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Accumulating evidence from studies in humans and animal models has elucidated that gut microbiota, acting as a complex ecosystem, contributes critically to colorectal cancer (CRC). The potential mechanisms often reported emphasize the vital role of carcinogenic activities of specific pathogens, but in fact, a series of metabolites produced from exogenous dietary substrates or endogenous host compounds occupy a decisive position similarly. Detrimental gut microbiota-derived metabolites such as trimethylamine-N-oxide, secondary bile acids, hydrogen sulfide and N-nitroso compounds could reconstruct the ecological composition and metabolic activity of intestinal microorganisms and formulate a microenvironment that opens susceptibility to carcinogenic stimuli. They are implicated in the occurrence, progression and metastasis of CRC through different mechanisms, including inducing inflammation and DNA damage, activating tumorigenic signaling pathways and regulating tumor immunity. In this review, we mainly summarized the intimate relationship between detrimental gut microbiota-derived metabolites and CRC, and updated the current knowledge about detrimental metabolites in CRC pathogenesis. Then, multiple interventions targeting these metabolites for CRC management were critically reviewed, including diet modulation, probiotics/prebiotics, fecal microbiota transplantation, as well as more precise measures such as engineered bacteria, phage therapy and chemopreventive drugs. A better understanding of the interplay between detrimental microbial metabolites and CRC would hold great promise against CRC.

Serine protease inhibitors of Kazal-type (SPINKs) were widely identified in vertebrates and invertebrates, and played regulatory roles in digestion, coagulation, and fibrinolysis. In this study, we reported the important role of SPINK7 in regulating immune defense of silkworm, Bombyx mori. SPINK7 contains three Kazal domains and has 6 conserved cysteine residues in each domain. Quantitative real-time PCR analyses revealed that SPINK7 was exclusively expressed in hemocytes and was upregulated after infection with two fungi, Saccharomyces cerevisiae and Candida albicans. Enzyme activity inhibition test showed that SPINK7 significantly inhibited the activity of proteinase K from C. albicans. Additionally, SPINK7 inhibited the growth of three fungal spores, including S. cerevisiae, C. albicans, and Beauveria bassiana. The pathogen-associated molecular patterns (PAMP) binding assays suggested that SPINK7 could bind to β-D-glucan and agglutinate B. bassiana and C. albicans. In vitro assays were performed using SPINK7-coated agarose beads, and indicated that SPINK7 promoted encapsulation and melanization of agarose beads by B. mori hemocytes. Furthermore, co-localization studies using immunofluorescence revealed that SPINK7 induced hemocytes to aggregate and entrap the fungi spores of B. bassiana and C. albicans. Our study revealed that SPINK7 could recognize fungal PAMP and induce the aggregation, melanization, and encapsulation of hemocytes, and provided valuable clues for understanding the innate immunity and cellular immunity in insects.

BackgroundHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. PAFAH1B3 plays an important role on occurrence and development in a variety tumor. However, the function of PAFAH1B3 in HCC remains unclear.MethodsThe TIMER, ONCOMINE, Human Protein Atlas (HPA), GEPIA, The Cancer Genome Atlas (TCGA), HCCDB, UALCAN and LinkedOmics database were used to analyze the prognostic value, co-expression genes and regulator networks of PAFAH1B3 in HCC. siRNA transfections and inhibitor of PAFAH1B3 P11 were used to verify the anti-tumor effect on HCC cell lines. Gene expression was detected by qRT-PCR. The functions of PAFAH1B3 downregulation in HCC cell lines were investigated using cell cycle analysis, apoptosis detection, CCK8 assay and transwell assay. Western blot was used to evaluate the role of PAFAH1B3 on metabolic pathways in HCC cells.ResultsBased on the data from databases, the expression of PAFAH1B3 was remarkably increased in HCC patients. High expression of PAFAH1B3 was associated with poorer overall survival (OS) and disease-free survival (DFS). And PAFAH1B3 was notably linked to age, sex, grade, stage, race, and TP53 mutational status. Then, the functional network analysis showed PAFAH1B3 may be involved in HCC through cell cycle, cell metabolism, spliceosome, and RNA transport. Furthermore, the mRNA expression of PAFAH1B3 was also increased in HCC cell lines. Flow cytometry analysis showed that PAFAH1B3 manipulated apoptosis and cell cycle regulation. CCK8 assay showed that PAFAH1B3 silencing or pharmacologic inhibitor of PAFAH1B3 inhibited the proliferation of HepG2, Huh7 and MHCC-97H cells. Transwell assay results showed that PAFAH1B3 silencing also significantly impaired the invasion and migratory ability of HCC cells. In addition, PAFAH1B3 silencing significantly downregulated the expression of glycolysis and lipid synthesis signaling pathways.ConclusionOur findings suggested that PAFAH1B3 plays a critical role in progression of HCC. PAFAH1B3 as a prognosis marker and potential target for HCC has prospective clinical significance.

