Crosstalk between CD8+ T cells and mesenchymal stromal cells in intestine homeostasis and immunity.

The intestine represents the most complex cellular network in the whole body. It is constantly faced with multiple types of immunostimulatory agents encompassing from food antigen, gut microbiome, metabolic waste products, and dead cell debris. Within the intestine, most T cells are found in three primary compartments: the organized gut-associated lymphoid tissue, the lamina propria, and the epithelium. The well-orchestrated epithelial-immune-microbial interaction is critically important for the precise immune response. The main role of intestinal mesenchymal stromal cells is to support a structural framework within the gut wall. However, recent evidence from stromal cell studies indicates that they also possess significant immunomodulatory functions, such as maintaining intestinal tolerance via the expression of PDL1/2 and MHC-II molecules, and promoting the development of CD103+ dendritic cells, and IgA+ plasma cells, thereby enhancing intestinal homeostasis. In this review, we will summarize the current understanding of CD8+ T cells and stromal cells alongside the intestinal tract and discuss the reciprocal interactions between T subsets and mesenchymal stromal cell populations. We will focus on how the tissue residency, migration, and function of CD8+ T cells could be potentially regulated by mesenchymal stromal cell populations and explore the molecular mediators, such as TGF-ß, IL-33, and MHC-II molecules that might influence these processes. Finally, we discuss the potential pathophysiological impact of such interaction in intestine hemostasis as well as diseases of inflammation, infection, and malignancies.

An insight into the gut microbiota after Schistosoma japonicum eggs immunization in an experimental ulcerative colitis model.

Schistosome infection and schistosome-derived products have been implicated in the prevention and alleviation of inflammatory bowel disease by manipulating the host immune response, whereas the role of gut microbiota in this protective effect remains poorly understood. In this study, we found that the intraperitoneal immunization with Schistosoma japonicum eggs prior to dextran sulfate sodium (DSS) application significantly ameliorated the symptoms of DSS-induced acute colitis, which was characterized by higher body weight, lower disease activity index score and macroscopic inflammatory scores. We demonstrated that the immunomodulatory effects of S. japonicum eggs were accompanied by an influence on gut microbiota composition, abundance, and diversity, which increased the abundance of genus Turicibacter, family Erysipelotrichaceae, phylum Firmicutes, and decreased the abundance of genus Odoribacter, family Marinifilaceae, order Bacteroidales, class Bacteroidia, phylum Bacteroidota. In addition, Lactobacillus was identified as a biomarker that distinguishes healthy control mice from DSS-induced colitis mice. The present study revealed the importance of the gut microbiota in S. japonicum eggs exerting protective effects in an experimental ulcerative colitis (UC) model, providing an alternative strategy for the discovery of UC prevention and treatment drugs.

A real-world evaluation of the diagnostic accuracy of radiologists using positive predictive values verified from deep learning and natural language processing chest algorithms deployed retrospectively.

Objectives: This diagnostic study assessed the accuracy of radiologists retrospectively, using the deep learning and natural language processing chest algorithms implemented in Clinical Review version 3.2 for: pneumothorax, rib fractures in digital chest X-ray radiographs (CXR); aortic aneurysm, pulmonary nodules, emphysema, and pulmonary embolism in CT images. Methods: The study design was double-blind (artificial intelligence [AI] algorithms and humans), retrospective, non-interventional, and at a single NHS Trust. Adult patients (≥18 years old) scheduled for CXR and CT were invited to enroll as participants through an opt-out process. Reports and images were de-identified, processed retrospectively, and AI-flagged discrepant findings were assigned to two lead radiologists, each blinded to patient identifiers and original radiologist. The radiologist's findings for each clinical condition were tallied as a verified discrepancy (true positive) or not (false positive). Results: The missed findings were: 0.02% rib fractures, 0.51% aortic aneurysm, 0.32% pulmonary nodules, 0.92% emphysema, and 0.28% pulmonary embolism. The positive predictive values (PPVs) were: pneumothorax (0%), rib fractures (5.6%), aortic dilatation (43.2%), pulmonary emphysema (46.0%), pulmonary embolus (11.5%), and pulmonary nodules (9.2%). The PPV for pneumothorax was nil owing to lack of available studies that were analysed for outpatient activity. Conclusions: The number of missed findings was far less than generally predicted. The chest algorithms deployed retrospectively were a useful quality tool and AI augmented the radiologists' workflow. Advances in knowledge: The diagnostic accuracy of our radiologists generated missed findings of 0.02% for rib fractures CXR, 0.51% for aortic dilatation, 0.32% for pulmonary nodule, 0.92% for pulmonary emphysema, and 0.28% for pulmonary embolism for CT studies, all retrospectively evaluated with AI used as a quality tool to flag potential missed findings. It is important to account for prevalence of these chest conditions in clinical context and use appropriate clinical thresholds for decision-making, not relying solely on AI.

