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Abstract Aedes aegypti is a primary vector for transmitting various arboviruses, including Yellow fever, dengue and Zika virus. The mosquito midgut is the principal organ for blood meal digestion, nutrient absorption and the initial site of arbovirus infection. Although a previous study delineated midgut’s transcriptome of Ae. aegypti at the single-nucleus resolution, there still lacks an established protocol for isolating and RNA sequencing of single cells of Ae. aegypti midgut, which is required for investigating arbovirus-midgut interaction at the single-cell level. Here, we established an atlas of the midgut cells for Ae. aegypti by single-cell RNA sequencing. We annotated the cell clusters including intestinal stem cells/enteroblasts (ISC/EB), cardia cells (Cardia), enterocytes (EC, EC-like), enteroendocrine cells (EE), visceral muscle (VM), fat body cells (FBC) and hemocyte cells (HC). This study will provide a foundation for further studies of arbovirus infection in mosquito midgut at the single-cell level.

Abstract Bioactive molecules in tick saliva are considered to be key to successful feeding and further the transmission of tick-borne pathogens. Problems such as pathogen transmission and animal weight loss result in tick infestation can cause tremendous economic losses to the livestock industry. Therefore, the development of a universal tick vaccine is urgently needed. In this paper, three serine protease inhibitor (serpin) proteins RMS-3, L7LRK7 and L7LTU1 were analyzed with bioinformatics methods. Subsequently the proteins were expressed and purified, and inoculated into Kunming mice for immune protection analysis. The amino acid sequence similarities between RMS-3, L7LRK7 and L7LTU1 were up to 90% in Rhipicephalus sanguineus. The recombinant RMS-3 + L7LRK7 + L7LTU1 showed anticoagulant reaction function and could inhibit the activity of CD4+ lymphocytes, when inoculated into Kunming mice. Additionally, After the immunized mice were challenged with Rhipicephalus sanguineus, the percentage of larvae and nymphs that were fully engorged dropped to 40.87% (P 0.05) in the RmS-3 + L7LRK7 immune group, 49.57% (P

Abstract This study aims to investigate the impact of digital capabilities on business model innovation, and emphasizes the pivotal mediating role of dynamic capabilities, comprising sensing, seizing, and reconfiguring resources, in translating digital strengths into innovative business models. And also uncovers a nuanced perspective on organizational inertia, showcasing its potential to positively moderate the relationship between digital capabilities and business model innovation. A questionnaire-based, time-lagged study with a 1-week interval. From January 2023 to March 2023, we collected a total of 262 questionnaires from entrepreneurs located in the Pearl River-West River Economic Belt, such as Guangzhou and Nanning, China. To analyse the moderation and mediation model, we utilized The PROCESS Model 5. Digital capabilities have a positive impact on the innovation of enterprises’ business models. Moreover, the connection between digital capabilities and business model innovation is mediated by dynamic capability. The findings also illustrate that organisational inertia moderates the relationship between digital capabilities and business model innovation. This study contributes to the existing literature on enterprise sustainable development by shedding light on the mediating and moderating mechanisms through which digital capabilities enhance business model innovation in enterprises. These findings offer valuable insights for enterprises aiming to thrive in dynamic markets, emphasizing the importance of a balanced approach to digital innovation, and instrumental for entrepreneurs seeking to refine their organisational strategies, particularly by bolstering their digital capabilities.

This study aimed to investigate the inhibitory effect of astragaloside IV (AS-IV) on enterovirus 71 (EV71)-induced pyroptosis. The results indicated that AST-IV inhibited EV71-induced pyroptosis in normal human gastric epithelial (GES-1) cells. Therefore, we investigated the mechanisms underlying pyroptosis inhibition by AST-IV. We found that EV71 inhibited the Nrf2-Keap1 pathway, whereas AST-IV treatment activated it. Overexpression of Nrf2 led to the inhibition of EV71-induced pyroptosis. EV71 infection and AST-IV treatment upregulated and downregulated thioredoxin interacting protein (TXNIP), respectively. Downregulation of TXNIP activated the Keap1/Nrf2 signaling pathway and inhibited EV71-induced pyroptosis. Furthermore, transcription factor 12 (TCF12) reduced the protein and mRNA levels of TXNIP, and AST-IV treatment upregulated TCF12. These results demonstrate that the TCF12-TXNIP-Keap1/Nrf2 axis participates in the inhibition of pyroptosis by AST-IV in EV71-infected GES-1 cells, suggesting that AST-IV could be used as a dietary supplement to alleviate EV71-induced pyroptosis.

Objective: High-grade glioma (HGG) patients frequently encounter treatment resistance and relapse, despite numerous interventions seeking enhanced survival outcomes yielding limited success. Consequently, this study, rooted in our prior research, aimed to ascertain whether leveraging circadian rhythm phase attributes could optimize radiotherapy results. Methods: In this retrospective analysis, we meticulously selected 121 HGG cases with synchronized rhythms through Cosinor analysis. Post-surgery, all subjects underwent standard radiotherapy alongside Temozolomide chemotherapy. Random allocation ensued, dividing patients into morning (N = 69) and afternoon (N = 52) radiotherapy cohorts, enabling a comparison of survival and toxicity disparities. Results: The afternoon radiotherapy group exhibited improved overall survival (OS) and progression-free survival (PFS) relative to the morning cohort. Notably, median OS extended to 25.6 months versus 18.5 months, with P = 0.014, with median PFS at 20.6 months versus 13.3 months, with P = 0.022, post-standardized radiotherapy. Additionally, lymphocyte expression levels in the afternoon radiation group 32.90(26.10, 39.10) significantly exceeded those in the morning group 31.30(26.50, 39.20), with P = 0.032. Conclusions: This study underscores the markedly prolonged average survival within the afternoon radiotherapy group. Moreover, lymphocyte proportion demonstrated a notable elevation in the afternoon group. Timely and strategic adjustments of therapeutic interventions show the potential to improve therapeutic efficacy, while maintaining vigilant systemic immune surveillance. A comprehensive grasp of physiological rhythms governing both the human body and tumor microenvironment can refine treatment efficacy, concurrently curtailing immune-related damage—a crucial facet of precision medicine.

Summary: The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy.

