0.26 to 6.33 ± 0.48, 5.53 ± 0.68, and 5.21 ± 1.31 h), Cmax (from 7.45 ± 0.44 to 6.03 ± 0.44, 5.24 ± 0.47, and 5.02 ± 0.56 μg/mL), and t1/2 (from 5.90 ± 1.27 to 4.84 ± 1.19, 3.48 ± 1.33, 3.09 ± 0.62 h) in rats. In vitro, tangeretin also reduced the metabolic stability of ligustrazine behaved as the decreased half‐life and increased intrinsic clearance rate. Co‐consumption of ligustrazine with tangeretin induced interactions, which shortens the system exposure of ligustrazine. This study provides theoretical guidance for the clinical prescription of ligustrazine‐ and tangeretin‐containing herbs.

Extracellular vesicles (EVs) are increasingly used as delivery vehicles for drugs and bioactive molecules, which usually require intravascular administration. The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow. Few studies demonstrate the interplay of red blood cell-derived EVs (RBCEVs) and endothelial cells. Thus, the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated. In this study, red blood cell-derived extracellular vesicles (RBCEVs) were constructed to investigate endothelial cell phagocytosis in vitro and animal models. Results showed that low magnitude shear stress including low shear stress (LSS) and oscillatory shear stress (OSS) could promote the uptake of RBCEVs by endothelial cells in vitro. In addition, in zebrafish and mouse models, RBCEVs tend to be internalized by endothelial cells under LSS or OSS. Moreover, RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS. In terms of mechanism, oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells. Overall, this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress, which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo.

Abstract Biomimetic cell membrane camouflaged technology has drawn extensive attention as a feasible and efficient way to realize the biological functions of nanoparticles from the parent cells. As the burgeoning nanotherapeutic, the right‐side‐out orientation self‐assembly and pathological dependent “on‐demand” cargo release of cell membrane camouflaged nanocarriers remarkably limit further development for practical applications. In the present study, a spontaneously right‐side‐out‐orientated coupling‐driven ROS‐sensitive nanotherapeutic has been constructed for target endothelial cells (ECs) repair through the synergistic effects of spontaneously right‐side‐out‐orientated camouflaging. This condition results from the specific affinity between the intracellular domain of key transmembrane receptors band 3 on cell membrane inner leaflet and the corresponding P4.2 peptide‐modified nanoparticles without the additional coextrusion. The “on‐demand” cargo release results from the pathological ROS‐cleavable prodrug. Particularly, the red blood cell camouflaged nanotherapeutics (RBC‐LVTNPs) can enhance target drug delivery through low oscillatory shear stress (LSS) blood flow in the injured ECs lesion. Both in vitro and in vivo results collectively confirm that RBC‐LVTNPs can restore the damaged ECs and function with the recovered vascular permeability and low inflammation microenvironment. The findings provide a powerful and universal approach for developing the biomimetic cell membrane camouflaged nanotechnology.

The 25 million Australians today are identified with more than 300 ancestries. People’s home language use and shift patterns had demonstrated great variations as more immigrants from Asia-Pacific regions entered Australia. The ethnolinguistic composition of Australia’s population had undergone substantial changes in the last few decades. Based on the statistics from Australian censuses, the present paper aims to analyze the changes of people’s home language use and the shift patterns in the new Millennium. Five sets of census data released by Australian Bureau of Statistics were adopted as the secondary data source and descriptive analysis was conducted to disclose the dynamic picture of different home languages in Australia after 2000. The results suggest that the number of home language speakers in Australia has soared up quickly in the last two decades and great variations have been found between the traditional European migrant groups and the newly Asian arrivers. Mandarin has overtaken Italian and Greek to become the most populous home language other than English used in Australia since 2011 and great regional differences were also found to exist among different states and territories. Moreover, the ranking order of different home language speakers had changed considerably as compared with that in the last century. The language shift rates of different language communities and their cross-tabulations with generations, gender, age, and duration of residence in the latest available censuses after 2000 also revealed diverse developmental directions. The findings give us a glimpse of the current status of different home languages in Australia and help us to identify the potential factors impacting the shifting trends of different language communities. A better understanding of the language needs of different migrant communities may further help policymakers set more effective plans to accommodate an increasingly diverse Australian society.