The impact of MIF deficiency on alterations of fecal microbiota in C57BL/6 mice induced by Trichinella spiralis infection.

Trichinellosis caused by Trichinella spiralis (T. spiralis) is a major food-borne parasitic zoonosis worldwide. Prevention of trichinellosis is an effective strategy to improve patient quality of life. Macrophage migration inhibitory factor (MIF) is closely related to the occurrence and development of several parasitic diseases. Studying the impact of MIF deficiency (Mif-/- ) on the alterations in host fecal microbiota due to T. spiralis infection may contribute to proposing a novel dual therapeutic approach for trichinellosis. To reveal the diversity and differences in fecal microbial composition, feces were collected from T. spiralis-uninfected and T. spiralis-infected wild-type (WT) and MIF knockout (KO) C57BL/6 mice at 0, 7, 14, and 35 days post-infection (dpi), and the samples were sent for 16S rRNA amplicon sequencing on the Illumina NovaSeq platform. Flow cytometry was used to determine the expression levels of IFN-γ and IL-4 in the CD4+ /CD8+ T-cell sets of mouse spleens. The results showed that operational taxonomic unit (OTU) clustering, relative abundance of microbial composition, alpha diversity, and beta diversity exhibited significant changes among the eight groups. The LEfSe analysis selected several potential biomarkers at the genus or species level, including Akkermansia muciniphila, Lactobacillus murinus, Coprococcus catus, Firmicutes bacterium M10_2, Parabacteroides sp. CT06, and Bacteroides between the KTs and WTs groups. The predicted bacterial functions of the fecal microbiota were mainly involved in metabolism, such as the metabolism of carbohydrates, amino acids, energy, cofactors, vitamins, nucleotides, glycans, and lipids. Flow cytometry revealed an increased CD3+ CD8- /CD3+ CD8+ T-cell ratio and increased IFN-γ and IL-4 levels in CD3+ CD8- T-cell sets from WT and MIF KO mice at 7 dpi. The results indicated that both MIF KO and infection time have a significant influence on the CD3+ CD8- IFN-γ+ and CD3+ CD8- IL-4+ response in mice after T. spiralis. In conclusion, this research showed alterations of the fecal microbiota and immune response in both WT and MIF KO mice before and after T. spiralis infection. These results revealed a potential role of MIF in regulating the pathogenesis of trichinellosis related to the intestinal microbiota. Importantly, the selected potential biomarkers combined with MIF will also offer a novel therapeutic approach to treat trichinellosis in the future.

Regulation of CD8+ T memory and exhaustion by the mTOR signals.

CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.

Cardiac exposure in left-sided breast cancer patients undergoing deep inspiratory breath hold radiation therapy.