ABSTRACT: The present study investigated the dosage and replication effects of lipopolysaccharide challenges on the serum oxidative and immune status, and the intestinal morphology and permeability of Linwu ducks at the growing stage. A total of 500 54-day-old Linwu ducks were randomly assigned into 10 treatments, which included a factorial arrangement of 2 levels of LPS challenge replications (1 and 2 times) × 5 levels of lipopolysaccharide challenging dosages (0, 0.1, 0.2, 0.4, and 0.8 mg/kg). Each treatment consisted of 5 cages and 10 ducks per cage. The results showed significant replication effects of LPS on the body weight gain of ducks, that 2 replicates of LPS challenges significantly decreased the body weight gain than one challenge (P = 0.036). Regarding to the serum oxidative and immune status, dosage effects of lipopolysaccharide were found on the serum levels of superoxide dismutase (P = 0.034) and immunoglobulin A (P = 0.007), that 0.4 mg/kg lipopolysaccharides significantly increased the levels of these 2 parameters. Additionally, replication effects were found in the serum levels of interlukin 1β, that 2 replicates of LPS challenges significantly increased the interlukin 1β levels comparing to one challenge (P = 0.010). Regarding to the intestinal conditions, dosage effects of lipopolysaccharides were found on the ratio of villus height and crypt depth (P = 0.005) in duodenum, and the wall thickness of duodenum (P = 0.010) and jejunum (P = 0.001), that lipopolysaccharides at 0.1, 0.2, and 0.8 mg/kg significantly deteriorated the intestinal morphologies, especially in the duodenum and jejunum. Moreover, the dosage effects of lipopolysaccharides and the interactions of dosages and replications significantly influenced the permeabilities of the intestinal segments (P < 0.05). It appeared that 2 replicates of lipopolysaccharides at the dosage at 0.4 mg/kg could trigger oxidative and immunological stress, and damage the intestinal morphology and permeability of Linwu ducks at the growing stage.

The present study investigated the effects of ferulic acid (FA) on the growth performance, serum cytokine profile, intestinal morphology, and intestinal microbiota in ducks at the growing stage. 300 female Linwu ducks at 28 days of age with similar body weights were randomly divided into five groups. Each group contained six replicates of 10 birds. The dietary treatments were corn-soybean-based diet supplemented with FA at the concentrations of 0 (control), 100, 200, 400, and 800 mg/kg diet. The results demonstrated that dietary FA at the levels of 200, 400, and 800 mg/kg increased the average daily gain (P = 0.01), 400 and 800 mg/kg FA increased the final body weight (P = 0.02), 100, 200, and 800 mg/kg FA increased the serum glutathione (P = 0.01), and 100, 400, and 800 mg/kg FA increased the glutathione peroxidase activities in birds (P < 0.01). Additionally, 200, 400, and 800 mg/kg dietary FA lowered the serum levels of interleukin-2 (P = 0.02) and interleukin-6 (P = 0.04). Moreover, the morphometric study of the intestines indicated that 400 mg/kg FA decreased the crypt depth in jejunum (P = 0.01) and caecum (P = 0.04), and increased the ratio of villus height to crypt depth in jejunum (P = 0.02). Significant linear and/or quadratic relationships were found between FA concentration and the measured parameters. 16S rRNA sequencing revealed that dietary FA increased the populations of genera Faecalibacterium, Paludicola, RF39, and Faecalicoccus in the cecum (P < 0.05), whereas decreased the populations of Anaerofilum and UCG-002 (P < 0.05). The Spearman correlation analysis indicated that phylum Proteobacteria were negatively, but order Oscillospirales, and family Ruminococcaceae were positively related to the parameters of the growth performance. Phylum Bacteroidetes, class Negativicutes and family Rikenellaceae were negatively associated with the parameters of the antioxidative capability. And phylum Cyanobacteria, Elusimicrobia, and Bacteroidetes, class Bacilli, family Rikenellaceae, and genus Prevotella were positively associated with the parameters of the immunological capability. Thus, it was concluded that the supplementations of 400 mg/kg FA in diet was able to improve the growth performance, antioxidative and immunological capabilities, intestinal morphology, and modulated the gut microbial construction of Linwu ducks at the growing stage.