Abstract Ulcerative colitis (UC), affecting millions of patients worldwide, is associated with disorders of the gut microbiota. Probiotics‐based therapy positively regulating the community structure of gut microbiota is regarded as an efficient intervention for UC. However, oral probiotics delivery is restricted by limited bioactivity, short retention time, complex pathological condition, and single therapeutic efficacy. Here, a bioengineered probiotic decorated with a multifunctional prodrug coating is constructed to ameliorate the aforementioned shortcomings. The results of UC mice induced by dextran sulfate sodium demonstrate that the intrinsic features of the fabricated coating integrate gut microbes protection, colon‐targeted drug release, prolonged drug retention, and inflammation regulation. In parallel, the probiotics Lactobacillus rhamnosus GG (LGG) could regulate the composition of the gut microbiota and improve epithelial barrier function, thereby synergistically ameliorating UC. These results provide ample shreds of evidence of the therapeutic effect on UC, therefore, demonstrate a great promise as the potential therapeutic strategy for UC treatment.

Lithium doping has been widely employed to modulate the photoluminescence of lanthanide-doped crystals. Despite its effectiveness, the underlying mechanism remains debatable. Using cubic sodium yttrium fluoride as a model crystal, first-principles calculations indicate that neutral substitution of host sodium with lithium ions can occur, irrespective of synthesis conditions. Unlike lithium substitution, the formation of lithium interstitials is likely accompanied by the substitution of F- with O2- ions. The lithium substitution shows negligible influence on the electronic structures of the host crystal and the 4f orbital energies of lanthanide ions. By comparison, the lithium-oxygen defect pairs could induce self-absorption losses in lanthanide luminescence or produce ligand-to-metal charge transfer states that could populate lanthanide 4f states.

The mitochondria are essential organelles that generate large amounts of ATP via the electron transport chain (ECT). Mitochondrial dysfunction causes reactive oxygen species accumulation, energy stress, and cell death. Endothelial mitochondrial dysfunction is an important factor causing abnormal function of the endothelium, which plays a central role during atherosclerosis development. Atherosclerosis-related risk factors, including high glucose levels, hypertension, ischemia, hypoxia, and diabetes, promote mitochondrial dysfunction in endothelial cells. This review summarizes the physiological and pathophysiological roles of endothelial mitochondria in endothelial function and atherosclerosis.

Objective The oxidative stress status and changes of chicken ovary tissue after shading were studied, to determine the mechanism of the effect of shading on follicular development. Methods Twenty healthy laying hens (40 weeks old) with uniform body weight and the same laying rate were randomly divided into two groups (the shading group and normal light group). In the shading group, the cage was covered to reduce the light intensity inside the cage to 0 without affecting ventilation or food intake. The normal lighting group received no additional treatment. After 7 days of shading, oxidative stress related indicators and gene expression were detected. Results Analysis of paraffin and ultrathin sections showed that apoptosis of ovarian granulosa cells (GCs) increased significantly after light shading. Enzyme linked immunosorbent assay results revealed that the levels of total antioxidant capacity, malondialdehyde, superoxide dismutase (SOD), glutathione, catalase (CAT), and other substances in the sera, livers, ovaries, and follicular GCs of laying hens increased significantly after shading for 7 days; and reactive oxygen species (ROS) levels in the livers of laying hens also increased significantly. ROS in the serum, ovarian and GCs also increased. After shading for 7 days, the levels of 8-hydroxy-2 deoxyguanosine in the sera and ovarian tissues of laying hens increased significantly. Cell counting kit-8 detection showed that the proliferation activity of GCs in layer follicles decreased after shading for 7 days; the expression level of the anti-apoptotic gene B-cell lymphoma-2 in ovarian tissue and follicular GCs was significantly reduced, and the expression levels of pro-apoptotic caspase 3 (casp3), and SOD, glutathione peroxidase 2 (GPX2), and CAT were all significantly increased. Conclusion Oxidative stress induced by shading light has a serious inhibitory effect on follicular development during reproduction in laying hens.

