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This study tried to develop the α-Hederin/Oxaliplatin (OXA) dual-loaded rHDL (α-Hederin-OXA-rHDL) modified liposomes to improve the therapeutic index on colon adenocarcinoma (COAD). The α-Hederin-OXA-rHDL were prepared and evaluated for characterizations, accumulate to tumor tissues, and antitumor activity. A thorough investigation into oxaliplatin resistant and KRAS-mutant related hub keg genes were identified and performed to assess the prognosis role of the genetic signature in COAD. The potential immune signatures and molecular docking for verifing the predicted targets of α-Hederin-OXA-rHDL in tumor-bearing mice. Results suggested that α-Hederin-OXA-rHDL could enhance the sensitivity of oxaliplatin in HCT116/L-OHP cells via the regulation of KEAP1/NRF2 -mediated signaling and HO1 or GPX4 proteins. Furthermore, α-Hederin-OXA-rHDL regulated the predicted targets of PRDM1 interaction with miR-140-5p, efficient activing CD8 T cell to improve therapeutic response in vivo. Collectively, this work provides drug delivery with rHDL dual-loaded α-Hederin and oxaliplatin synergistically targets cancer cells and effectory T cells combating COAD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic., Methods: This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records., Results: The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection ( p  < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p  = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p  < 0.001) emerged as independent risk factors for early MG exacerbation., Conclusion: Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Xu, Qin, Liu, Guo, Huang, Fan, Zhang, Qi, Zhang, Yang, Shi and Yang.)

Objective: Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models., Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments., Results: Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD., Interpretation: 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Grapevine (Vitis vinifera L.) incurs severe quality degradation and yield loss from powdery mildew, a major fungal disease caused by Erysiphe necator. ENHANCED DISEASE RESISTANCE1 (EDR1), a Raf-like mitogen-activated protein kinase kinase kinase, negatively regulates defense responses against powdery mildew in Arabidopsis (Arabidopsis thaliana). However, little is known about the role of the putatively orthologous EDR1 gene in grapevine. In this study, we obtained grapevine VviEDR1-edited lines using CRISPR/Cas9. Plantlets containing homozygous and bi-allelic indels in VviEDR1 developed leaf lesions shortly after transplanting into the soil and died at the seedling stage. Transgenic plants expressing wild-type VviEDR1 and mutant Vviedr1 alleles as chimera (designated as VviEDR1-chi) developed normally and displayed enhanced resistance to powdery mildew. Interestingly, VviEDR1-chi plants maintained a spatiotemporally distinctive pattern of VviEDR1 mutagenesis: while almost no mutations were detected from terminal buds, ensuring normal function of the apical meristem, mutations occurred in young leaves and increased as leaves matured, resulting in resistance to powdery mildew. Further analysis showed that the resistance observed in VviEDR1-chi plants was associated with callose deposition, increased production of salicylic acid and ethylene, H2O2 production and accumulation, and host cell death. Surprisingly, no growth penalty was observed with VviEDR1-chi plants. Hence, this study demonstrated a role of VviEDR1 in the negative regulation of resistance to powdery mildew in grapevine and provided an avenue for engineering powdery mildew resistance in grapevine., Competing Interests: Conflict of interest statement.All authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The optimal treatment for tracheal tumors necessitates sequential tumor elimination and tracheal cartilage reconstruction. This study introduces an innovative inorganic nanosheet, MnO 2 /PDA@Cu, comprising manganese dioxide (MnO 2 ) loaded with copper ions (Cu) through in situ polymerization using polydopamine (PDA) as an intermediary. Additionally, a specialized methacrylic anhydride modified decellularized cartilage matrix (MDC) hydrogel with chondrogenic effects is developed by modifying a decellularized cartilage matrix with methacrylic anhydride. The MnO 2 /PDA@Cu nanosheet is encapsulated within MDC-derived microneedles, creating a photothermal-controllable MnO 2 /PDA@Cu-MDC microneedle. Effectiveness evaluation involved deep insertion of the MnO 2 /PDA@Cu-MDC microneedle into tracheal orthotopic tumor in a murine model. Under 808 nm near-infrared irradiation, facilitated by PDA, the microneedle exhibited rapid overheating, efficiently eliminating tumors. PDA's photothermal effects triggered controlled MnO 2 and Cu release. The MnO 2 nanosheet acted as a potent inorganic nanoenzyme, scavenging reactive oxygen species for an antioxidant effect, while Cu facilitated angiogenesis. This intervention enhanced blood supply at the tumor excision site, promoting stem cell enrichment and nutrient provision. The MDC hydrogel played a pivotal role in creating a chondrogenic niche, fostering stem cells to secrete cartilaginous matrix. In conclusion, the MnO 2 /PDA@Cu-MDC microneedle is a versatile platform with photothermal control, sequentially combining antitumor, antioxidant, pro-angiogenic, and chondrogenic activities to orchestrate precise tracheal tumor eradication and cartilage regeneration., (© 2023 Wiley-VCH GmbH.)

Organic-inorganic hybrid perovskites have garnered significant attention in optoelectronics owing to their outstanding tunable optical characteristics. Controlled growth of perovskite nanocrystals from solutions is key for controlling the emission intensity and photoluminescence lifetime of perovskites. In particular, most studies have focused on controlling the crystallization of perovskite through chemical treatment using chelating ligands or physical treatment via antisolvent diffusion, and there exists a trade-off between the photoluminescence intensity and lifetime of perovskites. Herein, a selective solvent vapor-assisted crystallization with the aid of a functional polymer, which nanoscale perovskite crystals are grown andante from precursor solution, is presented for tuning the crystallization and optical properties of a common halide perovskite, methylammonium lead bromide (MAPbBr 3 ). The proposed method here produces perovskite nanocrystals in the range of 200-300 nm. The spin-coated thin film formed from the perovskite solution exhibits strong green photoluminescence with a long lifetime. The effects of the functional group and polymer dosage on the crystallization of MAPbBr 3 are systematically investigated, and the crystallization mechanism is explained based on a modified LaMer model. This study provides an advanced solution process for precisely controlling perovskite crystallization to enhance their optical properties for next-generation optoelectronic devices., (© 2023 Wiley-VCH GmbH.)