Abstract Background Toxocara canis is a roundworm that resides in the gastrointestinal tract of dogs and causes various pathological changes. The dog’s intestinal system consists of a diverse and dynamic bacterial community that has extensive effects on intestinal physiology, immunity and metabolics. In the case of intestinal parasites, interactions with the host intestinal flora are inevitable during the process of parasitism. Methods We studied the role of T. canis in regulating the composition and diversity of the intestinal flora of the host by high-throughput sequencing of the 16S ribosomal RNA gene and various bioinformatics analyses. Results The α-diversity analysis showed that Toxocara canis infection resulted in a significant decrease in the abundance and diversity of host intestinal flora. The β-diversity analysis showed that the intestinal flora of infected dogs was similar to that carried by T. canis. Analysis of the microflora composition and differences at the phylum level showed that the ratio of Firmicutes to Bacteroidetes (F/B ratio) increased with T. canis infection. Analysis of species composition and differences at the genus level revealed that the proportion of some of the pathogenic bacteria, such as Clostridium sensu stricto and Staphylococcus, increased after T. canis infection. Conclusions Toxocara canis infection affected the composition and diversity of the flora in the host intestinal tract. These results not only shed light on the potential mechanism of T. canis invasion and long-term survival in the intestinal tract, but also provide a new basis for the development of anthelmintic drugs. Graphical Abstract

Toxocara canis is an intestinal roundworm that can cause serious zoonotic parasitic diseases. Drontal Plus® Tasty (Dog) is a kind of commercial drug used to treat T. canis infection. Febantel, Praziquantel, and Pyrantel pamoate (PP) are its main component. However, there are few studies investigating the impact of Drontal Plus® Tasty (Dog) and its primary ingredients on the intestinal microbiota of dogs. In this study, we first collected the intestinal content samples of the dogs which administrated with anthelmintics or saline by sterile catheters, then used 16S rRNA high-throughput sequencing technology combined with a variety of bioinformatic analysis methods to analyze the effect of anthelmintics on intestinal microbiota. First, the results of the α and β diversity analysis showed that the abundance and diversity of intestinal microbiota decreased with T. canis infection, and increased after anthelmintic treatment. Then, we found the dominant species (the value of relative abundance > 0.05) was both 28 on phylum and genus levels, besides the most dominant species was Bacillota on phylum level and Segatella and Clostridium_sensu_stricto were most dominant on genus level. Futher analyzing the differences in microbiotal composition on phylum level, we found that Drontal Plus® Tasty treatment could significantly increase the proportion of Bacillota, while Febantel, Praziquantel, or PP could induce the significantly changes of Bacillota and Bacteroidota. In addition, by analyzing the differences in microbiotal composition on genus level, we found that anthelmintic could significantly decreased the relative abundance of Clostridium_sensu_stricto and significantly increased the abundance of Segatella. However, Drontal Plus® Tasty had no regulatory effect on the abundance of Segatella. In short, these finding showed that various anthelmintics all have significant effects for changing the abundance and diversity of host intestinal microbiota.

Abstract Using household detergents to clean oil stains has always caused global concerns, as these detergents negatively impact the ecosystem and are toxic. Therefore, it is essential to effectively attenuate the adhesion force between oil stains and substrates to create an easy and detergent‐saving cleaning pathway. To address this challenge, we herein develop a strategy to reduce the strength of oil adhesion on common substrates by ∼20 times through a lamination layer, which contains phase‐transitioned lysozyme nanofilm (PTL) and cellulose nanocrystals (CNCs). The resultant CNC/PTL coating significantly enhances the capability of cleaning oil stains in an underwater detergent‐free manner; this strategy is applicable to edible oil packaging material and tableware, without impairing the usability and aesthetics of these materials. This coating exhibits excellent mechanical stability and regeneration characteristics through simple soaking, ensuring its robustness in real applications in an infinite life cycle. By eliminating 100% detergent in routine cleaning, the CNC/PTL coating demonstrated remarkable cost‐effectiveness, saving 57.7% of water and 83.3% of energy when washing tableware only with water. This work presents an ingenious design to create oil‐repellent packaging materials and tableware toward detergent‐free water‐cleaning pathways, thereby greatly reducing the negative environmental impact of surfactant emissions.

In this study, amine vapor-sensitive films with ratiometric fluorescence attributes were developed. The pH-sensitive fluorescein 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) and its tetraphenylethylene derivative (TPB) were selected as ratiometric indicators and incorporated into a polyvinyl alcohol (PVA) matrix to produce HPTS/TPB-PVA films. The films responded well to amine vapors, and the interference of aromatic vapors did not substantially affect the fluorescence signals of the films. Under UV light at a wavelength of 365 nm, the fluorescence of the films changed from dark pink to light pink and finally to yellow when the freshness of the fish was visually checked during storage. In addition, the color difference values of the films showed a positive correlation with the total volatile basic nitrogen (TVB-N), ranging from 12.7 to 24.8 mg/100 g at 25 °C and 8.4 to 25.6 mg/100 g at 4 °C, respectively. This indicates that fluorescent films have good potential for quantifying fish freshness in the near future when connected to an automatic data processing system based on color differences.

Abstract Anaplasmosis is a highly prevalent tick-borne intracellular bacterial disease that affects various host species globally, particularly ruminants in tropical and subtropical regions. However, information regarding the distribution and epidemiology of anaplasmosis in small and large ruminants on Hainan Isalnd is limited. To address this knowledge gap, the present study aimed to assess the occurrence of Anaplasma spp. infections in goats (N = 731) and cattle (N = 176) blood samples using nested PCR and conventional PCR based assays. The results revealed an overall prevalence of 30.1% in goats and 14.8% in cattle. The infection rates of A. bovis, A. phagocytophilum, A. ovis and A. capra in goat samples were 22.7%, 13.8%, 2.0% and 3.4%, respectively, while the infection rates of A. bovis, A. phagocytophilum and A. marginale in cattle samples were 11.4%, 6.3% and 5.7%, respectively. A. bovis exhibited the highest prevalence among the Anaplasma spp. in both goat and cattle samples. In addition, the most frequent co-infection was the one with A. phagocytophilum and A. bovis. It was found that the age, sex and feeding habits of cattle and goats were considered to be important risk factors. Evaluation of the risk factor relating to the rearing system showed that the infection rate for the free-range goats and cattle was significantly higher when compared with stall-feeding system. This study represents one of the largest investigations on the distribution, prevalence, and risk factors associated with Anaplasma infection in ruminants on Hainan Island, highlighting a higher circulation of the infection in the region than previously anticipated. Further reasesrch is necessary to investigate tick vectors, reservoir animals, and the zoonotic potential of the Anaplasma spp. in this endemic region of Hainan Island.

iGABAR, a member of the Cys-loop ligand-gated ion channel superfamily, is a significant target of the insecticide ivermectin (IVM). GRD is the potential subunit of the insect iGABAR. However, little information about GRD in Ae. aegypti has been reported. In this study, we involved cloning and characterizing the iGABAR subunit GRD of Ae. aegypti (Ae-GRD). Sequence analysis indicated that Ae-GRD, as part of the cysteine-loop ligand-gated ion channel family, is similar to other insect GRD. RNA interference (RNAi) was employed to explore IVM resistance in Ae. aegypti, resulting in a significant reduction in Ae-GRD expression (p < 0.05), and the mortality of Ae. aegypti adults with Ae-GRD knockdown was significantly decreased after exposure to ivermectin. Bioinformatics prediction identified miR-71-5p as a potential regulator of Ae-GRD. In vitro, dual-luciferase reporter assays confirmed that Ae-GRD expression was regulated by miR-71-5p. Microinjection of miR-71-5p mimics upregulated miR-71-5p expression and downregulated Ae-GRD gene expression, reducing mortality by 34.52% following IVM treatment. Conversely, microinjection of a miR-71-5p inhibitor decreased miR-71-5p expression but did not affect the susceptibility to IVM despite increased Ae-GRD expression (p < 0.05). In conclusion, Ae-GRD, as one of the iGABA receptor subunits, is a potential target of ivermectin. It may influence ivermectin resistance by modulating the GABA signaling pathway. The inhibition of Ae-GRD expression by miR-71-5p decreased ivermectin resistance and consequently lowered the mortality rate of Ae. aegypti mosquitoes. This finding provides empirical evidence of the relationship between Ae-GRD and its miRNA in modulating insecticide resistance, offering novel perspectives for mosquito control strategies.