Abstract Background Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. Results In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate “homing” capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. Conclusions Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility. Graphical Abstract

Abstract Environmental exposures interact with genetic factors has been thought to influence susceptibility of systemic lupus erythematosus (SLE) development. To evaluate the effects of environmental exposures on SLE, we conducted a population-based cohort study across Jiangsu Province, China, to examine the associations between the living environment including air and water pollution, population density, economic income level, etc. and the prevalence and mortality of hospitalized SLE (h-SLE) patients. A total of 2231 h-SLE patients were retrieved from a longitudinal SLE database collected by the Jiangsu Lupus Collaborative Group from 1999 to 2009. The results showed that: It existed regional differences on the prevalence of h-SLE patients in 96 administrative districts; The distribution of NO2 air concentration monitored by atmospheric remote sensors showed that three of the ultra-high-prevalence districts were located in the concentrated chemical industry emission area; h-SLE patient prevalence was positively correlated with the excessive levels of nitrogen in drinking water; The positive ratio of pericarditis and proteinuria was positively correlated with the prevalence of h-SLE patients and pollution not only induced a high h-SLE patient prevalence but also a higher mortality rate, which might be attributed to NOx pollution in the air and drinking water. In summary, our data suggested that NOx in air and drinking water may be one of the important predispositions of SLE, especially for patients with renal involvement.

Epidermal growth factor receptor 2 (ERBB2) is commonly over-expressed in advanced or metastatic tissues of papillary thyroid cancer (PTC) with poor prognosis, while it remains unknown whether ERBB2 plays a role in the progression of PTC. Thus, we analyzed the data derived from online repositories, including TCGA, KEGG, GO, GeneMANIA, and STRING, to explore the relationship between ERBB2 expression and prognosis, tumor phenotypes of interest, and immune infiltrates in PTC. Compared to normal thyroid tissue, ERBB2 was up-regulated in PTC samples (p < 0.001); In comparison with the group with low expression of ERBB2, the group with high expression of ERBB2 had poorer progression-free interval in stage III/IV patients (p = 0.008) and patients aged >45 years (p = 0.019). The up-regulated ERBB2 was associated with iodine metabolism dysfunction, proliferation, metastasis, angiogenesis, and drug resistance. The expression of ERBB2 negatively correlated with enrichment scores of B cells (r = −0.176, p < 0.001), CD8+ T cells (r = −0.160, p < 0.001), cytotoxic cells (r = −0.219, p < 0.001), NK CD56dim cells (r = −0.218, p < 0.001), plasmacytoid dendritic cells (r = −0.267, p < 0.001), T cells (r = −0.164, p < 0.001), T follicular helper cells (r = −0.111, p = 0.012), gamma delta T cells (r = −0.105, p = 0.017), and regulatory T cells (r = −0.125, p = 0.005). In conclusion, ERBB2 may serve as a prognostic biomarker and an immunotherapeutic target in PTC, deserving further exploration.

Photon upconversion in lanthanide-doped nanoparticles enables important technological developments. Here the authors demonstrate a mechanism leading to enhanced upconversion emission in core-shell nanoparticles, and long-distance energy transfer between nanoparticles, through triplet state population of an organic surface ligand.

BackgroundThe aim of this study is to develop survival analysis models of hospitalized systemic lupus erythematosus (h-SLE) patients in Jiangsu province using data mining techniques to predict patient survival outcomes and survival status.MethodsIn this study, based on 1999–2009 survival data of 2453 hospitalized SLE (h-SLE) patients in Jiangsu Province, we not only used the Cox proportional hazards model to analyze patients’ survival factors, but also used neural network models to predict survival outcomes. We used semi-supervised learning to label the censored data and introduced cost-sensitivity to achieve data augmentation, addressing category imbalance and pseudo label credibility. In addition, the risk score model was developed by logistic regression.ResultsThe overall accuracy of the survival outcome prediction model exceeded 0.7, and the sensitivity was close to 0.8, and through the comparative analysis of multiple indicators, our model outperformed traditional classifiers. The developed survival risk assessment model based on logistic regression found that there was a clear threshold, i.e., a survival threshold indicating the survival risk of patients, and cardiopulmonary and neuropsychiatric involvement, abnormal blood urea nitrogen levels and alanine aminotransferase level had the greatest impact on patient survival time. In addition, the study developed a graphical user interface (GUI) integrating survival analysis models to assist physicians in diagnosis and treatment.ConclusionsThe proposed survival analysis scheme identifies disease-related pathogenic and prognosis factors, and has the potential to improve the effectiveness of clinical interventions.