Background: Left-sided breast cancer (BC) patients undergoing post-operative radiation therapy (PRT) may have higher risk of late cardiovascular toxicity, which may be reduced by hearth-sparing RT techniques. This study evaluated dosimetric parameters of the deep inspiration breath hold (DIBH) compared to free breathing (FB) RT. We analysed factors impacting on doses to the heart and cardiac substructures and sought anatomic factors allowing patient selection for DIBH. Methods: The study group included 67 left-sided BC patients who underwent RT after breast-conserving surgery or mastectomy. Patients treated with DIBH were trained to hold their breath. Computed tomography (CT) scans were performed in both FB and DIBH patients. Plans were generated using 3-dimensional (3D) conformal RT. The dosimetric variables were obtained from dose-volume histograms, and the anatomical variables were derived from the CT scans. The variables in the two groups were compared by t-test, the U test, and the chi-squared test. Correlation analysis was performed using Pearson's correlation coefficient. Receiver operating characteristic curves were used to analyze the efficacy of the predictors. Results: Compared to the FB, DIBH allowed for a mean dose reduction to the heart, left anterior descending coronary artery (LAD), left ventricle (LV), and right ventricle (RV) by 30.0%, 38.7%, 39.3%, and 34.7%, respectively. DIBH markedly increased the heart height (HH), heart chest wall distance (HCWD), the mean distance between the ipsilateral lung and breast (DBIB), and decreased the heart-chest wall length (HCWL) (P<0.05). The different value of HH, DBIB, HCWL, and HCWD between DIBH and FB were 1.31, 1.95, -0.67, and 0.22 cm, respectively (all P<0.05). ΔHH was an independent predictor of the mean dose to the heart, LAD, LV, and RV, with the area under the curve values of 0.818, 0.725, 0.821, and 0.820, respectively. Conclusions: DIBH significantly reduced the dose to the entire heart and its substructures in left-sided BC patients undergoing post-operative RT. ΔHH predicts the mean dose to the heart and its substructures. These results may inform patient selection for DIBH.

Transcriptional profile of Trichomonas vaginalis in response to metronidazole.

BACKGROUND: Trichomoniasis caused by Trichomonas vaginalis, combined with its complications, has long frequently damaged millions of human health. Metronidazole (MTZ) is the first choice for therapy. Therefore, a better understanding of its trichomonacidal process to ultimately reveal the global mechanism of action is indispensable. To take a step toward this goal, electron microscopy and RNA sequencing were performed to fully reveal the early changes in T. vaginalis at the cellular and transcriptome levels after treatment with MTZ in vitro. RESULTS: The results showed that the morphology and subcellular structures of T. vaginalis underwent prominent alterations, characterized by a rough surface with bubbly protrusions, broken holes and deformed nuclei with decreased nuclear membranes, chromatin and organelles. The RNA-seq data revealed a total of 10,937 differentially expressed genes (DEGs), consisting of 4,978 upregulated and 5,959 downregulated genes. Most DEGs for the known MTZ activators, such as pyruvate:ferredoxin oxidoreductase (PFOR) and iron-sulfur binding domain, were significantly downregulated. However, genes for other possible alternative MTZ activators such as thioredoxin reductase, nitroreductase family proteins and flavodoxin-like fold family proteins, were dramatically stimulated. GO and KEGG analyses revealed that genes for basic vital activities, proteostasis, replication and repair were stimulated under MTZ stress, but those for DNA synthesis, more complicated life activities such as the cell cycle, motility, signaling and even virulence were significantly inhibited in T. vaginalis. Meanwhile, increased single nucleotide polymorphism (SNP) and insertions - deletions (indels) were stimulated by MTZ. CONCLUSIONS: The current study reveals evident nuclear and cytomembrane damage and multiple variations in T. vaginalis at the transcriptional level. These data will offer a meaningful foundation for a deeper understanding of the MTZ trichomonacidal process and the transcriptional response of T. vaginalis to MTZ-induced stress or even cell death.

Prognostic value of 18F-FDG lesion dissemination features in patients with peripheral T-cell lymphoma (PTCL).