The construction of shield tunneling close to risk sources in urban has been a commonly encountered problem in recent years. The establishment of the analytical model used to calculate the immediate settlement of existing structures has been a major focus in approaching construction issues. It is obvious that after shield construction, the settlement will inevitably continue to increase for a long period. In this study, a novel model applied to calculate the long-term settlement considering the influence of soil consolidation was proposed. Based on this proposed analysis model, combined with building information modeling (BIM), geographic information system (GIS), city information model (CIM), geoscience modeling (Geo Model), and internet of things (IoT), a three-dimensional (3D) intelligent management and control platform for shield tunneling construction close to major risk sources was developed and introduced. In this platform, the analysis model was embedded to calculate the long-term settlement, and the risk data were determined by comparing calculated results, monitoring results, and control standard value. The intelligent platform adopts the analytical method and computer technology to solve the problem of approaching construction, such as management of construction information, pre-warning, and control of construction risk, and it has been successfully applied in Beijing shield tunneling projects. This platform can also provide the pre-warning function and economic value for similar construction projects.

Abstract Background Dirofilariasis, the disease caused by Dirofilaria spp., and in particular by Dirofilaria immitis and Dirofilaria repens in canines, occurs frequently in canids and felids, and occasionally in humans, in temperate, sub-tropical and tropical regions globally. Although highly effective, safe and convenient preventive medicines have been available for the treatment of dirofilariasis for the past three decades, the disease remains a major veterinary and public health concern in endemic areas. The insect vectors, host-parasite relationships and interactions of Dirofilaria spp. have received little attention in China, and there is very little information in English regarding the prevalence of dirofilariasis in animals and humans in the country. The aim of this systematic review and meta-analysis is to evaluate the status of canine dirofilariasis in China based on the available literature in English and in Chinese. Methods We systematically searched five databases for epidemiologic studies on the prevalence of canine dirofilariasis in China and finally selected 42 studies eligible for inclusion in the systematic review and meta-analysis. The meta-analysis was performed using the random effects model in the meta package in R v4.2.1. Results The random effects model gave a pooled and weighted prevalence of Dirofilaria infection among dogs in China in the past 100 years of 13.8% (2896/51,313, 95% confidence interval 8.2–20.4%) with a high level of heterogeneity (I 2 = 99.5%). Conclusions Our analyses indicated that the prevalence of canine dirofilariasis in China has gradually declined, but that the range of Dirofilaria spp. has expanded. Older and outdoor dogs presented a higher rate of positive infection. The findings indicated that more attention should be paid to host factors for the effective control and management of this disease. Graphical Abstract

Abstract Background The behaviors and ontogeny of Aedes aegypti are closely related to the spread of diseases caused by dengue (DENV), chikungunya (CHIKV), Zika (ZIKV), and yellow fever (YFV) viruses. During the life cycle, Ae. aegypti undergoes drastic morphological, metabolic, and functional changes triggered by gene regulation and other molecular mechanisms. Some essential regulatory factors that regulate insect ontogeny have been revealed in other species, but their roles are still poorly investigated in the mosquito. Results Our study identified 6 gene modules and their intramodular hub genes that were highly associated with the ontogeny of Ae. aegypti in the constructed network. Those modules were found to be enriched in functional roles related to cuticle development, ATP generation, digestion, immunity, pupation control, lectins, and spermatogenesis. Additionally, digestion-related pathways were activated in the larvae and adult females but suppressed in the pupae. The integrated protein‒protein network also identified cilium-related genes. In addition, we verified that the 6 intramodular hub genes encoding proteins such as EcKinase regulating larval molt were only expressed in the larval stage. Quantitative RT‒PCR of the intramodular hub genes gave similar results as the RNA-Seq expression profile, and most hub genes were ontogeny-specifically expressed. Conclusions The constructed gene coexpression network provides a useful resource for network-based data mining to identify candidate genes for functional studies. Ultimately, these findings will be key in identifying potential molecular targets for disease control.

In actual storage processes of rice, environment temperatures fluctuate rather than remain constant. Accumulated temperature is the sum of temperature during the storage period. In this research, six different temperature-varied conditions with two accumulated temperatures (low intensity: 7200°C⸱d; high intensity: 9000°C⸱d) were designed to store rice for 12 months and the stored rice samples were compared in quality. Three low-accumulated temperature conditions were set as follows: No. 4–15°C for 6 months followed by 25°C; No. 5–25°C for 6 months followed by 15°C; No. 8-alternating between 15°C and 25°C every 2 months. Similarly, three high-intensity conditions, No. 6, No. 7, and No. 9, were set with a temperature change from 25°C to 35°C. Three constant temperature conditions, No. 1, No. 2, and No. 3, with storage temperature of 15, 25, and 35°C, respectively, were used as controls. Under temperature-varied conditions, rice demonstrated a decline in germination rate (GR), catalase (CAT) and peroxidase (POD) activities, and an increase in fatty acid value (FAV) as storage time increased. After storage, rice exhibited higher water absorption rate (WAR) and volume expansion rate (VER), but reduced stickiness and sensory scores for appearance, taste and overall quality. Generally, three batches at high-accumulated temperature conditions had lower GR and sensory scores, and higher FAV, WAR, and VER compared to those under low-intensity conditions. Furthermore, variations in the sequence of temperature also affected quality parameters, even at the same accumulated temperature. These findings indicate that under temperature-varied conditions, increased accumulated temperature exacerbates rice deterioration, and different temperature sequences can influence quality at a given accumulated temperature.

Abstract Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated β-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms.

Background: Little is known about MBD2’s epigenetic regulation in the immune pathogenesis of CD4+T cell differentiation.Objective: This study attempted to explore the mechanism of methyl-cpg-binding domain protein 2 (MBD2) in CD4+T cell differentiation stimulated by environmental allergen ovalbumin (OVA).Methods: Mononuclear cells were separated from the spleen tissues of male C57BL/6 mice. The OVA interfered with the differentiation of splenic mononuclear cells and CD4+T cells. The CD4+T cells were obtained by magnetic beads and identified by CD4 labeled antibody. CD4+T cells were transfected with lentivirus to silence MBD2 gene. A methylation quantification kit was used to detect 5-mC levels.Results: The purity of CD4+T cells reached 95.99% after magnetic beads sorting. Treatment with 200 μg/mL OVA stimulated the CD4+T cells differentiation to Th17 cells and promoted the secretion of IL-17. After being induced, the Th17 cell ratio increased. 5-Aza inhibited the Th17 cell differentiation and the IL-17 level in a dose-dependent manner. Under the intervention of the Th17 induction and 5-Aza, MBD2 silencing inhibited the differentiation of Th17 cell, and decreased the IL-17 and 5-mC levels in the cell supernatants. MBD2 silencing reduced the scale of the Th17 cell and IL-17 levels in the OVA-treated CD4+T cells.Conclusion: MBD2 affected IL-17 and 5-mC levels by mediating the Th17 cell differentiation in splenic CD4+T cells that were interfered with 5-Aza. OVA induced Th17 differentiation and increased IL-17 levels, inhibited by MBD2 silencing.