Abdominal aortic aneurysm (AAA) is a progressive focal dilatation and weakening of the abdominal aorta, causing 1.3% of all deaths among men aged 65–85 years worldwide. The formation of AAA is a complex process with multiple risk factors. Therefore, this study aimed to determine the relationship of disease severity and physiological factors, and gut microbiota structures in AAA patients. Physiological indicators and fecal 16S rRNA gene sequences from healthy controls and patients with AAA were collected. The correlations between the diameter of the AAA and clinical parameters, and gut microbiota composition were then analyzed separately using multivariable analysis. The diameter of AAA was extremely positively correlated with smoking index, alkaline phosphatase, blood glucose, and blood triglycerides and negatively correlated with prealbumin and Cystatin C. As the diameter of AAA increased, the α-diversity, including Chao 1, Shannon, and Simpson indices, of the gut microbiota decreased and presented a negative linear relationship. Patients with AAA with more severe disease had significantly increased relative abundance of Enterobacteriaceae and decreased relative abundance of Veillonellaceae. A strong correlation was observed between the diameter and physiological data, as well as between diameter and gut microbiota composition. This study could improve the understanding of AAA, and gut microbiota may be a potential target to prevent and treat this deadly disease.

Though upconversion nanoparticles (UCNPs) are attractive for infrared detecting and modulating photonic devices, devising strategies to electrically manipulate upconversion emission remain a challenge. Here, the authors report molecule-assisted opto-electrochemical modulation of UCNP luminescence.

Abstract A probe‐fed dipole antenna with parasitic patches is proposed in this study as the element for wideband and wide‐scanning planar‐phased arrays. Parasitic patches are used to realize wideband performance by significantly reducing the active input impendence. The printed dipole antenna with parasitic patches is directly matched with the subminiature version A (SMA) connector through the modified probe structure. The cell size is 0.5 × 0.5 × 0.145 λhigh3. The planar and low‐profile characteristics make it suitable for modular phased array applications. It is shown that the infinite array simulation results achieve 45.2% bandwidth (7.86–12.45 GHz) with active voltage standing wave ratio (VSWR) < 2 at broadside, 60° scans in E‐, D‐planes and 50° scan in H‐plane. An 8 × 8 prototype array has been manufactured and measured to validate the proposed design and the active element patterns agree well with simulation results.

Abstract Background Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200–399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial registration ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Although biologically targeted therapies based on key oncogenic mutations have made significant progress in the treatment of locally advanced or metastatic thyroid cancer, the challenges of drug resistance are urging us to explore other potentially effective targets. Herein, epigenetic modifications in thyroid cancer, including DNA methylation, histone modifications, non-coding RNAs, chromatin remodeling and RNA alterations, are reviewed and epigenetic therapeutic agents for the treatment of thyroid cancer, such as DNMT (DNA methyltransferase) inhibitors, HDAC (histone deacetylase) inhibitors, BRD4 (bromodomain-containing protein 4) inhibitors, KDM1A (lysine demethylase 1A) inhibitors and EZH2 (enhancer of zeste homolog 2) inhibitors, are updated. We conclude that epigenetics is promising as a therapeutic target in thyroid cancer and further clinical trials are warranted.