Virus-like particle (VLP)-based vaccines are required to be associated with a suitable adjuvant to potentiate their immune responses. Herein, we report a novel, biodegradable, and biocompatible polyphosphoester-based amphiphilic cationic polymer, poly(ethylene glycol)- b -poly(aminoethyl ethylene phosphate) (PEG-PAEEP), as a Hepatitis B surface antigen (HBsAg)-VLP vaccine adjuvant. The polymer adjuvant effectively bound with HBsAg-VLP through electrostatic interactions to form a stable vaccine nanoformulation with a net positive surface charge. The nanoformulations exhibited enhanced cellular uptake by macrophages. HBsAg-VLP/PEG-PAEEP induced a significantly higher HBsAg-specific IgG titer in mice than HBsAg-VLP alone after second immunization, indicative of the antigen-dose sparing advantage of PEG-PAEEP. Furthermore, the nanoformulations exhibited a favorable biocompatibility and in vivo tolerability. This work presents the PEG-PAEEP copolymer as a promising vaccine adjuvant and as a potentially effective alternative to aluminum adjuvants.

Background: Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression and are known to mediate endocrine and chemotherapy resistance through paracrine signaling. Additionally, they directly influence the expression and growth dependence of ER in Luminal breast cancer (LBC). This study aims to investigate stromal CAF-related factors and develop a CAF-related classifier to predict the prognosis and therapeutic outcomes in LBC., Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to obtain mRNA expression and clinical information from 694 and 101 LBC samples, respectively. CAF infiltrations were determined by estimating the proportion of immune and cancer cells (EPIC) method, while stromal scores were calculated using the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) algorithm. Weighted gene co-expression network analysis (WGCNA) was used to identify stromal CAF-related genes. A CAF risk signature was developed through univariate and least absolute shrinkage and selection operator method (LASSO) Cox regression model. The Spearman test was used to evaluate the correlation between CAF risk score, CAF markers, and CAF infiltrations estimated through EPIC, xCell, microenvironment cell populations-counter (MCP-counter), and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms. The TIDE algorithm was further utilized to assess the response to immunotherapy. Additionally, Gene set enrichment analysis (GSEA) was applied to elucidate the molecular mechanisms underlying the findings., Results: We constructed a 5-gene prognostic model consisting of RIN2, THBS1, IL1R1, RAB31, and COL11A1 for CAF. Using the median CAF risk score as the cutoff, we classified LBC patients into high- and low-CAF-risk groups and found that those in the high-risk group had a significantly worse prognosis. Spearman correlation analyses demonstrated a strong positive correlation between the CAF risk score and stromal and CAF infiltrations, with the five model genes showing positive correlations with CAF markers. In addition, the TIDE analysis revealed that high-CAF-risk patients were less likely to respond to immunotherapy. Gene set enrichment analysis (GSEA) identified significant enrichment of ECM receptor interaction, regulation of actin cytoskeleton, epithelial-mesenchymal transition (EMT), and TGF-β signaling pathway gene sets in the high-CAF-risk group patients., Conclusion: The five-gene prognostic CAF signature presented in this study was not only reliable for predicting prognosis in LBC patients, but it was also effective in estimating clinical immunotherapy response. These findings have significant clinical implications, as the signature may guide tailored anti-CAF therapy in combination with immunotherapy for LBC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Xu, Luo, Huang, Gong and Fu.)

A new hypoxia-tolerant variety of blunt snout bream was obtained by successive breeding of the wild population, which markedly improved hypoxia tolerance. In this study, the hypoxia-tolerant variety was exposed to hypoxia (2.0 mg O 2 ·L -1 ) for 4, 7 days. The contents of blood biochemical indicators including the number of red blood cells (RBC), total cholesterol (T-CHO), total protein (TP), triglyceride (TG), glucose (GLU), and lactic acid (LD) increased significantly (P < 0.05) under hypoxia. The glycogen content in the liver and muscle decreased significantly (P < 0.05) and the LD content in the brain, muscle and liver increased significantly (P < 0.05) under hypoxia. The levels of oxidative stress-related indicators i.e., superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and total antioxidant capacity (T-AOC) also changed significantly (P < 0.05) in the heart, liver, and intestine of the new variety under hypoxia. Additionally, hypoxia has caused injuries to the heart, liver, and intestine, but it shows amazing repair ability during reoxygenation. The apoptotic cells and apoptosis rate in the heart, liver, and intestine increased under hypoxia. Under hypoxia, the expression of the B-cell lymphomas 2 (Bcl-2) gene in the heart, liver, and intestine was significantly (P < 0.05) down-regulated, while the expression of the BCL2-associated agonist of cell death (Bad) gene was significantly (P < 0.05) up-regulated. These results are of great significance for enriching the basic data of blunt snout bream new variety in response to hypoxia and promoting the healthy development of its culture industry., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