PURPOSE: To explore the prognostic value of the distance between the two lesions that were farthest apart (Dmax) on baseline 18F-FDG PET/CT in peripheral T lymphoma (PTCL) and establish a new prognostic model for predicting the survival outcomes of patients with PTCL. METHODS: In this study, a retrospective analysis of 95 patients with PTCL who underwent baseline 18F-FDG PET/CT was performed to assess the predictive value of Dmax. The total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), standardized uptake value (SUV), and Dmax were calculated with LIFEx software. Progression-free survival (PFS) and overall survival (OS) were used as endpoints. The prognostic model was developed based on the results of the multivariate analysis. The time-dependent area under the ROC curve (tdAUC), calibration curves, Harrell C-index, and decision curve analysis (DCA) were used to assess the model. RESULTS: Patients were followed up for a median of 17.0 months. Multivariate analysis showed that bone marrow biopsy (BMB) and Dmax were independent predictors of PFS (HR: 1.889, P = 0.039; HR: 1.965, P = 0.047) and OS (HR: 1.923, P = 0.031; HR: 1.982, P = 0.034). The model consisting of Dmax, TMTV, and BMB had substantial prognostic value for survival outcomes of PTCL and could successfully identify four groups of patients with significantly different prognoses (χ2 = 13.731, P = 0.003 for PFS; χ2 = 11.841, P = 0.008 for OS). The tdAUC, C-index, calibration curves, and DCA supported that the model was superior to the prognostic index for T-cell lymphoma (PIT) and International Prognostic Index (IPI) scores. CONCLUSION: BMB and Dmax were independent predictors of PTCL in our study. Moreover, a prognostic model based on the Dmax, TMTV, and BMB could be useful for predicting the survival outcomes of patients with PTCL.

Prognostic value of the cervical lymph node necrosis ratio in nasopharyngeal carcinoma.

PURPOSE: Whether cervical lymph node necrosis (CNN) is an independent adverse prognostic factor in nasopharyngeal carcinoma (NPC) has not been determined. In this study, the CNN ratio was graded quantitatively to explore the prognostic value in NPC. PARTICIPANTS AND METHODS: We retrospectively reviewed a total of 648 pathologically confirmed as NPC. We outlined metastatic lymph nodes and necrotic area of lymph nodes slice by slice on the magneticresonanceimages (MRI) cross section, and calculated the corresponding CNN ratio. RESULTS: The median CNN ratio (17.37 %) was taken as the cut-off point, 256 (39.51 %) patients were divided into CNN1 group (<17.37 %, n = 128) and CNN2 group (≥17.37 %, n = 128), 392 (60.49 %) patients without lymph nodes necrosis were CNN0. Among the CNN0, CNN1 and CNN2 groups, five-year overall survival (OS) was 82.4 %, 76.6 % and 71.1 %, locoregional recurrence-free survival (LRRFS) was 91.3 %, 91.1 % and 90.5 %, distant metastasis-free survival (DMFS) was 83.7 %, 78.5 % and 68.7 %, progression-free survival (PFS) was 78.3 %, 71.7 % and 61.6 % respectively. By multivariate analysis, CNN was an independent prognostic factor for OS (P = 0.003), DMFS (P = 0.019) and PFS (P = 0.007). More than 3 cycles of chemotherapy significantly increased OS (P = 0.024) and DMFS (P = 0.015) in the CNN1 group. CONCLUSIONS: This study indicated that CNN is one of the factors with the negative prognosis of NPC. The CNN ratio might be used as one of the reference factors in the formulation of individualized treatment plan.

Influence of Heat Treatment on Microstructure, Mechanical Property, and Corrosion Behavior of Cold-Sprayed Zn Coating on Mg Alloy Substrate.