Abstract Background Chronic intestinal schistosomiasis has been reported to be associated with colonic polyps, colorectal cancer and ulcerative colitis. We aim to investigate the clinical characteristics of intestinal-related lesions caused by chronic intestinal schistosomiasis japonicum. Methods Patients with and without chronic intestinal schistosomiasis were retrospectively enrolled from the endoscopy center of Wuhan Union Hospital from September 1, 2014, to June 30, 2019 with a ratio of 4:1. The characteristics of infected intestinal segments were analyzed in patients with chronic intestinal schistosomiasis. We also compared the characteristics of intestinal-related lesions, including colorectal polyps, colorectal cancer (CRC), ulceration or erosion of the intestinal mucosa and hemorrhoids, between the two groups. Results A total of 248 patients with chronic intestinal schistosomiasis and 992 patients without chronic intestinal schistosomiasis were analyzed. The most common sites of chronic intestinal schistosomiasis were the sigmoid colon (79.0%) and rectum (84.7%). The frequency of intestinal polyps (64.5% vs. 42.8%, p

Zika virus (ZIKV) is a mosquito-borne flavivirus and can cause neurodevelopmental disorders in fetus. As a neurotropic virus, ZIKV persistently infects neural tissues during pregnancy but the viral pathogenesis remains largely unknown. ZIKV has a positive-sense and single-stranded RNA genome, which encodes 7 non-structural (NS) proteins, participating in viral replication and dysregulation of host immunity. Like those in many other viruses, NS proteins are considered to be products evolutionarily beneficiary to viruses and some are virulence factors. However, we found that some NS proteins encoded by ZIKV genome appeared to function against the viral replication. In this report we showed that exogenously expressed ZIKV NS2A and NS4A inhibited ZIKV infection by inhibiting viral RNA replication in microglial cells and astrocytes. To understand how viral NS proteins suppressed viral replication, we analyzed the transcriptome of the microglial cells and astrocytes and found that expression of NS4A induced the upregulation of ISGs, including MX1/2, OAS1/2/3, IFITM1, IFIT1, IFI6, IFI27, ISG15 or BST2 through activating the ISGF3 signaling pathway. Upregulation of these ISGs seemed to be related to the inhibition of ZIKV replication, since the anti-ZIKV function of NS4A was partially attenuated when the cells were treated with Abrocitinib, an inhibitor of the ISGF3 signaling pathway, or were knocked down with STAT2. Aborting the protein expression of NS4A, but not its nucleic acid, eliminated the antiviral activity of NS4A effectively. Dynamic expression of viral NS proteins was examined in ZIKV-infected microglial cells and astrocytes, which showed comparatively NS4A occurred later than other NS proteins during the infection. We hypothesize that NS4A may possess intrinsic features to serve as a unique type of pathogen associated molecular pattern (PAMP), detectable by the cells to induce an innate immune response, or function with other mechanisms, to restrict the viral replication to a certain level as a negative feedback, which may help ZIKV maintain its persistent infection in fetal neural tissues.

Abstract Background Myocardial infarction (MI) is the leading cause of death from cardiovascular disease (CVD). Currently, the efficacy for MI treatment remains unsatisfactory. Therefore, it is urgent to develop a novel therapeutic strategy. Methods Left anterior descending arteries (LAD) of mice were ligated to induce MI. Another set of mice were intravenously injected with PTEN inhibitor BPV (1 mg/kg) 1 h after LAD ligation and continued to receive BPV injection daily for the following 6 days. Mice were performed echocardiography 14 days after surgery. Results Mice in MI group displayed an increased expression of PTEN with impaired cardiac function, enhanced cardiomyocyte apoptosis and decreased angiogenesis. BPV treatment significantly improved cardiac function, with reduced cardiomyocyte apoptosis, promoted angiogenesis, and activated PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway. Conclusion PTEN inhibitor BPV could effectively prevent myocardial infarction in mice, highlighting its potential as a candidate therapeutic drug.

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies today. Patients suffer from HCC since its high malignancy and limited treatment means. With the development of genetic research, new therapeutic strategy comes up in the way of gene editing. Clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) was discovered as an immune sequence in bacteria and archaea. After artificial transformation and follow-up research, it is widely used as a gene editing tool. In this review, the development of CRISPR/Cas9 is summarized in retrospect. Through the evaluation of novel research in HCC, it is concluded that CRISPR/Cas9 would promote cancer research and provide a new tool for genetic treatment in prospect.