Melatonin is an important bioactive molecule in plants. Two synthetases, N-acetylserotonin methyltransferase (ASMT) and serotonin N-acetyltransferase (SNAT) are involved in the final two steps of melatonin synthesis. Melatonin participates in responses to a variety of biotic and abiotic stresses in plants, but few studies have addressed the roles of endogenous melatonin in pathogen resistance. We investigated the role of endogenous melatonin in resistance to Botrytis cinerea infection in an Arabidopsis thaliana model system. Plant lines that overexpressed ASMT or SNAT through genetic manipulation showed upregulated expression of resistance genes PR1 and PR5, transcription factor gene WRKY33, and jasmonic acid (JA) defense pathway marker gene PDF1.2, and downregulated transcription factor gene MYC2 in JA signaling pathway. Higher melatonin content also enhanced the activity of antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD), increased JA content, reduced plant disease symptoms, and reduced lesion size in leaves. These findings indicate that endogenous melatonin enhances plant resistance to B. cinerea infection. In contrast, ASMT and SNAT gene silencing lines showed opposite results and were more susceptible to B. cinerea. Thus, it can be demonstrated that melatonin functions as an effective regulator of plant stress resistance at the genetic level. A schematic model is presented for its role in resistance to B. cinerea infection. Our findings also helped to elucidate the associated signal transduction pathways and interactions between melatonin and other plant hormones.

Abstract Background The virological or clinical relapse is common in chronic hepatitis B (CHB) patients after stopping long-term nucleos(t)ide analogue (NA) therapy. Soluble growth stimulation expressed gene 2 (sST2), one of the Toll-like/interleukin-1 receptor members, is involved in a variety of inflammatory processes and immune responses. However, the expression and function of serum sST2 in CHB patients after stopping NA treatment remains unknown. Methods A total of 91 non-cirrhotic Asian patients with CHB who discontinued NA therapy according to international guidelines were prospectively followed up to 240 weeks. All patients were divided into clinical relapse group and non-clinical relapse (including sustained virological response and only virological relapse) group according HBV DNA and ALT levels. The serum levels of sST2 of all participants were determined by ELISA and compared between each two groups. Results Clinical relapse occurred in 26 patients and virological relapse occurred in 57 patients. We found that there was a positive correlation between sST2 expression and HBsAg, ALT, HBV DNA, and anti-HBc levels in CHB patients after discontinuation of NA treatment. Levels of serum sST2 in clinical relapse patients showed a rising trend and most patients showed peak sST2 levels at the point of clinical relapse. Moreover, the sST2 levels of clinical relapse group at week 12, week 24 and week 48 were relatively higher than non-clinical relapse group. However, the level of sST2 at the end of treatment was not an effective biological marker for the early prediction of clinical relapse after discontinuation of long-term NA therapy. Conclusions In conclusion, we found that an increase in sST2 in clinical relapse patients might be associated with an inflammation-related immune response after discontinuation of NA treatment. Trial registration The trial was retrospectively registered at Chinese Clinical Trial Registry: ChiCTR-OOC-17013970. Registration date: December 15, 2017.

In this paper, a novel modulation scheme called enhanced asymmetrically clipped DC-biased optical OFDM (eADO-OFDM) is proposed to accommodate different demands of multi-users in downlink multiple access for visible light communication systems. Meanwhile, to satisfy various dimming levels, enhanced negative ADO-OFDM (eNADO-OFDM) is investigated and combined with eADO-OFDM for multiplexing transmission. By adjusting the proportion of these two signals, the dimming control scheme can be achieved, while the entire dynamic range of light-emitting diodes is exploited. In order to achieve superior transmission performance, the optimal power allocation under the desired dimming level is studied to minimize the overall bit error rate (BER). Moreover, to obtain more accurate estimation, an iterative receiver with interference cancellation, in which the pairwise averaging and pairwise clipping are exploited, is proposed. The simulation results show that the proposed scheme can effectively carry out the dimming control with wide dimming range for illumination and achieve superior BER performance at the same signal-to-noise ratio compared to the conventional counterparts, while only a few iterations are required.

The civilian airplane is a common transportation mode for the local people in the Qinghai-Tibet Plateau (QTP). Due to the profound dynamic and thermal effects, the QTP can trigger strong windstorms during the warm season, during which downbursts can cause severe low-level wind shear and threaten aviation safety. However, the study of downbursts over QTP has not been given much attention. This study analyzes and interprets a typical traveling dry microburst line that happened at the Xining Caojiapu International Airport (ZLXN) on 14 May 2020, intending to show a better understanding of the dry downbursts over QTP and explore the synergetic usage of different remote sensing technologies for downburst detection and warning in plateau airports. Specifically, the characteristics of synoptic conditions, the convective system formation process, and the structure and evolution of downbursts and relevant low-level winds are comprehensively investigated. The results show that, under the control of an upstream shallow trough, features of the local atmosphere state, including a dry-adiabatic stratification, a shallow temperature inversion, increases in solar radiation heating, and strong vertical shears of horizontal winds, can be favorable atmospheric prerequisites for the formation and development of dry storms and downbursts. Low-reflectivity storm cells of the Mesoscale Convective System (MCS) organize to form narrow bow echoes, and downbursts show features of radial wind convergences and rapid descending reflectivity cores with hanging virga as observed by a Doppler weather radar. Moreover, details of gales, gust fronts, convergences, turbulences, wind collisions, and outflow interactions triggered by the downburst line are also detected and interpreted by a scanning Doppler wind lidar from different perspectives. In addition, the findings in this work have been compared with the results observed in Denver, U.S., and some simulation studies. Finally, a few conceptual models of low-level wind evolutions influenced by the dry downburst line are given.