The influence of post-process heat treatment on cold-sprayed Zn coatings on the Mg alloy substrate was investigated at different temperatures (150, 250, and 350 °C) and times (2, 8, and 16 h). Phase, microstructure, microhardness, and tensile strength of Zn coatings were analyzed before and after heat treatment. Corrosion properties of Zn coatings after heat treatment were investigated in simulated body fluid by using potentiodynamic polarization and immersion testing. Results show that although the heat treatment presented little effect on phase compositions of Zn coatings, the full width at half maxima of the Zn phase decreased with the heat temperature and time. Zn coatings presented comparable microstructures before and after heat treatment in addition to the inter-diffusion layers, and the inter-diffusion layer was dependent on the heat temperature and time. Both the thickness and the microhardness of inter-diffusion layers were increased with the heat temperature and time, with the largest thickness of 704.1 ± 32.4 µm and the largest microhardness of 323.7 ± 104.1 HV0.025 at 350 °C for 2 h. The microhardness of Zn coating was significantly decreased from 70.8 ± 5.6 HV0.025 to 43.9 ± 12.5 HV0.025, with the heat temperature from the ambient temperature to 350 °C, and was slightly decreased with the heat time at 250 °C. Although the tensile strength of Zn coating was slightly increased by heat treatment, with the highest value of 40.9 ± 3.9 MPa at 150 °C for 2 h, excessive heat temperature and time were detrimental to the tensile strength, with the lowest value of 6.6 ± 1.6 MPa at 350 °C for 2 h. The heat temperature and heat time presented limited effects on the corrosion current and corrosion ratio of the Zn coatings, and Zn coatings before and after heat treatment effectively hindered the simulated body fluid from penetrating into the substrate. The corrosion behavior of Zn coatings was discussed in terms of corrosion products and microstructures after immersion.

In Vitro Antioxidant Properties and Phenolic Profile of Acid Aqueous Ethanol Extracts from Torreya grandis Seed Coat.

Torreya grandis is an important economic forestry product in China, whose seeds are often consumed as edible nuts, or used as raw materials for oil processing. To date, as an important by-product of Torreya grandis, comprehensive studies regarding the Torreya grandis seed coat phenolic composition are lacking, which greatly limits its in-depth use. Therefore, in the present study, the Torreya grandis seed coat was extracted by acid aqueous ethanol (TE), and NMR and UHPLC-MS were used to identify the major phenolics. Together with the already known phenolics including protocatechuic acid, catechin, epigallocatechin gallate, and epicatechin gallate, the unreported new compound 2-hydroxy-2-(4-hydroxyphenylethyl) malonic acid was discovered. The results of the antioxidant properties showed that both TE and 2-hydroxy-2-(4-hydroxyphenylethyl) malonic acid exhibited strong ABTS, DPPH, and hydroxyl radical-scavenging activity, and significantly improved the O/W emulsion's oxidation stability. These results indicate that the TE and 2-hydroxy-2-(4-hydroxyphenylethyl) malonic acid could possibly be used in the future to manufacture functional foods or bioactive ingredients. Moreover, further studies are also needed to evaluate the biological activity of TE and 2-hydroxy-2-(4-hydroxyphenylethyl) malonic acid to increase the added value of Torreya grandis by-products.

Deficiency of migration inhibitory factor influences the gut microbiota of C57BL/6 mice infected with Plasmodium berghei ANKA.

Cerebral malaria (CM), as one of the most common complications in severe malaria, has threatened millions of individuals' neurological health and even their lives. Macrophage migration inhibitory factor (MIF), a pleiotropic proinflammatory factor in humans, seems to be a risk factor for death in patients with CM, but its functional mechanism remains unclear. To verify whether affecting the intestinal microbes of the host was one of the mechanisms by which MIF regulates CM, C57BL/6 mice, including WT + PbA, MIF-KO + PbA and their uninfected controls, were sent for 16S rRNA-based sequencing targeting the V4 region of the intestinal microbiota through the Illumina MiSeq platform. The results showed that OTU clustering, alpha and beta diversity in the four groups involved had evident variation. The relative abundance at different taxonomic levels, especially the dominant intestinal flora, was obviously changed. The LEfSe analysis screened out several biomarkers, including significantly reduced Ligilactobacillus (Lactobacillus murinus) in WPbA mice compared to the WT group and Akkermansia (Akkermansia_muciniphila) in KPbA mice compared to the WPbA group. For MIF KO groups, mice infected with PbA or uninfected showed significant enrichment of producers of short-chain fatty acids, including Dubosiella and Faecalibaculum (Faecalibaculum rodentium) in KPbA, and Lachnospiraceae_NK4A136_group and Firmicutes_bacterium_M10-2 in KO. This study not only further proved the gut microbiota changes in C57BL/6 mice caused by PbA infection, but also found that MIF deletion directly affected the changes in the gut microbiota of C57BL/6 mice before and after PbA infection. This finding reveals a potential mechanism by which MIF regulates CM. Combining MIF with potential microbial biomarkers will provide a promising idea to develop combined drugs for improving CM in the future.