The magnitude of the feedback between soil microbial respiration and increased mean temperature may decrease (a process called thermal adaptation) or increase over time, and accurately representing this feedback in models improves predictions of soil carbon loss rates. However, climate change entails changes not only in mean temperature but also in temperature fluctuation, and how this fluctuation regulates the thermal response of microbial respiration has never been systematically evaluated. By analysing subtropical forest soils from a 2,000 km transect across China, we showed that although a positive relationship between soil microbial biomass-specific respiration and temperature was observed under increased constant incubation temperature, an increasing temperature fluctuation had a stronger negative effect. Our results further indicated that changes in bacterial community composition and reduced activities of carbon degradation enzymes promoted the effect of temperature fluctuation. This adaptive response of soil microbial respiration suggests that climate warming may have a lesser exacerbating effect on atmospheric CO 2 concentrations than predicted., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Patients with type 2 diabetes mellitus have a high cardiovascular risk due, in part, to abnormalities of high-density lipoprotein mediated cholesterol efflux. The ATP-binding cassette A1 and G1 play a pivotal role in the regulation of cholesterol efflux. However, the regulation of these transporters in type 2 diabetes mellitus remains obscure., Objectives: This study aimed to investigate the expression of ATP-binding cassette A1 and G1 and their regulation by Liver X receptors in monocyte-derived macrophages in type 2 diabetes mellitus, and to determine whether the alteration of these transporters might affect cholesterol efflux from macrophages., Methods: Blood was collected from type 2 diabetic patients and healthy controls. Peripheral monocytes were differentiated into macrophages. Quantitative real-time PCR, western blots, and cholesterol efflux assays were performed. The Liver X receptor and Liver X receptor element complex in the ATP-binding cassette G1 gene promoter were detected by electrophoretic mobility supershift assay., Results: Macrophage ATP-binding cassette G1 expression and high density lipoproteininduced cholesterol efflux were significantly reduced in type 2 diabetic patients. However, the mRNA expression of ATP-binding cassette G1 in type 2 diabetic patients was not inhibited by Liver X receptor siRNA and the Liver X receptor- Liver X receptor element complexes remain unchanged similarly., Conclusion: The study suggested that the expression of ATP-binding cassette G1 and high density lipoprotein-induced cholesterol efflux in macrophages were reduced in type 2 diabetes mellitus. Impairment of cholesterol efflux and ATP-binding cassette G1 gene expression in type 2 diabetes mellitus might be regulated by a Liver X receptorindependent pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Colorectal cancer (CRC) can be resistant to platinum drugs, possibly through ferroptosis suppression, albeit the need for further work to completely understand this mechanism. This work aimed to sum up current findings pertaining to oxaliplatin resistance (OR) or resistance to ascertain the potential of ferroptosis to regulate oxaliplatin effects. In this review, tumor development relating to iron homeostasis, which includes levels of iron that ascertain cells' sensitivity to ferroptosis, oxidative stress, or lipid peroxidation in colorectal tumor cells that are connected with ferroptosis initiation, especially the role of c-Myc/NRF2 signaling in regulating iron homeostasis, coupled with NRF2/GPX4-mediated ferroptosis are discussed. Importantly, ferroptosis plays a key role in OR and ferroptotic induction may substantially reverse OR in CRC cells, which in turn could inhibit the imbalance of intracellular redox induced by oxaliplatin and ferroptosis, as well as cause chemotherapeutic resistance in CRC. Furthermore, fundamental research of small molecules, ferroptosis inducers, GPX4 inhibitors, or natural products for OR coupled with their clinical applications in CRC have also been summarized. Also, potential molecular targets and mechanisms of small molecules or drugs are discussed as well. Suggestively, OR of CRC cells could significantly be reversed by ferroptosis induction, wherein this result is discussed in the current review. Prospectively, the existing literature discussed in this review will provide a solid foundation for scientists to research the potential use of combined anticancer drugs which can overcome OR via targeting various mechanisms of ferroptosis. Especially, promising therapeutic strategies, challenges ,and opportunities for CRC therapy will be discussed.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Currently, effects of nanomaterials and their ions, such as silver nanoparticles (Ag NPs) and silver ions (Ag + ), on living organisms are not yet fully understood. One of the vital questions is whether nanomaterials have distinctive effects on living organisms from any other conventional chemicals (e.g., their ions), owing to their unique physicochemical properties. Due to various experimental protocols, studies of this crucial question have been inconclusive, which hinders rational design of effective regulatory guidelines for safely handling NPs. In this study, we chronically exposed early developing zebrafish embryos (cleavage-stage, 2 hours post-fertilization, hpf) to a dilution series of Ag + (0-1.2 μM) in egg water (1 mM NaCl, solubility of Ag + = 0.18 μM) until 120 hpf. We systematically investigated effects of Ag + on developing embryos and compared them with our previous studies of effects of purified Ag NPs on developing embryos. We found the concentration- and time-dependent effects of Ag + on embryonic development, and only half of the embryos developed normally after being exposed to 0.25 μM (27 μg/L) Ag + until 120 hpf. As the Ag + concentration increases, the number of embryos that developed normally decreases, while the number of embryos that became dead increases. The number of abnormally developing embryos increases as the Ag + concentration increases from 0 to 0.3 μM and then decreases as the concentration increases from 0.3 to 1.2 μM because the number of embryos that became dead increases. The concentration-dependent phenotypes were observed, showing fin fold abnormality, tail and spinal cord flexure, and yolk sac edema at low Ag + concentrations (≤0.2 μM) and head and eye abnormalities along with fin fold abnormality, tail and spinal cord flexure, and yolk sac edema at high concentrations (≥0.3 μM). Severities of phenotypes and the number of abnormally developing embryos were far less than those observed in Ag NPs. The results also show concentration-dependent effects on heart rates and hatching rates of developing embryos, attributing to the dose-dependent abnormally developing embryos. In summary, the results show that Ag + and Ag NPs have distinctive toxic effects on early developing embryos, and toxic effects of Ag + are far less severe than those of Ag NPs, which further demonstrates that the toxicity of Ag NPs toward embryonic development is attributed to the NPs themselves and their unique physicochemical properties but not the release of Ag + from the Ag NPs., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Seasonal changes, diurnal variations, and eutrophication result in periodic hypoxia in fish habitats, thus affecting the success of commercial aquaculture. In this study, the grass carp (Ctenopharyngodon idella) presented moderate hypoxia tolerance; they showed a medium critical oxygen tension during the loss of equilibrium. In response to 7 d of hypoxic exposure, the erythrocyte count and hemoglobin (Hb) concentration significantly increased (p < 0.01). To cope with the hypoxic environment, the grass carp underwent gill remodeling marked by reduction in the interlamellar cell mass (ILCM) and an increase in respiratory surface area. The gill remodeling under hypoxia was enabled by apoptosis induction. Although apoptotic signals were not found on ILCM cells, transferase dUTP nick end labeling (TUNEL) assay results indicated that after 1 d of hypoxic exposure, the number of TUNEL-positive cells per lamella increased until 4 d and then began to decrease. Consistent with the results of the TUNEL assay, the mRNA expression of apoptosis-related genes, caspase-3, Bax, and Bcl-2, increased at 1, 4, and 7 d of the hypoxia treatment. In addition, gill remodeling significantly (p < 0.01) decreased the concentration of sodium and chloride ions in the fish serum. These findings provide evidence that grass carps increase their respiratory surface area through gill remodeling by apoptosis in the gill filaments to acclimate to a hypoxic environment. This study expands our understanding of the morphological and physiological changes in grass carp in response to a hypoxic environment; therefore, it could be useful for maintaining grass carp production., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumour microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumour cells and even enhance their aggressive phenotype. This review summarises the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumour ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumour cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumour cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumour therapies for colorectal cancer.