Egg production is a pivotal indicator for evaluating the fertility of poultry, and the ovary is an essential organ for egg production and plays an indispensable role in poultry production and reproduction. In order to investigate different aspects of egg production mechanisms in different poultry, in this study we performed a metabolomic analysis of the transcriptomic combination of the ovaries of two chicken breeds, the high-production Ninghai indigenous chickens and the low-production Wuliangshan black-boned chickens, to analyze the biosynthesis and potential key genes and metabolic pathways in the ovaries during egg production. We predicted four genes in the transcriptomic that are associated with egg production, namely P2RX1, INHBB, VIPR2, and FABP3, and identified three important pathways during egg production, “Calcium signaling pathway”, “Neuroactive ligand–receptor interaction” and “Cytokine–cytokine receptor interaction”, respectively. In the metabolomic 149 significantly differential metabolites were identified, 99 in the negative model and 50 in the positive model, of which 17α-hydroxyprogesterone, iloprost, spermidine, and adenosine are important metabolites involved in reproduction. By integrating transcriptomics and metabolomics, the correlation between specific differential genes and differential metabolites identified important gene-metabolite pairs “VIPR2-Spermidine” and “P2RX1-Spermidine” in egg production. In conclusion, these data provide a better understanding of the molecular differences between the ovaries of low- and high-production hens and provide a theoretical basis for further studies on the mechanics of poultry egg production.

Objectives: To evaluate whether incorporating the radiomics, genomics, and clinical features allows prediction of metastasis in colorectal cancer (CRC) and to develop a preoperative nomogram for predicting metastasis.Methods: We retrospectively analyzed radiomics features of computed tomography (CT) images in 134 patients (62 in the primary cohort, 28 in the validation cohort, and 44 in the independent-test cohort) clinicopathologically diagnosed with CRC at Dazhou Central Hospital from February 2018 to October 2019. Tumor tissues were collected from all patients for RNA sequencing, and clinical data were obtained from medical records. A total of 854 radiomics features were extracted from enhanced venous-phase CT of CRC. Least absolute shrinkage and selection operator regression analysis was utilized for data dimension reduction, feature screen, and radiomics signature development. Multivariable logistic regression analysis was performed to build a multiscale predicting model incorporating the radiomics, genomics, and clinical features. The receiver operating characteristic curve, calibration curve, and decision curve were conducted to evaluate the performance of the nomogram.Results: The radiomics signature based on 16 selected radiomics features showed good performance in metastasis assessment in both primary [area under the curve (AUC) = 0.945, 95% confidence interval (CI) 0.892–0.998] and validation cohorts (AUC = 0.754, 95% CI 0.570–0.938). The multiscale nomogram model contained radiomics features signatures, four-gene expression related to cell cycle pathway, and CA 19-9 level. The multiscale model showed good discrimination performance in the primary cohort (AUC = 0.981, 95% CI 0.953–1.000), the validation cohort (AUC = 0.822, 95% CI 0.635–1.000), and the independent-test cohort (AUC = 0.752, 95% CI 0.608–0.896) and good calibration. Decision curve analysis confirmed the clinical application value of the multiscale model.Conclusion: This study presented a multiscale model that incorporated the radiological eigenvalues, genomics features, and CA 19-9, which could be conveniently utilized to facilitate the individualized preoperatively assessing metastasis in CRC patients.

Object: We aimed to identify the relationship between vertigo symptoms and the involvement of vestibular dysfunction in sudden sensorineural hearing loss (SSNHL) and the contribution of audiogram classification.Methods: A total of 50 patients with unilateral SSNHL were retrospectively divided into the vertigo group and non-vertigo group depending on the presence of vertigo. The involved vestibular end organs (VEOs) were verified by a battery of vestibular function tests including video head impulse test (vHIT), cervical vestibular-evoked myogenic potential (cVEMP), and ocular VEMP (oVEMP). The correlations of audiogram configurations, initial pure-tone average (PTA), number of involved VEOs, prognosis (complete recovery rate), and vestibular functions were analyzed between the two groups. Additionally, the vestibular functions in a subgroup of profound SSNHL patients were further compared within groups with or without vertigo.Results: Significant differences in the initial audiogram configurations (p = 0.033) and the abnormal rates of the posterior semicircular canal (PSC) (p = 0.035) and oVEMP (p = 0.046) were found between the two groups. The number of involved VEOs was related to the initial PTA in the vertigo group (p = 0.002, r = 0.541) and non-vertigo group (p = 0.042, r = 0.446). The prognosis was related to the abnormal rate of cVEMP and the number of involved VEOs in both vertigo group (p = 0.008, r = 0.482; p = 0.039, r = 0.385, respectively) and non-vertigo group (p = 0.016, r = 0.520; p = 0.022, r = 0.495, respectively), and it was especially related to the audiogram configurations in the vertigo group (p < 0.001, r = 0.692). However, after classification by audiogram configurations, there was no statistical difference in the abnormal rates of all vestibular function tests or the number of involved VEOs between the profound SSNHL patients with or without vertigo.Conclusion: The relationship between the involvement of vestibular dysfunction and vertigo symptoms in patients with SSNHL was significantly different before and after audiogram classification. When evaluating the vestibular dysfunction in SSNHL patients, more attention should be paid to the audiogram configuration.