Differentially Expressed Genes in Nasopharyngeal Carcinoma Tissues and Their Correlation with Recurrence and Metastasis of Nasopharyngeal Carcinoma.

In this study, bioinformatics tools were used to identify key genes to study the molecular mechanism of nasopharyngeal carcinoma (NPC) development and to explore the correlation of these key genes with the recurrence and metastasis of NPC. The GSE61218 microarray dataset obtained from the Gene Expression Omnibus Database (GEO) was used. The limma R package was used to screen differentially expressed genes (DEGs) between NPC and normal nasopharyngeal (NP) tissues. KEGG functional enrichment was performed on these selected DEGs. Protein-protein interaction (PPI) networks were constructed using Cytoscape software to identify key node proteins. The NPC-metastasis microarray dataset GSE103611 was obtained from GEO to analyze the expression of DEGs in NPC metastasis. A total of 239 DEGs were identified. DEGs were mainly enriched in oocyte maturation-related pathways, cytokine-related pathways, cell cycle-related pathways, cancer-related pathways, and homologous recombination-related pathways. In addition, the top 10 nodes with the higher degree in the DEG PPI network were as follows: CDK1, CCNB2, BUB1, CCNA2, AURKB, BUB1B, MAD2L1, NDC80, BIRC5, and CENPF. The results indicated that DEGs may be involved in the pathogenesis of NPC by regulating cell cycle and mitosis, which can be used as molecular biomarkers for the diagnosis of NPC. In addition, we identified 87 DEGs with FC > 2 and P < 0.01 from the metastasis spectrum of NPC. The intersection gene between DEGs of NPC and normal NP tissue samples and those of the metastatic spectrum of NPC was identified to be VRK2. The expression of VRK2 in NPC samples was significantly higher than that in normal NP tissue, and similarly, VRK2 expression was significantly upregulated in metastatic samples compared with nonmetastatic samples (P < 0.05). Therefore, VRK2 may be a biomarker for predicting the metastasis of NPC patients after treatment.

The Nutritional Intervention of Resveratrol Can Effectively Alleviate the Intestinal Inflammation Associated With Celiac Disease Induced by Wheat Gluten.

Background and Aims: Wheat gluten is a critical trigger for celiac disease, often causing inflammatory lesions and oxidative stress damage in the intestines of patients. In daily life, it is difficult for celiac disease patients to strictly avoid the dietary intake of gluten, which makes complementary preventive therapy particularly urgent. As such, we investigated the alleviating effects of resveratrol in vivo and in vitro models of celiac disease. Methods: We established in vivo and in vitro models of gluten protein-induced celiac disease. The intervention effect of resveratrol was defined well based on relevant indicators of inflammation, immunity and oxidative stress, and its possible involvement in signaling pathways and genes were also identified. Results: Resveratrol was effective in reducing intestinal oxidative stress and inflammatory damage induced by wheat gluten in both cell and mouse models for celiac disease. We identified correlations between the genes (Fgf15, Nr0b2, Aire and Ubd) and signaling pathways (PPAR, AMPK and FoxO) in which resveratrol performed critical roles. Conclusions: Resveratrol contributed to regulate development of autoimmunity through up-regulation of Aire and Ubd genes and promote nutrient absorption in intestine through down-regulation of Fgf15 and Nr0b2 genes, as well as played a role in regulating complex response system of oxidative stress, inflammatory response and immune response in intestine by activating PPAR, AMPK and FoxO signaling pathways, thus effectively alleviating the intestinal symptoms of celiac disease.