Objective: To analyze the labor progression characteristics of primiparous term singleton pregnant women with adenomyosis. Methods: From April 2014 to May 2021, pregnant women underwent regular antenatal examination in Peking University Third Hospital were enrolled in this retrospective study, 109 primiparous term pregnant women with adenomyosis who underwent singleton, primipara, cephalic and vaginal delivery were referred as the adenomyosis group, while 109 pregnant women without adenomyosis primiparous term pregnant women at the same time were referred as the control group. The general clinical information, labor process intervention, pregnancy outcomes and labor course time of the two groups were analyzed. Results: (1) General clinical conditions: the pre-pregnancy uterine volume of the adenomyosis group was larger than that of the control group [(66.8±23.7) vs (41.4±13.1) cm 3 , P <0.05]. The proportion of assisted reproductive pregnancy and endometriosis in the adenomyosis group were higher than those in the control group [31.2% (34/109) vs 7.3% (8/109); 31.2% (34/109) vs 5.5% (6/109); all P <0.05]. There were no significant differences in maternal age, gestational age at delivery, pre-pregnancy body mass index, gestational weight gain, gravidity, incidence of pregnancy complications (gestational diabetes mellitus, pre-eclampsia and thyroid diseases) and premature rupture of membranes between the two groups (all P> 0.05). (2) Labor process intervention and maternal and fetal outcomes: postpartum hemorrhage was higher in the adenomyosis group than the control group (median: 300 vs 260 ml, P =0.018). There were no significant differences in the proportion of labor onset, use of oxytocin, artificial rupture of membranes, perineal laceration Ⅲ and above, episiotomy, newborn weight and 1-minute Apgar score between the two groups (all P> 0.05). (3) Time of labor process: there were no significant differences between the two groups in the time required for the first stage, third stage, total stage and cervical dilation 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7 cm (all P> 0.05). The time required for cervical dilation 7-8, 8-9, 9-10 cm and the second stage of labor in adenomyosis group (median: 20, 18, 15 and 12 minutes, respectively) were shorter than those of the control group (median: 23, 23, 23 and 26 minutes, respectively), and the differences were statistically significant (all P <0.05). (4) The effect of endometriosis on labor: there was no significant difference in the effect of endometriosis on labor in adenomyosis group ( P >0.05). Conclusions: The labor process of primiparous term pregnant women with adenomyosis is significantly accelerated after the cervical dilatation for 7 cm, which should be closely observed. The third stage of labor course is managed aggressively with drugs to prevent postpartum hemorrhage.

Marine-derived microorganisms possess the unique metabolic pathways to produce structurally novel secondary metabolites with potent biological activities. In this study, bioactivity-guided isolation of the marine deep-sea-derived fungus Aspergillus flavipes DS720 led to the characterization of four indole alkaloids (compounds 1 - 4 ) and four polyketides (compounds 5 - 8 ), such as two new indoles, flavonoids A ( 1 ) and B ( 2 ) with a C-6 reversed prenylation, and a new azaphilone, flaviazaphilone A ( 5 ). Their chemical structures were unambiguously established by an extensive interpretation of spectroscopic data, such as 1D/2D NMR and HRESIMS data. The absolute configurations of the new compound 5 were solved by comparing the experimental and calculated Electronic Circular Dichroism (ECD) spectra. Since sufficient amount of flavonoids A ( 1 ) was obtained, 1 was subjected to a large-scale cytotoxic activity screening against 20 different human tumor cell lines. The results revealed that 1 showed broad-spectrum cytotoxicities against HeLa, 5637, CAL-62, PATU8988T, A-375, and A-673 cell lines, with the inhibition rates of more than 90%. This study indicated that the newly discovered indole alkaloid 1 may possess certain potential for the development of lead compounds in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Xu, Zhang, Li, Liu and Fu.)