Ovarian hyperstimulation syndrome (OHSS) is a common complication caused by ovulatory stimulation therapy, which manifests as an increase in ovarian volume, an increase in the number of oocytes retrieved, and increased vascular permeability throughout the body and especially in ovarian tissue. In our previous study, we found that electroacupuncture (EA) could prevent the progression of OHSS, by mainly affecting ovary. However, the specific molecules and the mechanism of this process were still unknown. In order to explore the underlying mechanism, OHSS rat model was established and EA treatment was performed, which was followed by proteomic analysis of ovaries. Results showed a significant increase in the expression level of CD200 in the ovaries of OHSS group treated with EA than those of OHSS group. Clinical data showed that the level of CD200 in follicular fluid was negatively correlated with the number of oocytes retrieved and serum E2 level. Further in vitro experiments showed a concentration-dependent role of human chorionic gonadotropin (hCG) in reducing CD200 and CD200R levels, and increasing inflammatory cytokine levels in cultured KGN cells. In human umbilical vein endothelial cells (HUVECs), the vascular barrier function was improved by CM (cultural medium from KGN cell) which treated with CD200Fc (CD200R agonist). Meanwhile, the results of in vivo experiments indicated that EA reduced the number of ovarian corpora lutea, decreased inflammatory response, and improved the vascular barrier function by increasing the expression of CD200 and CD200R in rat ovaries. These findings suggest that EA treatment may reduce oocyte number and maintain vascular barrier against OHSS through ovarian anti-inflammatory response mediated by CD200. Therefore, this study is the first to identify CD200 as a main of EA in the ovary and elucidate the possible mechanism of EA on preventing and treating OHSS, which provide a scientific basis for CD200 as an effector and indicator in EA treatment.

In the mammalian skeletal system, osteogenesis and angiogenesis are closely linked by type H vessels during bone regeneration and repair. Our previous studies confirmed the promotion of these processes by copper-containing metal (CCM) in vitro and in vivo. However, whether and how the coupling of angiogenesis and osteogenesis participates in the promotion of bone regeneration by CCM in vivo is unknown. In this study, M2a macrophages but not M2c macrophages were shown to be immunoregulated by CCM. A CCM, 316L−5Cu, was applied to drilling hole injuries of the tibia of C57/6 mice for comparison. We observed advanced formation of cortical bone and type H vessels beneath the new bone in the 316L−5Cu group 14 and 21 days postinjury. Moreover, the recruitment of CD206-positive M2a macrophages, which are regarded as the primary source of platelet-derived growth factor type BB (PDGF-BB), was significantly promoted at the injury site at days 14 and 21. Under the stimulation of CCM, mitochondria-derived reactive oxygen species were also found to be upregulated in CD206hi M2a macrophages in vitro, and this upregulation was correlated with the expression of PDGF-BB. In conclusion, our results indicate that CCM promotes the evolution of callus through the generation of type H vessels during the process of bone repair by upregulating the expression of PDGF-BB derived from M2a macrophages.

Although organic polymer thermoelectric (TE) materials have witnessed explosive advances in the recent decade, the molecular mechanism of crystallization engineering of TE performance, even for the most successful polymer of poly(3,4-ethylenedioxythiophene) : poly(styrene sulfonate) (PEDOT : PSS), is still far from clear. Here, we deepen the understanding of the role of annealing-induced crystalline microstructure evolution on TE performance of the PEDOT : PSS film with thickness of 10 μm, which is usually more effective than thin ones in applications. Annealed at optimized temperature of 220°C, the film displays a power factor of 162.5 times of that of the pristine film before annealing. The enhanced TE performance is associated with the changes of crystallographic and morphologic microstructures, including increased crystallinity and crystal grain size, a domain morphology transformation from granular to crystalline nanofibril, and reduced insulating PSS in the skin layer. These variances facilitate the carrier transport by a transition from 3D to 1D hopping, reduce the activation energy, and improve the carrier mobility. The mechanism of crystallization engineering reported here can be conceptually extended to other TE polymers and guides the future rational design of preparation principles for organic and composite TE materials.