Konjac glucomannan (KGM) is a kind of excellent food additive and also be used for the modification of biological macromolecules. Starch is an important natural macromolecule that provides energy for the human body, while it has regenerate easily, weak shear resistance, heat instability and other defects. Physical method has the characteristics of convenience, environmental protection and low cost, and is commonly used to modify starch properties in food industry. Herein, this paper introduces the research progress of starch modification by KGM, and summarizes the beneficial improvements of rheological properties, regeneration properties and digestive properties of starch modification by KGM. In addition, the application of KGM in functional foods, such as active substance delivery, diet food, and disease-prevention food are also systematically reviewed. This work would provide a scientific basis for starch modification by KGM and a new strategy for the development of functional foods.

Abstract Background Pulsatilla decoction (Bai-Tou-Weng-Tang, BTWT) is a classic formula prescription of a traditional Chinese medicine that is used to treat ulcerative colitis (UC). However, its active components and underlying mechanism of action remain unclear. In the present study, we aimed to identify potential immunomodulators from BTWT that act at therapeutic targets for UC. Methods The protective effects of BTWT granules were examined in mice with colitis induced by dextran sulfate sodium. The absorbed components of BTWT were identified using LC-MS, and selected protein targets of these components in UC were investigated using molecular docking. Results Oral administration of BTWT granules significantly alleviated disease severity and colon shortening, and inhibited the inflammatory response in mice with chronic colitis. In these mice, 11 compounds from the BTWT granules were detected in the serum and/or colon. The molecular docking study demonstrated that compounds from Radix pulsatillae, such as anemoside A3, interacted with STAT3 and S1PR1; compounds from Rhizoma coptidis and/or Cortex phellodendri, such as palmatine, interacted with JAK3, PD-1, and PD-L1; and components of Cortex fraxini such as aesculin interacted with S1PR1, JAK3, STAT3 and PD-L1. Further in-vitro experiments showing that the compounds inhibited TNF-α and IL-6 production and STAT3 activation in RAW 264.7 cells suggested that these compounds have immunomodulatory activities. Conclusion We revealed for the first time that 11 absorbed ingredients from BTWT were immunomodulators against therapeutic targets for UC. These findings suggest that the identified compounds are the active components of BTWT, and the identified protein targets underlie the mechanism of action of BTWT against UC.

Toxocariasis is a significant food-borne zoonotic parasitic disease, and a range of birds and mammals are the paratenic hosts of Toxocara canis. The consumption of raw or undercooked meat and viscera of these paratenic hosts frequently leads to T. canis infection and the development of human toxocariasis. In this review, we will perform an analysis of relevant papers published in the National Center for Biotechnology Infrastructure database on the parasitism, migration, and infection of T. canis in chickens, pigeons, quail, pigs, cattle, sheep, and other food-producing animals, so as to make the public aware of the risk factors of human toxocariasis, improve the public’s understanding of T. canis infection, and provide evidence for targeted prevention and control measures.

The rotator cuff tear has emerged as a significant global health concern. However, existing therapies fail to fully restore the intricate bone-to-tendon gradients, resulting in compromised biomechanical functionalities of the reconstructed enthesis tissues. Herein, a tri-layered core–shell microfibrous scaffold with layer-specific growth factors (GFs) release is developed using coaxial electrohydrodynamic (EHD) printing for in situ cell recruitment and differentiation to facilitate gradient enthesis tissue repair. Stromal cell-derived factor-1 (SDF-1) is loaded in the shell, while basic fibroblast GF, transforming GF-beta, and bone morphogenetic protein-2 are loaded in the core of the EHD-printed microfibrous scaffolds in a layer-specific manner. Correspondingly, the tri-layered microfibrous scaffolds have a core–shell fiber size of (25.7 ± 5.1) μ m, with a pore size sequentially increasing from (81.5 ± 4.6) μ m to (173.3 ± 6.9) μ m, and to (388.9 ± 6.9 μ m) for the tenogenic, chondrogenic, and osteogenic instructive layers. A rapid release of embedded GFs is observed within the first 2 d, followed by a faster release of SDF-1 and a slightly slower release of differentiation GFs for approximately four weeks. The coaxial EHD-printed microfibrous scaffolds significantly promote stem cell recruitment and direct their differentiation toward tenocyte, chondrocyte, and osteocyte phenotypes in vitro . When implanted in vivo , the tri-layered core–shell microfibrous scaffolds rapidly restored the biomechanical functions and promoted enthesis tissue regeneration with native-like bone-to-tendon gradients. Our findings suggest that the microfibrous scaffolds with layer-specific GFs release may offer a promising clinical solution for enthesis regeneration.

BackgroundMycoplasma pneumoniae (MP) is a commonly occurring pathogen causing community-acquired pneumonia (CAP) in children. The global prevalence of macrolide-resistant MP (MRMP) infection, especially in Asian regions, is increasing rapidly. However, the prevalence of MRMP and its clinical significance during the COVID-19 pandemic is not clear.MethodsThis study enrolled children with molecularly confirmed macrolide-susceptible MP (MSMP) and MRMP CAP from Beijing Children’s Hospital Baoding Hospital, Capital Medical University between August 2021 and July 2022. The clinical characteristics, laboratory findings, chest imaging presentations, and strain genotypes were compared between patients with MSMP and MRMP CAP.ResultsA total of 520 hospitalized children with MP-CAP were enrolled in the study, with a macrolide resistance rate of 92.7%. Patients with MRMP infection exhibited more severe clinical manifestations (such as dyspnea and pleural effusion) and had a longer hospital stay than the MSMP group. Furthermore, abnormal blood test results (including increased LDH and D-dimer) were more common in the MRMP group (P

Background: Intracerebral hemorrhage (ICH) is a serious brain condition with high mortality and disability rates. In recent decades, several risk factors related to death risk have been identified, with several models predicting mortality, but rarely used and accepted in daily clinical practice. Aims: To establish and validate a predictive nomogram of spontaneous ICH death that can be used to predict patient death within 7 days. Study Design: Cohort study. Methods: A cohort of 449 patients with ICH, diagnosed clinically from January 2015 to December 2017, were identified as the model training cohort. Univariate analysis and least absolute contraction and selection operator (Lasso) regression were used to determine the most powerful predictors of patients with ICH. Discrimination, calibration, and clinical applicability were used to assess the function of the new nomogram. In external validation, we also evaluated the nomogram in another 148 subjects (validation cohort) examined between January and December 2018. Results: We observed no significant differences in patient baseline characteristics in the training and validation cohorts, including sex, age, Glasgow coma scale (GCS) score, and one-week mortality rates. The model included three predictive variables from univariate and multivariate analysis, including GCS scores, hematoma volume, and brainstem hemorrhage (BSH). Internal validation revealed that the nomogram had a good discrimination, the area under the receiver operating characteristic curve (AUC) was 0.935, and calibration was good (U = -0.004, P = 0.801). Similarly, this nomogram also showed good differentiation ability (AUC = 0.925) and good accuracy (U = -0.007, P = 0.241) in the validation cohort data. Decision curve analysis indicated that the new prediction model was helpful. Conclusion: At the early stages of the condition, our prediction model accurately predicts the death of patients with ICH.