Zika virus (ZIKV) is a positive-sense RNA flavivirus and can cause serious neurological disorders including microcephaly in infected fetuses. As a mosquito-borne arbovirus, it enters the bloodstream and replicates in various organs. During pregnancy, it can be transmitted from the blood of the viremic mother to the fetus by crossing the placental barrier. Monocytes and macrophages are considered the earliest blood cell types to be infected by ZIKV. As a first line defense, these cells are crucial components in innate immunity and host responses and may impact viral pathogenesis in humans. Previous studies have shown that ZIKV infection can activate inflammasomes and induce proinflammatory cytokines in monocytes. In this report, we showed that ZIKV could infect and induce cell death in human and murine macrophages. In addition to the presence of cleaved caspase-3, indicating that apoptosis was involved, we identified the cleaved caspase-1 and gasdermin D (GSDMD) as well as increased secretion of IL-1β and IL-18. This suggests that the inflammasome was activated and that may lead to pyroptosis in infected macrophages. The pyroptosis was NLRP3-dependent and could be suppressed in the macrophages treated with shRNA to target and knockdown caspase-1. It was also be inhibited by an inhibitor for caspase-1, indicating that the pyroptosis was triggered via a canonical approach. Our findings in this study demonstrate a concomitant occurrence of apoptosis and pyroptosis in ZIKV-infected macrophages, with two mechanisms involved in the cell death, which may have potentially significant impacts on viral pathogenesis in humans.

Prefabricated construction has attracted worldwide concern and promotion due to its environmental friendliness, high quality, and high efficiency. In China, the application of prefabricated construction still lags due to its high cost. To improve prefabricated construction development, the Chinese government and provinces have launched subsidy policies for different objects that offer subsidies to the assembler, the manufacturer, or consumers. Subsidy policies for different subsidy objects have different impacts on the manufacturer wholesale price and assembler retail price and assembly rate and make their decisions more complicated. Therefore, this study uses game theory and builds three models to analyze the effects of government subsidies on manufacturer pricing, assembler pricing, assembly rate decisions, and profit. We find that government subsidy policies can bring more profit to prefabricated construction enterprises, reduce their costs, and benefit the promotion of prefabricated construction. Through comparison and numerical analysis, we also find that when the government subsidizes enterprises more, it is better to subsidize the assembler, because it is good for all three parties. First, consumers can obtain a lower retail price. Second, enterprises can obtain more profits. Finally, for the government, this approach can increase the demand for prefabricated construction and increase the assembly rate, which is conducive to the promotion of prefabricated construction. When the government subsidizes customers more, it is better for the assembler and the manufacturer to subsidize customers, because they can obtain more profits. It is better for the government and customers to subsidize the assembler or the manufacture, because consumers can get the lower retail price. Although the assembly rate and enterprises' profits are not optimal, they have also been improved. In addition, when the government directly subsidizes enterprises, the enterprises will actively cooperate with the subsidy policy and are more willing to adopt prefabricated construction. This approach will benefit the promotion of prefabricated construction.

Gelatin-based hydrogels have a broad range of biomedical fields due to their biocompatibility, convenience for chemical modifications, and degradability. However, gelatin-based hydrogels present poor antibacterial ability that hinders their applications in treating infected wound healing. Herein, a series of multifunctional hydrogels (Gel@Zn) were fabricated through free-radical polymerization interaction based on gelatin methacrylate (GelMA) and dopamine methacrylate (DMA), and then immersed them into zinc nitrate solutions based on the metal coordination and ionic bonding interaction. These designed hydrogels wound dressings show strong antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by increasing intracellular reactive oxygen species (ROS) level and changing bacterial membrane permeability. Meanwhile, the hydrogels exhibit good cytocompatibility, enhance the adhesion, proliferation, and migration of NIH-3T3 cells. Furthermore, Gel@Zn-0.08 (0.08 ​M Zn2+ immersed with Gel sample) presents a good balance between antibacterial effect, cell viability, and hemolytic property. Compared with 3 ​M commercial dressings, Gel@Zn-0.04, and Gel@Zn-0.16, the Gel@Zn-0.08 could significantly improve the healing process of S. aureus-infected full-thickness wounds via restrained the inflammatory responses, enhanced epidermis and granulation tissue information, and stimulated angiogenesis. Our study indicates that the Zn-incorporated hydrogels are promising bioactive materials as wound dressings for infected full-thickness wound healing and skin regeneration.