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF-α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF-α; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF-κB signaling pathway stimulated by TNF-α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF-α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF-α. Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis.

Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

The improvements in muscle growth rate and meat quality are the major breeding aims in pigeon industry. Liver and muscle are recognized as important sites for fatty acid metabolism; understanding the role of specific transcripts in the breast muscle and liver might lead to the elucidation of interrelated biological processes. In this study, RNA-Sequencing (RNA-Seq) was applied to compare the transcriptomes of breast muscle and liver tissues among pigeons at five developmental periods (0, 1, 2, 3, 4 weeks post-hatching) to identify candidate genes related to muscle growth and lipid metabolism. There were 3142 differentially expressed genes (DEGs) identified in the breast muscle libraries; 1794 genes were up-regulated while 1531 genes were down-regulated. A total of 1323 DEGs were acquired from the liver libraries, with 791 up-regulated genes and 591 down-regulated genes. By pathway enrichment analysis, a set of significantly enriched pathways were identified for the DEGs, which are potentially involved in cell proliferation and differentiation, lipid metabolism and energy metabolism in pigeon breast muscle and liver. Our results are consistent with previous partial reports from domestic animals and poultry and provide some unidentified genes involved in muscle growth and lipid metabolism. The reliability of the sequencing data was verified through qPCR analysis of 16 genes from eight comparison groups (two genes per group). The findings from this study could contribute to future investigations of muscle growth and lipid metabolism mechanisms and establish molecular approaches to improve muscle growth rate and meat quality in domestic pigeon breeding.

Objective: Antiviral therapy during pregnancy has always presented difficulties in clinical practice. This review covers the safety and efficacy of the direct use of antivirals during pregnancy. Mechanism: We conducted literature research to summarize the available evidence on the use of direct-acting antivirals during pregnancy for infections due to influenza, hepatitis B and C, human immunodeficiency, herpes simplex virus, cytomegalovirus, varicella-zoster virus, Ebola, and Zika viruses, and human coronavirus. Findings in brief: To support further the rational use of antivirals during pregnancy, the discussion includes the influence of pregnancy on pharmacokinetics, safety, and transplacental permeability, and the protection of mothers and children from vertical transmission. Conclusion: Data on the use of antiviral drugs during pregnancy are currently insufficient. Promoting research on the ethics of drug experimentation, and pharmacokinetics, drug metabolism, and pharmacological effects of pregnancy, is essential to improve the care of pregnant women and even save lives during current and future outbreaks.

Mammographic density (MD) is a strong and independent factor for breast cancer (BC) risk and is increasingly associated with BC progression. We have previously shown in mice that high MD, which is characterized by the preponderance of a fibrous stroma, facilitates BC xenograft growth and metastasis. This stroma is rich in extracellular matrix (ECM) factors, including heparan sulfate proteoglycans (HSPGs), such as the BC-associated syndecan-1 (SDC1). These proteoglycans tether growth factors, which are released by heparanase (HPSE). MD is positively associated with estrogen exposure and, in cell models, estrogen has been implicated in the upregulation of HPSE, the activity of which promotes SDC expression. Herein we describe a novel measurement approach (single-sided NMR) using a patient-derived explant (PDE) model of normal human (female) mammary tissue cultured ex vivo to investigate the role(s) of HPSE and SDC1 on MD. Relative HSPG gene and protein analyses determined in patient-paired high vs. low MD tissues identified SDC1 and SDC4 as potential mediators of MD. Using the PDE model we demonstrate that HPSE promotes SDC1 rather than SDC4 expression and cleavage, leading to increased MD. In this model system, synstatin (SSTN), an SDC1 inhibitory peptide designed to decouple SDC1-ITGαvβ3 parallel collagen alignment, reduced the abundance of fibrillar collagen as assessed by picrosirius red viewed under polarized light, and reduced MD. Our results reveal a potential role for HPSE in maintaining MD via its direct regulation of SDC1, which in turn physically tethers collagen into aligned fibers characteristic of MD. We propose that inhibitors of HPSE and/or SDC1 may afford an opportunity to reduce MD in high BC risk individuals and reduce MD-associated BC progression in conjunction with established BC therapies.

Past research about social entrepreneurial intention has centered on the impact of bright personalities; however, dark personalities such as the dark triad are also considered to have advantages. This study explored the relationship between the dark triad and social entrepreneurial intention by focusing on the mediating role of moral disengagement and the moderating role of empathic concern and perspective taking. Based on a sample of 491 undergraduates and 412 students in a master in business administration program in China, the dark triad was found to be negatively related to social entrepreneurial intention through moral disengagement. Moreover, high levels of empathic concern and perspective taking weakened the direct effect of the dark triad on moral disengagement, as well as the indirect effect of the dark triad on social entrepreneurial intention. Our study extends the research in the field of personality and entrepreneurship. Given the findings on the role of moral disengagement, empathic concern, and perspective taking, education efforts may assist in decreasing the negative effects of the dark triad on social entrepreneurial intention.