Quantum dot nanobeads (QBs) were used as signal source to develop competitive lateral flow immunoassay (LFIA) for the detection of chloramphenicol (CAP). The quantitative detection of CAP was achieved by calculating the total color difference (∆E) values of the test line (T line) using the images of test strips. QB-based LFIA (QBs-LFIA) allowed the effective dynamic linear detection of CAP in the range of 0.1–1.5 ng/mL. The limit of detection (LOD) was 3.0 ng/mL, which was 50 and 667 times lower than those achieved for two different brands of colloidal gold kits. The recoveries of CAP during real-sample detection were 82.82–104.91% at spiked levels of 0.1, 0.7, and 1.5 ng/mL. These results indicate that the developed QBs-LFIA facilitates the sensitive detection of CAP.

In the present study, an oligosaccharide SPO-1 from Spirulina platensis was prepared by glycosidase from a marine bacterium. The prebiotic activity of SPO-1 on the growth of Lactobacillus paracasei and Bifidobacterium animalis, and its effect on human gut microbiota were examined in vitro. The molecular weight of the tetrasaccharide SPO-1 was 650.2 Da, and it was mainly composed of glucose with α-type glycosidic linkages. The prebiotic activity score of SPO-1 was the highest for the growth of probiotic strains L. paracasei and B. animalis. Furthermore, as fermentation proceeded, SPO-1 was gradually degraded and utilized by intestinal bacteria. The results showed that after treatment with SPO-1, carbohydrate consumption and short-chain fatty acids levels were increased, especially those of i-butyric and i-valeric acids. Moreover, SPO-1 significantly promoted the abundance, diversity and composition of gut microbiota, especially stimulating the growth of Bacteroides, Escherichia-Shigella and Megamonas. In addition, the change in intestinal microbiota function predicted by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) after treatment with SPO-1 is mainly related to the terms “carbohydrate metabolism” and “amino acid metabolism”. These results suggest that SPO-1 is a potential oligosaccharide in regulation of intestinal microbiota.

Abstract Background Recurrent implantation failure (RIF) is a major limitation of assisted reproductive technology, which is associated with impaired endometrial receptivity. Although N6-methyladenosine (m6A) has been demonstrated to be involved in various biological processes, its potential role in the endometrium of women with RIF has been poorly studied. Methods Global m6A levels and major m6A methyltransferases/demethylases mRNA levels in mid-secretory endometrium from normal and RIF women were examined by colorimetric m6A quantification strategy and quantitative real-time PCR, respectively. The effects of METTL3-mediated m6A modification on embryo attachment were evaluated by an vitro model of a confluent monolayer of Ishikawa cells co-cultured with BeWo spheroids, and the expression levels of homeo box A10 (HOXA10, a well-characterized marker of endometrial receptivity) and its downstream targets were evaluated by quantitative real-time PCR and Western blotting in METTL3-overexpressing Ishikawa cells. The molecular mechanism for METTL3 regulating HOXA10 expression was determined by methylated RNA immunoprecipitation assay and transcription inhibition assay. Results Global m6A methylation and METTL3 expression were significantly increased in the endometrial tissues from women with RIF compared with the controls. Overexpression of METTL3 in Ishikawa cells significantly decreased the ration of BeWo spheroid attachment, and inhibited HOXA10 expression with downstream decreased β3-integrin and increased empty spiracles homeobox 2 expression. METTL3 catalyzed the m6A methylation of HOXA10 mRNA and contributed to its decay with shortened half-life. Enforced expression of HOXA10 in Ishikawa cells effectively rescued the impairment of METTL3 on the embryo attachment in vitro. Conclusion Increased METTL3-mediated m6A modification represents an adverse impact on embryo implantation by inhibiting HOXA10 expression, contributing to the pathogenesis of RIF.

Abstract Background Clip domain serine proteases (CLIPs), a very diverse group of proteolytic enzymes, play a crucial role in the innate immunity of insects. Innate immune responses are the first line of defense in mosquitoes against the invasion of pathogenic microorganisms. The Toll pathway, immunodeficiency (IMD) pathway and melanization are the main processes of innate immunity in Aedes aegypti. CLIPS are classified into five subfamilies—CLIPA, CLIPB, CLIPC, CLIPD, and CLIPE—based on their sequence specificity and phylogenetic relationships. We report the functional characterization of the genes that code for two CLIPs in Ae. aegypti (Ae): Ae-CLIPB15 and Ae-CLIPB22. Methods Clustal Omega was used for multiple amino acid sequence alignment of Ae-CLIPB15 and Ae-CLIPB22 with different CLIP genes from other insect species. The spatiotemporal expression profiles of Ae-CLIPB15 and Ae-CLIPB22 were examined. We determined whether Ae-CLIPB15 and Ae-CLIPB22 respond to microbial challenge and tissue injury. RNA interference (RNAi) was used to explore the function of Ae-CLIPB15 and Ae-CLIPB22 in the defense of Ae. aegypti against bacterial and fungal infections. The expression levels of nuclear factor kappa B (NF-κB) transcription factors REL1 and REL2 in the Toll pathway and IMD pathway after bacterial infection were investigated. Finally, the change in phenoloxidase (PO) activity in Ae-CLIPB15 and Ae-CLIPB22 knockdown adults was investigated. Results We performed spatiotemporal gene expression profiling of Ae-CLIPB15 and Ae-CLIPB22 genes in Ae. aegypti using quantitative real-time polymerase chain reaction. These genes were expressed in different stages and tissues. The messenger RNA (mRNA) levels for both genes were also up-regulated by Gram-negative bacteria Escherichia coli, Gram-positive bacteria Staphylococcus aureus and fungal Beauveria bassiana infections, as well as in the tissue injury experiments. RNAi-mediated knockdown of Ae-CLIPB15 led to a significant decrease of PO activity in the hemolymph of Ae. aegypti, while other RNAi experiments revealed that both Ae-CLIPB15 and Ae-CLIPB22 were involved in immune defense against bacterial and fungal infections. The mRNA expression of NF-κB transcription factors REL1 and REL2 in the Toll pathway and IMD pathway differed between Ae-CLIPB15 and Ae-CLIPB22 knockdown mosquitoes infected with bacteria and wild type mosquitoes infected with bacteria. Conclusions Our findings suggest that Ae-CLIPB15 and Ae-CLIPB22 play a critical role in mosquito innate immunity, and that they are involved in immune responses to injury and infection. Their regulation of transcription factors and PO activity indicates that they also play a specific role in the regulation of innate immunity. Graphical Abstract