As a necessary supplement to social medical insurance, commercial health insurance is an important part of the Healthy China strategy. This study, based on the Chinese General Social Survey (CGSS) data in 2017, uses the probit model to analyze and study the internal relationship between Internet use and commercial health insurance purchase of urban and rural residents. The research results show that the use of the Internet significantly promoted commercial health insurance purchases of residents, and the promotion effect for rural residents is apparently better than that among urban residents. In addition, the social level of residents is improved through the use of Internet, which can promote commercial health insurance purchases. It provides a significant reference value for the effective integration of Internet use and commercial health insurance, and the high-quality development of the modern insurance industry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Xu, Zhao and Zhang.)

Background & Aims: Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive., Methods: A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed., Results: A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P < .001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P < .001) and alcohol consumption (HR, 1.86; P < .001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea., Conclusions: Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297)., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Uranium (U) induces generation of excessive intracellular reactive oxygen species (ROS), which is generally considered as a possible mediator of U-triggered kidney tubular cells injury and nephrotoxicity. Our goal is designed to elucidate that the precise molecular mechanism in ROS downstream is association with U-induced NRK-52 E cells apoptosis. The results show that U intoxication in NRK-52 E cells reduced cell activity and triggered apoptosis, as demonstrated by flow cytometry and apoptotic marker cleaved Caspase-3 expression. U exposure triggered endoplasmic reticulum (ER) stress, which is involvement of apoptosis determined by marker molecules including GRP78, PERK, IRE1, ATF6, CHOP, cleaved Caspase-12, and Caspase-3. Administration of antioxidant N-acetylcysteine (NAC) effectively blocked U-triggered ROS generation, ER stress, and apoptosis. U contamination evidently decreased the expression of phosphorylation PI3K, AKT, and mTOR and ratios of their respective phosphorylation to the corresponding total proteins. Application of a PI3K activator IGF-1 significantly abolished these adverse effects of U intoxication on PI3K/AKT/mTOR signaling and subsequently abrogated U-triggered apoptosis. NAC also effectively reversed down-regulation of phosphorylated PI3K induced by U exposure. Taken together, these data strongly suggest that U treatment induces NRK-52 E cells apoptosis through ROS production, ER stress, and down-regulation of PI3K/AKT/mTOR signaling. Targeting ROS formation-, ER stress-, and PI3K/AKT/mTOR pathway-mediated apoptosis could be a novel approach for attenuating U-triggered nephrotoxicity., (© 2022 Wiley Periodicals LLC.)

Background and study aims  Endoscopists have been at increased risk because of their direct contact with patients during the COVID-19 pandemic. For patients, being diagnosed with and monitored for gastrointestinal cancer and digestive diseases in timely fashion has been challenging, given pandemic-related adjustments in endoscopy departments. We developed a novel noncontact magnetically controlled capsule endoscopy (ncMCE) system in our medical center. In the current study, we aimed to evaluate the feasibility and safety of ncMCE for gastric examination. Patients and methods  Patients were randomly assigned to groups that received ncMCE or MCE in a 1:1 ratio from March 26, 2020 to April 26, 2020. Primary endpoints were feasibility assessed by completion rate (CR) and safety based on the occurrence of adverse events (AEs) including infection. Secondary endpoints included maneuverability of endoscopists, pre-procedure perception and post-procedure satisfaction of patients, gastric examination time (GET), and diagnostic yield (DY). Results  Forty patients were enrolled with 100 % CR in both groups without any AEs. Neither the endoscopist nor the patients were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 14 days after gastric examination. There were no significant differences in maneuverability (19.3 vs. 20.0, P  = 0.179), pre-procedure perception (9 vs. 9, P  = 0.626) and post-procedure satisfaction (45 vs. 44, P =  0.999), ord DY (20 % vs. 30 %, P  = 0.465). Conclusions  ncMCE is a feasible and safe method of gastric examination, which has the potential to protect both medical staff and patients from COVID-19 infection while providing serving as an essential endoscopy service., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