This study sought to investigate the role of miR-206 in polymyositis/dermatomyositis (PM/DM) development. Transwell and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay were performed to investigate cell migration and proliferation. Real-time polymerase chain reaction (PCR) analysis was used to determine the expression of miR-206, interleukin-17A (IL-17A), IL-17 receptor A (IL-17RA), and regenerating islet-derived protein 3-alpha (REG3A). Significantly, miR-206 mimics decreased macrophage migration and proliferation, while miR-206 inhibitors exhibited the opposite effects. Indeed, elevating IL-17RA levels resulted in increased REG3A expression, which was inhibited by IL-17RA siRNA. Besides, miR-206 mimics decreased IL-17A and REG3A expressions, but miR-206 inhibitors showed opposite effects. Moreover, miR-206 expression in PM/DM patients was significantly reduced compared with the healthy controls, while IL-17A and REG3A expressions substantially increased among PM/DM patients. These findings suggested that downregulation of miR-206 increased the migration and proliferation of macrophages via IL-17A/REG3A signaling pathway, which could promote the inflammatory infiltration in PM/DM.

The SARS-CoV-2 outbreak has spread rapidly and widely since December 2019, and the effective drugs are urgently needed. The two key proteins, Mpro and Spike, are attractive therapy targets for developing drugs against SARS-CoV-2 infection. In this study, we searched for the potential inhibitors targeting Mpro and Spike based on protein sequences and structural pharmacological analysis. We found that both Mpro and Spike of SARS-CoV-2 were homologous with bat SARS-like-CoV. SARS-CoV-2 Mpro showed high conservation (sequence similarities >99%), and the existing few point mutants in different patients from diverse cities suggested that SARS-CoV-2 probably underwent adaptive evolution when the virus infection transmitted from Wuhan patients to other non-Wuhan patients. Moreover, some inhibitors for SARS-CoV Mpro could probably inhibit the activity of SARS-CoV-2 Mpro, because they do not target conserved mutated sites of SARS-CoV-2 Mpro, such as SDJ, ACE-THR-VAL-ALC-HIS-H, B4Z inhibitor, Beclabuvir, Saquinavir, and Lopinavir. In contrast, Spike of SARS-CoV-2 had more mutations and some mutant sites were distributed in the interaction domain between Spike and ACE2. A new peptide FRKSNLKPFERDISTEIYQAGSTPC, based on interactions between Spike and ACE2, could be a potential drug to treat SARS-CoV-2 patients. In summary, our study provided potential new inhibitors for targeting Mpro and Spike in SARS-CoV-2 virus-infected patients based on sequence and structural pharmacology analysis.

BACKGROUND:Valid and reliable outcome measures are needed to determine and compare treatment results of port wine stain (PWS) studies. Besides, uniformity in outcome measures is crucial to enable inter-study comparisons and meta-analyses. This study aimed to assess the heterogeneity in reported PWS outcome measures by mapping the (clinical) outcome measures currently used in prospective PWS studies. METHODS:OVID MEDLINE, OVID Embase, and CENTRAL were searched for prospective PWS studies published from 2005 to May 2020. Interventional studies with a clinical efficacy assessment were included. Two reviewers independently evaluated methodological quality using a modified Downs and Black checklist. RESULTS:In total, 85 studies comprising 3,310 patients were included in which 94 clinician/observer-reported clinical efficacy assessments had been performed using 46 different scoring systems. Eighty-one- studies employed a global assessment of PWS appearance/improvement, of which -82% was expressed as percentage improvement and categorized in 26 different scoring systems. A wide variety of other global and multi-item scoring systems was identified. As a result of outcome heterogeneity and insufficient data reporting, only 44% of studies could be directly compared. A minority of studies included patient-reported or objective outcomes. Thirteen studies of good quality were found. CONCLUSION:Clinical PWS outcomes are highly heterogeneous, which hampers study comparisons and meta-analyses. Consensus-based development of a core outcome-set would benefit future research and clinical practice, especially considering the lack of high-quality trials.