AIM: To explore the effect of different energy parameters of femtosecond laser small incision lenticule extraction(SMILE)on stage Ⅰ opaque bubble layer(OBL)and visual quality. METHODS: A retrospective analysis of the clinical data of 216 patients(432 eyes)who came to our hospital for SMILE surgery from July 2018 to December 2019. According to whether stage Ⅰ OBL occurred, they were divided into OBL group(42 eyes)and non-OBL group(390 eyes). The age, visual acuity parameters, corneal parameters, microlens parameters and energy parameters were compared between the two groups, and multivariate regression analysis was used to analyze the relationship between the difference in energy settings and the OBL of stage Ⅰ. The uncorrected visual acuity(UCVA), best corrected visual acuity(BCVA), and modulation transfer function cut-off spatial frequency(MTFcut-off), Strehl Ratio(SR)and Objective Scattering Index(OSI)with energy parameters of 130, 135, 140, 145, and 150 nJ before and 1mo after surgery were compared. The correlation between energy parameters and stage Ⅰ OBL, UCVA, BCVA, MTFcut-off, SR, OSI were analyzed. RESULTS: Multivariate regression analysis showed that the energy setting with a difference of 5nJ did not show an association with stage Ⅰ OBL. In the different energy parameter groups, LogMAR UCVA, MTFcut-off, and OSI at 1mo after surgery were improved compared with preoperatively(P

Abstract Background Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

Objective: This network meta-analysis aimed to explore the effect of different drugs on mortality and neurological improvement in patients with traumatic brain injury (TBI), and to clarify which drug might be used as a more promising intervention for treating such patients by ranking.Methods: We conducted a comprehensive search from PubMed, Medline, Embase, and Cochrane Library databases from the establishment of the database to 31 January 2022. Data were extracted from the included studies, and the quality was assessed using the Cochrane risk-of-bias tool. The primary outcome measure was mortality in patients with TBI. The secondary outcome measures were the proportion of favorable outcomes and the occurrence of drug treatment–related side effects in patients with TBI in each drug treatment group. Statistical analyses were performed using Stata v16.0 and RevMan v5.3.0.Results: We included 30 randomized controlled trials that included 13 interventions (TXA, EPO, progesterone, progesterone + vitamin D, atorvastatin, beta-blocker therapy, Bradycor, Enoxaparin, Tracoprodi, dexanabinol, selenium, simvastatin, and placebo). The analysis revealed that these drugs significantly reduced mortality in patients with TBI and increased the proportion of patients with favorable outcomes after TBI compared with placebo. In terms of mortality after drug treatment, the order from the lowest to the highest was progesterone + vitamin D, beta-blocker therapy, EPO, simvastatin, Enoxaparin, Bradycor, Tracoprodi, selenium, atorvastatin, TXA, progesterone, dexanabinol, and placebo. In terms of the proportion of patients with favorable outcomes after drug treatment, the order from the highest to the lowest was as follows: Enoxaparin, progesterone + vitamin D, atorvastatin, simvastatin, Bradycor, EPO, beta-blocker therapy, progesterone, Tracoprodi, TXA, selenium, dexanabinol, and placebo. In addition, based on the classification of Glasgow Outcome Scale (GOS) scores after each drug treatment, this study also analyzed the three aspects of good recovery, moderate disability, and severe disability. It involved 10 interventions and revealed that compared with placebo treatment, a higher proportion of patients had a good recovery and moderate disability after treatment with progesterone + vitamin D, Bradycor, EPO, and progesterone. Meanwhile, the proportion of patients with a severe disability after treatment with progesterone + vitamin D and Bradycor was also low.Conclusion: The analysis of this study revealed that in patients with TBI, TXA, EPO, progesterone, progesterone + vitamin D, atorvastatin, beta-blocker therapy, Bradycor, Enoxaparin, Tracoprodi, dexanabinol, selenium, and simvastatin all reduced mortality and increased the proportion of patients with favorable outcomes in such patients compared with placebo. Among these, the progesterone + vitamin D had not only a higher proportion of patients with good recovery and moderate disability but also a lower proportion of patients with severe disability and mortality. However, whether this intervention can be used for clinical promotion still needs further exploration.

Rhipicephalus sanguineus, the brown dog tick, is the most widespread tick in the world and a predominant vector of multiple pathogens affecting wild and domestic animals. There is an increasing interest in understanding the role of tick microbiome in pathogen acquisition and transmission as well as in environment–vector interfaces. Several studies suggested that the tick microbial communities are under the influence of several factors including the tick species, dietary bloodmeal, and physiological stress. Compared with insects, very little of the microbial community is known to contribute to the nutrition of the host. Therefore, it is of significance to elucidate the regulation of the microbial community of Rh. Sanguineus under starvation stress. Starvation stress was induced in wild-type adults (1 month, 2 months, 4 months, 6 months) and the microbial composition and diversity were analyzed before and after blood feeding. After the evaluation, it was found that the microbial community composition of Rh. sanguineus changed significantly with starvation stress. The dominant symbiotic bacteria Coxiella spp. of Rh. sanguineus gradually decreased with the prolongation of starvation stress. We also demonstrated that the starvation tolerance of Rh. sanguineus was as long as 6 months. Next, Coxiella-like endosymbionts were quantitatively analyzed by fluorescence quantitative PCR. We found a pronounced tissue tropism in the Malpighian tubule and female gonad, and less in the midgut and salivary gland organs. Finally, the blood-fed nymphs were injected with ofloxacin within 24 h. The nymphs were allowed to develop into adults. It was found that the adult blood-sucking rate, adult weight after blood meal, fecundity (egg hatching rate), and feeding period of the newly hatched larvae were all affected to varying degrees, indicating that the removal of most symbiotic bacteria had an irreversible effect on it.

Plateau pikas (Ochotona curzoniae) are high-altitude model animals and famous “ecosystem engineers” on the Qinghai-Tibet Plateau. Pika activities may accelerate the degradation of alpine meadows. Nevertheless, little is known about the responses of bacterial, fungal, and archaeal communities, and ecosystem multifunctionality to pika perturbations. To address this question, we studied the impacts of only pika disturbance and combined disturbance (pika disturbance and grazing) on ecological networks of soil microbial communities and ecosystem multifunctionality. Our results demonstrated that Proteobacteria, Ascomycota, and Crenarchaeota were dominant in bacteria, fungi, and archaea, respectively. Bacteria, fungi, and archaea were all influenced by the combined disturbance of grazing and pika. Most fungal communities became convergent, while bacterial and archaeal communities became differentiated during the succession of surface types. In particular, the bacterial and fungal networks were less stable than archaeal networks. In response to the interference, cross-domain cooperation between bacterial and fungal communities increased, while competitive interactions between bacterial and archaeal communities increased. Pika disturbance at high intensity significantly reduced the ecosystem multifunctionality. However, the mixed effects of grazing and pika weakened such influences. This study revealed how pika activities affected microbial networks and ecosystem multifunctionality. These results provide insights to designing reasonable ecological management strategies for alpine grassland ecosystems.