β-Galactosidase is one of the most important enzymes used in dairy processing. It converts lactose into glucose and galactose, and also catalyzes galactose to form galactooligosaccharides (GOS), so-called prebiotics. However, most of the β-galactosidases from the starter cultures have low transgalactosylation activities, the process that results in galactose accumulation in yogurt. Here, a site-directed mutation strategy was attempted, to genetically modify β-galactosidase from Streptococcus thermophilus. Out of 28 Strep. thermophilus strains, a β-galactosidase gene named bgaQ, encoded for high β-galactosidase hydrolysis activity (BgaQ), was cloned from the strain Strep. thermophilus SDMCC050237. It was 3,081 bp in size, with 1,027 deduced amino acid residuals, which belonged to the GH2 family. After replacing the Tyr 801 and Pro 802 around the active sites of BgaQ with His 801 and Gly 802 , the GOS synthesis of the generated mutant protein BgaQ-8012 increased from 20.5% to 26.7% at 5% lactose, and no hydrolysis activity altered obviously. Subsequently, the purified BgaQ or BgaQ-8012 was added to sterilized milk inoculated with 2 starters from Strep. thermophilus SDMCC050237 and Lactobacillus delbrueckii ssp. bulgaricus ATCC11842. The GOS yields with added BgaQ or BgaQ-8012 increased to 5.8 and 8.3 g/L, respectively, compared with a yield of 3.7 g/L without enzymes added. Meanwhile, the addition of the BgaQ or BgaQ-8012 reduced the lactose content by 49.3% and 54.4% in the fermented yogurt and shortened the curd time. Therefore, this study provided a site-directed mutation strategy for improvement of the transgalactosylation activity of β-galactosidase from Strep. thermophilus for GOS-enriched yogurt making., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Aesculin (AES), an effective component of Cortex fraxini, is a hydroxycoumarin glucoside that has diverse biological properties. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing 3 (NLRP3) inflammasome has been heavily interwoven with the development of myocardial ischemia/reperfusion injury (MIRI). Nevertheless, it remains unclear whether AES makes a difference to the changes of the NLRP3 inflammasome in MIRI., Purpose: We used rats that were subjected to MIRI and neonatal rat cardiomyocytes (NRCMs) that underwent oxygen-glucose deprivation/restoration (OGD/R) process to investigate what impacts AES exerts on MIRI and the NLRP3 inflammasome activation., Methods: The establishment of MIRI model in rats was conducted using the left anterior descending coronary artery ligation for 0.5 h ischemia and then untying the knot for 4 h of reperfusion. After reperfusion, AES were administered intraperitoneally using 10 and 30 mg/kg doses. We evaluated the development of reperfusion ventricular arrhythmias, hemodynamic changes, infarct size, and the biomarkers in myocardial injury. The inflammatory mediators and pyroptosis were also assessed. AES at the concentrations of 1, 3, and 10 μM were imposed on the NRCMs immediately before the restoration process. We also determined the cell viability and cell death in the NRCMs exposed to OGD/R insult. Furthermore, we also analyzed the levels of proteins that affect the NLRP3 inflammasome activation, pyroptosis, and the AKT serine/threonine kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/nuclear factor-kappa B (NF-κB) signaling pathway via western blotting., Results: We found that AES notably attenuated reperfusion arrhythmias and myocardia damage, improved the hemodynamic function, and ameliorated the inflammatory response and pyroptosis of cardiomyocytes in rats and NRCMs. Additionally, AES reduced the NLRP3 inflammasome activation in rats and NRCMs. AES also enhanced the phosphorylation of Akt and GSK3β, while suppressing the phosphorylation of NF-κB. Moreover, the allosteric Akt inhibitor, MK-2206, abolished the AES-mediated cardioprotection and the NLRP3 inflammasome suppression., Conclusions: These findings indicate that AES effectively protected cardiomyocytes against MIRI by suppressing the NLRP3 inflammasome-mediated pyroptosis, which may relate to the upregulated Akt activation and disruption of the GSK3β/NF-κB pathway., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background: The relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP., Aims: The aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP., Methods: This was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model., Results: Before diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P < 0.001), harboring the SPINK1 mutation(P < 0.001), diabetes(P < 0.001) and steatorrhea(P < 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P < 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors., Conclusions: SPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP)., Methods: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients' demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status., Results: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered., Conclusions: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

The invalid patents associated with schistosomiasis control were retrieved in the Chinese Patent Database of China National Intellectual Property Administration, the Baiten database and the incoPat database, and the overall trends, legal status, types, patent indexing and technical fields of all retrieved invalid patents were analyzed. As of December 30, 2020, there were totally 859 patents relating to schistosomiasis control, and 512 were invalid patents, with an invalid rate of 59.6%. The number of patent applications and invalid patents peaked in 2018, including 71 patent applications and 53 invalid patents. Among the 511 schistosomiasis control-related invalid patents with complete records, there were 425 invention patents, 81 utility model patents and 5 design patents, and 219 patents (42.9%) were invalid due to the termination of the patented right and 292 (57.1%) due to loss of the right for patent applications. The major technical points included medicines (chemicals), basic research, devices and detections, and the specialized fields were mainly concentrated in A61P33, G01N33, C12N15, C07K14 and A01N65. Our data demonstrate a high invalid rate of patents relating to schistosomiasis control in China. Secondary development and mining of the invalid patents in relation to schistosomiasis are recommended to make use of their values in the national schistosomiasis elimination program of China.

Background: Many valuable and productive patented technologies have been developed to control schistosomiasis in China in the past 70 years. We conducted a research to analyse patented technologies for schistosomiasis control and prevention filed by Chinese applicants for determining the future patent layout., Methods: The patent databases of China National Intellectual Property Administration and Baiten were comprehensively searched, and patented technologies for schistosomiasis control and prevention, published between January 1950 and December 2020 filed by Chinese applicants were sorted on 30 December 2020. The patent types, technical fields, and patent development trends were analysed using patent indexing., Results: There are 184 valid schistosomiasis control technology patents, among them 128 invention patents. The patents related to schistosomiasis control and prevention technology have gone through the germination, growth, and maturity stages. These phases correspond with three phases in schistosomiasis control in China. The main technical aspects were fundamental research (n = 37), detection (n = 13), chemotherapy (n = 61), and armamentarium/devices (n = 73), of which the number of patents for detection for diagnosis was smaller. The top three specialised technical fields for patents subgroups, focusing on antiparasitic agents, DNA or RNA, vectors and medicines, of which schistosomicides are the major dominant subgroup., Conclusions: We recommend that technologies to be patented for schistosomiasis control and prevention be focused on detection, preliminary studies for molecular detection methods should be significantly enhanced, and patent layout must be performed, which will, in turn, promote accuracy of early diagnosis, not only in humans but also in livestock. It is necessary to develop more anti-schistosomal drugs safely and effectively, exceptionally eco-friendly molluscicides and herbal extracts anti-schistosomes, improve treatment, develop vaccines for use in humans.