Vaccines as a Strategy to Control Trichinellosis.

Trichinellosis caused by Trichinella spiralis is a worldwide food-borne parasitic zoonosis. Several approaches have been performed to control T. spiralis infection, including veterinary vaccines, which contribute to improving animal health and increasing public health by preventing the transmission of trichinellosis from animals to humans. In the past several decades, many vaccine studies have been performed in effort to control T. spiralis infection by reducing the muscle larvae and adult worms burden. Various candidate antigens, selected from excretory-secretory (ES) products and different functional proteins involved in the process of establishing infection have been investigated in rodent or swine models to explore their protective effect against T. spiralis infection. Moreover, different types of vaccines have been developed to improve the protective effect against T. spiralis infection in rodent or swine models, such as live attenuated vaccines, natural antigen vaccines, recombinant protein vaccines, DNA vaccines, and synthesized epitope vaccines. However, few studies of T. spiralis vaccines have been performed in pigs, and future research should focus on exploring the protective effect of different types of vaccines in swine models. Here, we present an overview of the strategies for the development of effective T. spiralis vaccines and summarize the factors of influencing the effectiveness of vaccines. We also discuss several propositions in improving the effectiveness of vaccines and may provide a route map for future T. spiralis vaccines development.

Monomerization of abscisic acid receptors through CARKs-mediated phosphorylation.

Cytosolic ABA Receptor Kinases (CARKs) play a pivotal role in abscisic acid (ABA)-dependent pathway in response to dehydration, but their regulatory mechanism in ABA signaling remains unexplored. In this study, we showed that CARK4/5 of CARK family physically interacted with ABA receptors (RCARs/PYR1/PYLs), including RCAR3, RCAR11-RCAR14, while CARK2/7/11 only interacted with RCAR11-RCAR14, but not RCAR3. It indicates that the members in CARK family function redundantly and differentially in ABA signaling. RCAR12 can form heterodimer with RCAR3 in vitro and in vivo. Moreover, the members of CARK family can form homodimer or heterodimer in a kinase activity dependent manner. ITC (isothermal titration calorimetry) analysis demonstrated that the phosphorylation of RCAR12 by CARK1 enhanced the ABA binding affinity. The phosphor-mimic RCAR12T105D significantly displayed ABA-induced inhibition of the phosphatase ABI1 (ABA insensitive 1) activity, leading to upregulation of ABA-responsive genes RD29A and RD29B in cark157:RCAR12T105D transgenic plants, which exhibited ABA hypersensitive phenotype. The transcription factor ABI5 (ABA insensitive 5) activates the transcriptions of CARK1 and CARK3 by binding to ABA-response elements (ABREs) of their promoters. Collectively, our data imply that the dimeric CARKs phosphorylate homodimer or heterodimer ABA receptors, leading to monomerization for triggering ABA responses in Arabidopsis.

A Nanodrug Coated with Membrane from Brain Microvascular Endothelial Cells Protects against Experimental Cerebral Malaria.

Human malaria is a global life-threatening infectious disease. Cerebral malaria (CM) induced by Plasmodium falciparum parasites accounts for 90% of malaria deaths. Treating CM is challenging due to inadequate treatment options and the development of drug resistance. We describe a nanoparticle formulation of the antimalarial drug dihydroartemisinin that is coated in a biomimetic membrane derived from brain microvascular endothelial cells (BMECs) and test its therapeutic efficacy in a mouse model of experimental cerebral malaria (ECM). The membrane-coated nanoparticle drug has a prolonged drug-release profile and enhanced dual targeting killing efficacy toward parasites residing in red blood cells (iRBCs) and iRBCs obstructed in the BMECs (for both rodent and human). In a mice ECM model, the nanodrug protects the brain, liver, and spleen from infection-induced damage and improves the survival rate of mice. This so-called nanodrug offers new insight into engineering nanoparticle-based therapeutics for malaria and other parasitic pathogen infections.