Recently, fibroblast activation protein (FAP), an overexpressed transmembrane protein of activated fibroblast in pulmonary fibrosis, has been considered as the new target for diagnosing and treating pulmonary fibrosis. In this work, mesoporous polydopamine (MPDA), which is facile prepared and easily modified, is developed as a carrier to load antifibrosis drug pirfenidone (PFD) and linking FAP inhibitor (FAPI) to realize lesion-targeted drug delivery for pulmonary fibrosis therapy. We have found that PFD@MPDA-FAPI is well biocompatible and with good properties of antifibrosis, when ICG labels MPDA-FAPI, the accumulation of the nanodrug at the fibrosis lung in vivo can be observed by NIR imaging, and the antifibrosis properties of PFD@MPDA-FAPI in vivo were also better than those of pure PFD and PFD@MPDA; therefore, the easily produced and biocompatible nanodrug PFD@MPDA-FAPI developed in this study is promising for further clinical translations in pulmonary fibrosis antifibrosis therapy.

The global impact of mosquito-borne diseases has increased significantly over recent decades. Ebinur Lake virus (EBIV), a newly classified orthobunyavirus, is reported to be highly pathogenic in adult mice. The evaluation of vector competence is essential for predicting the arbovirus transmission risk. Here, Aedes aegypti was applied to evaluate EBIV infection and dissemination in mosquitos. Our experiments indicated that Ae. aegypti had the possibility to spread EBIV (with a transmission rate of up to 11.8% at 14 days post-infection) through biting, with the highest viral dose in a single mosquito's saliva reaching 6.3 plaque-forming units. The highest infection, dissemination and ovary infection rates were 70%, 42.9%, and 29.4%, respectively. The high viral infection rates in Ae. aegypti ovaries imply the possibility of EBIV vertical transmission. Ae. aegypti was highly susceptible to intrathoracic infection and the saliva-positive rate reached 90% at 10 days post-infection. Transcriptomic analysis revealed Toll and Imd signaling pathways were implicated in the mosquito's defensive response to EBIV infection. Defensin C and chitinase 10 were continuously downregulated in mosquitoes infected via intrathoracic inoculation of EBIV. Comprehensive analysis of the vector competence of Ae. aegypti for EBIV in laboratory has indicated the potential risk of EBIV transmission through mosquitoes. Moreover, our findings support a complex interplay between EBIV and the immune system of mosquito, which could affect its vector competence.

Urban parks reduce air temperatures within parks and surroundings by exerting the cooling island effect, significant for mitigating the urban microclimate. However, the park cooling effect may be influenced by the surrounding building configuration, and this needs to be studied in more detail, in particular, to explore how to maximize the cooling effect of parks by adjusting the surrounding building configuration. Thus, in this study, the effects of building height, building interval, and building orientation on the cooling effect of a small urban park were investigated using field measurements and ENVI-met numerical simulations. The results demonstrated that (1) building height, building interval, and building orientation all impact the park cooling effect, but their impacts vary. (2) Building height had the strongest effect on the park cooling intensity, and adjusting building height provided the maximum park cooling intensity (1.2 °C). (3) Building orientation had the most effect on the park cooling distance, 100 m downwind of the park. (4) The park cooling effect is best when the surrounding buildings were parallel to the prevailing wind direction, and the park cool island has the greatest intensity and range. This study can guide decision-makers in optimizing building configuration to maximize the park cooling effect.

Anaplasmosis is a serious infection which is transmitted by ticks and mosquitos. There are very few reports and studies that have been carried out to understand the prevalence, distribution, and epidemiological profile of Anaplasma spp. infection in dogs in Hainan province/island. In the present study, we have tried to understand the prevalence, distribution, and occurrence of Anaplasma spp. infections in dogs (n = 1051) in Hainan Island/Province to establish a surveillance-based study. The confirmed positive samples by Polymerase chain reaction (PCR) were subjected to capillary sequencing for further strain-specific confirmation, followed by the construction of phylogenetic trees to determine their genetic relations. Various statistical tools were used to analyze related risk factors. There were three species of Anaplasma detected from the Hainan region; namely, A. phagocytophilum, A. bovis, and A. platys. The overall prevalence of Anaplasma is 9.7% (102/1051). A. phagocytopihum was prevalent in 1.0% of dogs (11/1051), A. bovis was found in 2.7% of dogs (28/1051), and A. platys in 6.0% of dogs (63/1051). Our surveillance-based study conducted to understand the occurrence and distribution pattern of Anaplasma spp. in Hainan will help in designing effective control measures along with management strategies so as to treat and control the infection in the area.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

ObjectivesThe purpose of this study was to investigate the baseline independent risk factors for predicting 6-month mortality of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM) and develop a matrix prediction model formed by these risk factors.MethodsThe hospitalized patients with DM who completed at least 6-month follow-up were recruited as a derivation cohort. The primary exposure was defined as positive anti-MDA5 at the baseline. The primary outcome was all-cause 6-month mortality after enrollment. A matrix prediction model was developed in the derivation cohort, and another published cohort was used for external validation.ResultsIn derivation cohort, 82 patients with DM were enrolled (mean age of onset 50 ± 11 years and 63% women), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489–17.708), arthritis (OR: 5.184, 95%CI: 1.455–18.467), interstitial lung disease (OR: 7.034, 95%CI: 1.157–42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002–1.017) were the independent associators with positive anti-MDA5 in patients with DM. Patients with anti-MDA5-positive DM had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30 vs. 0%). Among the patients with anti-MDA5-positive DM, compared to the survivors, non-survivors had significantly advanced age of onset (59 ± 6 years vs. 46 ± 9 years), higher rates of fever (75 vs. 18%), positive carcinoma embryonic antigen (CEA, 75 vs. 14%), higher level of ferritin (median 2,858 ug/L vs. 619 ug/L, all p < 0.05). A stepwise multivariate Cox regression showed that ferritin ≥1,250 μg/L (HR: 10.4, 95%CI: 1.8–59.9), fever (HR: 11.2, 95%CI: 2.5–49.9), and positive CEA (HR: 5.2, 95%CI: 1.0–25.7) were the independent risk factors of 6-month mortality. A matrix prediction model was built to stratify patients with anti-MDA5-positive DM into different subgroups with various probabilities of 6-month mortality risk. In an external validation cohort, the observed 6-month all-cause mortality was 78% in high-risk group, 43% in moderate-risk group, and 25% in low-risk group, which shows good accuracy of the model.ConclusionBaseline characteristics such as fever, ferritin ≥1,250 μg/L, and positive CEA are the independent risk factors for 6-month all-cause mortality in patients with anti-MDA5-positive DM. A novel matrix prediction model composed of these three clinical indicators is first proposed to provide a chance for the exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk.