Bisphenol S (BPS) is associated with neurotoxicity, but its molecular mechanisms are unclear. Our aim was to investigate the role of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB)/cAMP-response element-binding protein (CREB) signaling pathway in BPS-induced cytotoxicity in SK-N-SH cells. The cells were treated with various concentrations of BPS, and cell viability, apoptosis rate, mitochondrial membrane potential (MMP), and the BDNF, cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), TrkB, CREB, and phospho-CREB (p-CREB) levels were determined. The effects of pretreatment with the TrkB activator 7,8-dihydroxyflavone (7,8-DHF) were also explored. BPS decreased SK-N-SH cell viability and altered their morphology. Their apoptosis rate was increased, as were the levels of the proapoptotic proteins Bax and cleaved-caspase-3, but MMP was decreased. Thus, BPS may induce mitochondria-dependent apoptosis pathways. BPS also reduced the BDNF, TrkB, and p-CREB levels, and pretreatment with 7,8-DHF alleviated its cytotoxic effects. Thus, BPS-induced cytotoxicity might be mediated by the BDNF/TrkB/CREB signaling pathway., (© 2021 Wiley Periodicals LLC.)

The Editors of JBUON issue an Expression of Concern to ' Kutkoside-an iridoid glycoside, exerts anti-proliferative effects in drug-resistant human oral carcinoma cells by targeting PI3K/AKT signalling pathway, inducing apoptosis and suppressing cell migration and invasion', by Jun-Chi Hou, Xiao-Nan Xu, JBUON 2020;25(1):338-343; PMID: 32277652. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

We numerically investigate the nonequilibrium behaviors of classic particles with competing interactions confined in a two-dimensional logarithmic trap. We reveal a quench-induced surprising dynamics exhibiting rich dynamic patterns depending upon confinement strength and trap size, which is attributed to the time-dependent competition between interparticle repulsions and attractions under a circular confinement. Moreover, in the collectively diffusive motions of the particles, we find that the emergence of dynamic structure transformation coincides with a diffusive mode transition from superdiffusion to subdiffusion. These findings are likely useful in understanding the pattern selection and evolution in various chemical and biological systems in addition to modulated systems, and add a new route to tailoring the morphology of pattern-forming systems.

One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators., (Copyright © 2020 Pereira, Xu and Akbar.)

Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.

Depletion of CD4+ T cells during HIV-1 infection is mostly mediated by inflammatory cells via indirect but not clearly defined mechanisms. In this report, we used single-cell RNA-Seq (scRNA-Seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-Seq on hCD45+hCD3-hCD19- human leukocytes isolated from spleens of humanized NOD/Rag2-/-γc-/- (NRG) mice transplanted with human CD34+ hematopoietic stem progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells, including plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), macrophages, NK cells, and innate lymphoid cells (ILCs). HIV-1 infection significantly upregulated genes involved in type I IFN inflammatory pathways in each of the innate immune subsets. Interestingly, we found that TRAIL was upregulated in the innate immune populations, including pDCs, mDCs, macrophages, NK cells, and ILCs. We further demonstrated that blockade of the TRAIL signaling pathway in NRG-hu HSC mice prevented HIV-1-induced CD4+ T cell depletion in vivo. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells, and defined an important role of the TRAIL signaling pathway in HIV-1-induced CD4+ T cell depletion in vivo.

We collected evapotranspiration data of Dajiuhu peatland in Shennongjia from 2016 to 2017 with eddy covariance method and estimated the value of crop coefficient (K c ) using FAO56 Penman-Monteith equation and the linear relationship between actual evapotranspiration (ET a ) and referenced evapotranspiration (ET 0 ). We analyzed the characteristics of referenced evapotranspiration and its main influencing factors and calculated the crop coefficient of the wetland dominated by Sphagnum. The results showed that the daily averaged ET a were 1.63 and 1.38 mm·d -1 in 2016 and 2017, the daily averaged ET 0 were 1.61 and 1.23 mm·d -1 in 2016 and 2017. Environmental factors influencing ET 0 included net radiation, air temperature, vapor pressure deficit, wind speed, and relative humidity. The K c values for the growing seasons of 2016, 2017, and 2016-2017 were 0.95 (R 2 of linear regression between ET a and ET 0 was 0.96), 1.03 (R 2 =0.95), and 0.98 (R 2 =0.95). The K c values in 2016, 2017, and 2016-2017 were 0.92 (R 2 =0.94), 0.95 (R 2 =0.89), and 0.93 (R 2 =0.92). K c was effective in the range of 0.92-1.03 for the wetland dominated by Sphagnum. The identified parameters could be widely used in studies on climate change, ecosystem services, and water management in peatlands.