Observation of the Gut Microbiota Profile in C57BL/6 Mice Induced by Plasmodium berghei ANKA Infection.

The genus of Plasmodium parasites can cause malaria, which is a prevalent infectious disease worldwide, especially in tropical and subtropical regions. C57BL/6 mice infected with P. berghei ANKA (PbA) will suffer from experimental cerebral malaria (ECM). However, the gut microbiota in C57BL/6 mice has rarely been investigated, especially regarding changes in the intestinal environment caused by infectious parasites. P. berghei ANKA-infected (PbA group) and uninfected C57BL/6 (Ctrl group) mice were used in this study. C57BL/6 mice were infected with PbA via intraperitoneal injection of 1 × 106 infected red blood cells. Fecal samples of two groups were collected. The microbiota of feces obtained from both uninfected and infected mice was characterized by targeting the V4 region of the 16S rRNA through the Illumina MiSeq platform. The variations in the total gut microbiota composition were determined based on alpha and beta diversity analyses of 16S rRNA sequencing. The raw sequences from all samples were generated and clustered using ≥ 97% sequence identity into many microbial operational taxonomic units (OTUs). The typical microbiota composition in the gut was dominated by Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia at the phylum level. Bacteroidetes and Verrucomicrobia were considerably decreased after PbA infection compared with the control group (Ctrl), while Firmicutes and Proteobacteria were increased substantially after PbA infection compared with Ctrl. The alpha diversity index showed that the observed OTU number was increased in the PbA group compared with the Ctrl group. Moreover, the discreteness of the beta diversity revealed that the PbA group samples had a higher number of OTUs than the Ctrl group. LEfSe analysis revealed that several potential bacterial biomarkers were clearly related to the PbA-infected mice at the phylogenetic level. Several bacterial genera, such as Acinetobacter, Lactobacillus, and Lachnospiraceae_NK4A136_group, were overrepresented in the PbA-infected fecal microbiota. Meanwhile, a method similar to gene coexpression network construction was used to generate the OTU co-abundance units. These results indicated that P. berghei ANKA infection could alter the gut microbiota composition of C57BL/6 mice. In addition, potential biomarkers should offer insight into malaria pathogenesis and antimalarial drug and malaria vaccine studies.

Adjuvant Radiotherapy After Minimally Invasive Surgery in Patients With Stage IA1-IIA1 Cervical Cancer.

To estimate whether adjuvant radiotherapy is necessary for patients with stage IA1-IIA1 cervical cancer after laparoscopic hysterectomy, 221 patients were retrospectively analyzed. Sixty-two of them were treated with laparoscopic hysterectomy and adjuvant radiotherapy (group A), 115 underwent open surgery (group B) and 44 received laparoscopic hysterectomy alone (group C). Results showed that the 3-year local recurrence-free survival (LRFS) rates of group A, B and C were 98.4%, 97.4% and 86.4%, respectively. The LRFS rates of group A and B surpassed C (A vs. B, p=0.634; A vs. C, p=0.011; B vs. C, p=0.006). The inter-group differences of 3-year overall survival (OS) and distant metastasis free survival (DMFS) were not statistically significant. In subgroup analysis of stage IB disease, the 3-year LRFS rates of group A, B and C were 100%, 98.8% and 83.1%, the 3-year OS rates of group A, B and C were 100%, 98.9% and 91.5%, respectively. The 3-year LRFS and OS rates of group A and B were significantly superior to group C (p<0.05). Our findings suggest that adjuvant radiotherapy can reduce the risk of recurrence for women with early-stage cervical cancer after laparoscopic hysterectomy and bring survival benefits for patients with stage IB disease.