Abstract Detection of chemical cues via chemosensory receptor proteins are essential for most animals, and underlies critical behaviors, including location and discrimination of food resources, identification of sexual partners and avoidance of predators. The current knowledge of how chemical cues are detected is based primarily on data acquired from studies on insects, while our understanding of the molecular basis for chemoreception in acari, mites in particular, remains limited. The poultry red mite (PRM), Dermanyssus gallinae, is one of the most important blood-feeding ectoparasites of poultry. PRM are active at night which suck the birds' blood during periods of darkness and hide themselves in all kinds of gaps and cracks during the daytime. The diversity in habitat usage, as well as the demonstrated host finding and avoidance behaviors suggest that PRM relies on their sense of smell to orchestrate complex behavioral decisions. Comparative transcriptome analyses revealed the presence of candidate variant ionotropic receptors, odorant binding proteins, niemann-pick proteins type C2 and sensory neuron membrane proteins. Some of these proteins were highly and differentially expressed in the forelegs of PRM. Rhodopsin-like G protein-coupled receptors were also identified, while insect-specific odorant receptors and odorant co-receptors were not detected. Furthermore, using scanning electron microscopy, the tarsomeres of all leg pairs were shown to be equipped with sensilla chaetica with or without tip pores, while wall-pored olfactory sensilla chaetica were restricted to the distal-most tarsomeres of the forelegs. This study is the first to describe the presence of chemosensory genes in any Dermanyssidae family. Our findings make a significant step forward in understanding the chemosensory abilities of D. gallinae.

Abstract Background Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development. Results In the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression. Conclusions Our investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

Background and objective: Idiopathic pulmonary fibrosis (IPF) is an aggressive fibrotic pulmonary disease with spatially and temporally heterogeneous alveolar lesions. There are no early diagnostic biomarkers, limiting our understanding of IPF pathogenesis.Methods: Lung tissue from surgical lung biopsy of patients with early-stage IPF (n = 7), transplant-stage IPF (n = 2), and healthy controls (n = 6) were subjected to mRNA sequencing and verified by real-time quantitative PCR (RT-qPCR), immunohistochemistry, Western blot, and single-cell RNA sequencing (scRNA-Seq).Results: Three hundred eighty differentially expressed transcripts (DETs) were identified in IPF that were principally involved in extracellular matrix (ECM) remodeling, lipid metabolism, and immune effect. Of these DETs, 21 (DMD, MMP7, POSTN, ECM2, MMP13, FASN, FADS1, SDR16C5, ACAT2, ACSL1, CYP1A1, UGT1A6, CXCL13, CXCL5, CXCL14, IL5RA, TNFRSF19, CSF3R, S100A9, S100A8, and S100A12) were selected and verified by RT-qPCR. Differences in DMD, FASN, and MMP7 were also confirmed at a protein level. Analysis of scRNA-Seq was used to trace their cellular origin to determine which lung cells regulated them. The principal cell sources of DMD were ciliated cells, alveolar type I/II epithelial cells (AT cells), club cells, and alveolar macrophages (AMs); MMP7 derives from AT cells, club cells, and AMs, while FASN originates from AT cells, ciliated cells, and AMs.Conclusion: Our data revealed a comprehensive transcriptional mRNA profile of IPF and demonstrated that ECM remodeling, lipid metabolism, and immune effect were collaboratively involved in the early development of IPF.

Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

Long-chain fatty acid elongases (ELOs) play important roles in the metabolism of fatty acids in insects. In this study, the genes for two elongases from Aedes aegypti were identified, AeELO2 and AeELO9. Quantitative real time PCR showed that AeELO2 and AeELO9 are expressed at all developmental stages and some body parts, but with different expression patterns. RNAi-mediated knockdown of AeELO2 and AeELO9 was performed to investigate their roles in the development, growth, osmotic balance, and cold tolerance of Ae. aegypti. Knockdown of AeELO2 slowed larval growth and development by causing molting abnormalities. Additionally, 33% ± 3.3% of adults died during oviposition, accompanied by an abnormal extension of cuticles in AeELO2-dsRNA knockdown mosquitos. Knockdown of AeEL09 resulted in abnormal balance of cuticular osmotic pressure and a reduction in egg production. The maximal mRNAs of AeELO2 and AeELO9 were detected in eggs at 72 h after oviposition. Moreover, AeELO2 knockdown reduced the egg hatching rates and AeELO9 knockdown larvae did not develop well. In summary, AeELO2 is involved in larval molting and growth, and its knockdown affects the flexibility and elasticity of adult mosquito cuticles. AeELO9 regulates cold tolerance, osmotic balance, and egg development in Ae. aegypti.

Objectives: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5+ DM-ILD) is a life-threatening disease. The current study aimed to quantitatively assess the pulmonary high-resolution computed tomography (HRCT) images of MDA5+ DM-ILD by applying the radiomics approach and establish a multidimensional risk prediction model for the 6-month mortality.Methods: This retrospective study was conducted in 228 patients from two centers, namely, a derivation cohort and a longitudinal internal validation cohort in Renji Hospital, as well as an external validation cohort in Guangzhou. The derivation cohort was randomly divided into training and testing sets. The primary outcome was 6-month all-cause mortality since the time of admission. Baseline pulmonary HRCT images were quantitatively analyzed by radiomics approach, and a radiomic score (Rad-score) was generated. Clinical predictors selected by univariable Cox regression were further incorporated with the Rad-score, to enhance the prediction performance of the final model (Rad-score plus model). In parallel, an idiopathic pulmonary fibrosis (IPF)-based visual CT score and ILD-GAP score were calculated as comparators.Results: The Rad-score was significantly associated with the 6-month mortality, outperformed the traditional visual score and ILD-GAP score. The Rad-score plus model was successfully developed to predict the 6-month mortality, with C-index values of 0.88 [95% confidence interval (CI), 0.79–0.96] in the training set (n = 121), 0.88 (95%CI, 0.71–1.0) in the testing set (n = 31), 0.83 (95%CI, 0.68–0.98) in the internal validation cohort (n = 44), and 0.84 (95%CI, 0.64–1.0) in the external validation cohort (n = 32).Conclusions: The radiomic feature was an independent and reliable prognostic predictor for MDA5+ DM-ILD.

Background: Ovarian cancer is the most lethal gynecological malignancy, and chemotherapy remains the cornerstone for ovarian cancer management. Due to the unsatisfactory prognosis, a better understanding of the underlying molecular carcinogenesis is urgently required. Methods: Assays for determining cell growth, cell motility, and apoptosis were employed to evaluate the potential antitumor effects of metformin against ovarian cancer cells. Molecular biological methods were employed to explore the underlying mechanism. Human ovarian cancer samples and Gene Expression Profiling Interactive Analysis (GEPIA) dataset were used for uncovering the clinical significances of mesothelin (MSLN) on ovarian cancer. Results: In the present work, we found that metformin treatment led to cell growth and cell migration inhibition, and induced cell apoptosis. Metformin administration also impaired cancer cell stemness and the capillary-like structure formation capacity of SKOV3 cells. On mechanism, metformin treatment remarkably reduced mesothelin (MSLN) expression, downregulated IL-6/STAT3 signaling activity, subsequently resulted in VEGF and TGFβ1 expression. We also observed an oncogenic function of MSLN on ovarian cancer. Conclusions: Collectively, our findings suggested that metformin exerts anticancer effects by suppressing ovarian cancer cell malignancy, which attributed to MSLN inhibition mediated IL6/STAT3 signaling and VEGF and TGFβ1 downregulation.