Multidrug membrane transporters exist in both prokaryotic and eukaryotic cells, which causes multidrug resistance (MDR) and urgent need of new and more effective therapeutic agencies. In this study, we used three different sized antibiotic nanocarriers to study their mode of actions and their size-dependent inhibitory effects against Escherichia coli (E. coli ). The antibiotic nanocarriers (AgMUNH-Oflx NPs) with 8.6×10 2 , 9.4×10 3 and 6.5×10 5 Oflx molecules per nanoparticle (NP) were prepared by functionalizing the Ag NPs (2.4 ± 0.7, 13.0 ± 3.1 and 92.6 ± 4.4 nm) with a monolayer of 11-amino-1-undecanethiol (MUNH 2 ) and covalently linking ofloxacin (Oflx) with the amine group of AgMUNH 2 NPs, respectively. We designed a modified cell culture medium for nanocarriers to be stable (non-aggregated) over 18 h of cell culture, which enables us to quantitatively study their size and dose dependent inhibitory effects against E. coli . We found that inhibitory effects of Oflx against E. coli highly depend upon dose of Oflx and size of nanocarriers, showing that the equal amount of Oflx delivered by the largest nanocarriers (92.6 ± 4.4 nm) were the most potent with the lowest minimum inhibitory concentration (MIC 50 ) and created the longest and highest percentage of filamentous cells, while the smallest nanocarriers (2.4 ± 0.7) were the least potent with the highest MIC 50 and produced the shortest and lowest percentage of filamentous cells. Interestingly, the same amount of Oflx on 2.4 ± 0.7 nm nanocarriers showed the 2x higher MIC and created the 2x shorter filamentous cells than free Oflx, while the Oflx on 13.0 ± 3.1 and 92.6 ± 4.4 nm nanocarriers exhibited 2x and 6x lower MICs, and produced 2x and 3x longer filamentous cell than free Oflx, respectively. Notably, three sized AgMUNH 2 NPs (absence of Oflx) showed negligible inhibitory effects and did not create filamentous cells. The results show that the filamentation of E. coli highly depends upon the sizes of nanocarriers, which leads to the size-dependent inhibitory effects of nanocarriers against E. coli .

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment., (© 2019 Wiley Periodicals, Inc.)

Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke, and avoids the complications of general hypothermia. However, the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown. In this study, we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein, a key factor in the mitochondrial fission system, during focal cerebral ischemia/reperfusion injury. Sprague-Dawley rats were divided into four groups. In the sham group, the carotid arteries were exposed only. In the other three groups, middle cerebral artery occlusion was performed using the intraluminal filament technique. After 2 hours of occlusion, the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group. Saline, at 4°C and 37°C, were perfused through the carotid artery in the hypothermia and normothermia groups, respectively, followed by restoration of blood flow. Neurological function was assessed with the Zea Longa 5-point scoring method. Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Fis1 and cytosolic cytochrome c levels were assessed by western blot assay. Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. Mitochondrial ultrastructure was evaluated by transmission electron microscopy. Compared with the sham group, apoptosis, Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups. These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group. These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis, thereby ameliorating focal cerebral ischemia/reperfusion injury in rats. Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No. 2019008)., Competing Interests: None

Purpose: To investigate the effect of human bone marrow mesenchymal stem cells (hBM-MSCs) on invasion of tongue squamous cell carcinoma cell line Cal-27 and its mechanism., Methods: hBM-MSCs and Cal-27 were cultured respectively, and the morphology of the cells was observed under an inverted microscope. The co-cultured Cal-27 cells were obtained by co-culture of hBM-MSCs and Cal-27. The migration area of Cal-27 was observed by scratch test;transwell migration and invasion experiments were performed to observe migration and invasion of Cal-27, and a bar graph was then drawn. Fluorescence quantitative PCR was used to observe the effect of hBM-MSCs on gene expression of the tumor markers E-cadherin, twist, slug, snail, MMP-2 and MMP-9. Western blot was used to observe the effect of hBM-MSCs on protein expression of MMP-2 and MMP-9, related to the invasion of Cal-27. SPSS 19.0 software package was used for statistical analysis of the data., Results: Under the influence of hBM-MSCs, the invasion of Cal-27 was promoted, accompanied by down-regulation of E-cadherin, up-regulation of twist, slug, snail, MMP-2, MMP-9 and up-regulation of MMP-2 and MMP-9 expression., Conclusions: hBM-MSCs can promote invasion of Cal-27 cells, which may be related to up-regulation of the expression of tumor markers related to invasion of Cal-27 cells.

Objective: This study aimed to explore the effects of silencing farnesyltransferase (FTase) on the migration and invasion of tongue squamous cell carcinoma (TSCC) through RNA interference., Methods: TSCC cells (CAL27 and SCC-4) were cultured in vitro and then transfected with siRNA to silence FTase expression. The tested cells were categorized as follows: experimental group (three RNA interference groups), negative control group, and blank control group. mRNA expression of FTase and HRAS in each group was analyzed by quantitative real-time polymerase chain reaction. On the basis of FTase mRNA expression, the optimum interference group (highest silencing efficiency) was selected as the experimental group for further study. The protein expression of FTase, HRAS, p65, p-p65(S536), matrix metalloprotein-9 (MMP-9), hypoxia inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was analyzed by Western blot. The invasion and migration abilities of TSCC cells were determined by Transwell invasion assay and cell wound healing assay., Results: The mRNA and protein expression of FTase in the experimental group decreased compared with that in the negative control and blank control groups (P<0.05). The mRNA and protein expression of HRAS was not significantly different among the groups (P>0.05). In the experimental group, the protein expression of p-p65(S536), MMP-9, HIF-1α, and VEGF decreased (P<0.05), whereas that of p65 had no significant change (P>0.05). The migration and invasion abilities of the experimental group were inhibited significantly (P<0.05)., Conclusions: Silencing FTase in vitro could effectively downregulate its expression in TSCC cell lines and reduce the migration and invasion abilities to a certain extent. FTase could be a new gene therapy target of TSCC, and this research provided a new idea for the clinical treatment of TSCC.

A 24-year-old man born in Guizhou province was diagnosed with obstructive jaundice and bile duct stones in 2013. Four living trematodes were found during laparotomy and cholecystectomy. Based on the morphology and molecular genetics analysis of internal transcribed spacer and pcox1 genes of the flatworm specimens, the trematodes from the patient were confirmed to be Fasciola hepatica. This report provided the clinical and molecular diagnosis information on human fascioliasis, which is an emerging sanitary problem still ignored in China. Human fascioliasis constantly occurs due to climatic changes and frequency of human travel. Therefore, it deserves more attention from physicians working in both developing and developed countries.