C-X-C motif chemokine ligand 8 (CXCL8) is involved in tumor proliferation, migration, and invasion. However, the function of CXCL8 in colorectal cancer (CRC) is controversial. Here, we analyzed RNA-sequencing (RNA-seq) data to identify differentially expressed genes and pathways according to gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with CRC. The levels of the mRNA encoding CXCL8 were significantly increased in early and advanced stages of CRC, as well as in metastases and nonmetastasis cases using RNA-seq analysis (n = 91). These findings were consistent with immunohistochemical analysis of CXCL8 expression (n = 87). Protein-protein interaction (PPI) prediction combined with transcriptional profiling data revealed that CXCL8 levels positively correlated with cAMP responsive element binding protein 1 (CREB1)/ribosomal protein S6 kinase B1 (RPS6KB1) expression, which promotes cell proliferation and differentiation in high expression, while inversely correlated with the expression of Bcl2 associated agonist of cell death (BAD) protein to inhibit apoptosis during the progression of CRC. These findings provide compelling clinical and molecular evidence to support the conclusion that CXCL8 contributes to the genesis and progression of CRC.

Abstract The Sertoli cell is the only somatic cell within the seminiferous tubules, and is vital for testis development and spermatogenesis. Rosiglitazone (RSG) is a member of the thiazolidinedione family and is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. It has been reported that RSG protects various types of cells from fatty acid-induced damage. However, whether RSG serves a protective role in Sertoli cells against palmitic acid (PA)-induced toxicity remains to be elucidated. Therefore, the aim of the present study was to investigate the effect of RSG on PA-induced cytotoxicity in Sertoli cells. MTT assay and Oil Red O staining revealed that RSG ameliorated the PA-induced decrease in TM4 cell viability, which was accompanied by an alleviation of PA-induced lipid accumulation in cells. In primary mouse Sertoli cells, RSG also showed similar protective effects against PA-induced lipotoxicity. Knockdown of PPARγ verified that RSG exerted its protective role in TM4 cells through a PPARγ-dependent pathway. To evaluate the mechanism underlying the protective role of RSG on PA-induced lipotoxicity, the present study analyzed the effects of RSG on PA uptake, and the expression of genes associated with both fatty acid oxidation and triglyceride synthesis. The results demonstrated that although RSG did not affect the endocytosis of PA, it significantly elevated the expression of carnitine palmitoyltransferase (CPT)-1A, a key enzyme involved in fatty acid oxidation, which indicated that the protective effect of RSG may have an important role in fatty acid oxidation. On the other hand, the expression of CPT1B was not affected by RSG. Moreover, the expression levels of diacylglycerol O-acyltransferase (DGAT)-1 and DGAT2, both of which encode enzymes catalyzing the synthesis of triglycerides, were not suppressed by RSG. The results indicated that RSG reduced PA-induced lipid accumulation by promoting fatty acid oxidation mediated by CPT1A. The effect of RSG in protecting cells from lipotoxicity was also found to be specific to Sertoli cells and hepatocytes, and not to other cell types that do not store excess lipid in large quantities, such as human umbilical vein endothelial cells. These findings provide insights into the cytoprotective effects of RSG on Sertoli cells and suggest that PPARγ activation may be a useful therapeutic method for the treatment of Sertoli cell dysfunction caused by dyslipidemia.

Alzheimer disease (AD) is characterized as a chronic neurodegenerative disease associated with aging. The clinical manifestations of AD include latent episodes of memory and cognitive impairment, psychiatric symptoms and behavioral disorders, as well as limited activities in daily life. In developed countries, AD is now acknowledged as the third leading cause of death, following cardiovascular disease and cancer. The pathogenesis and mechanism of AD remain unclear, although some theories have been proposed to explain AD, such as the theory of β-amyloid, the theory of the abnormal metabolism of tau protein, the theory of free radical damage, the theory of the inflammatory response, the theory of cholinergic damage, etc. Effective methods to predict, prevent or reverse AD are unavailable, and thus the development of new, efficient therapeutic drugs has become a current research hot spot worldwide. The isolation and extraction of active components from natural drugs have great potential in treating AD. These drugs possess the advantages of multiple targets in multiple pathways, fewer side effects and a long duration of curative effects. This article summaries the latest research progress regarding the mechanisms of natural drugs in the treatment of AD, providing a review of the literature and a theoretical basis for improving the clinical treatment of AD.

Background/Aims: Previous studies showed that CD38 deficiency protected heart from ischemia/reperfusion injury and high fat diet (HFD)-induced obesity in mice. However, the role of CD38 in HFD-induced heart injury remains unclear. In the present study, we have investigated the effects and mechanisms of CD38 deficiency on HFD-induced heart injury. Methods: The metabolites in heart from wild type (WT) and CD38 knockout (CD38-/-) mice were examined using metabolomics analysis. Cell viability, lactate hydrogenase (LDH) release, super oxide dismutase (SOD) activity, reactive oxygen species (ROS) production, triglyceride concentration and gene expression were examined by biochemical analysis and QPCR. Results: Our results revealed that CD38 deficiency significantly elevated the intracellular glutathione (GSH) concentration and GSH/GSSG ratio, decreased the contents of free fatty acids and increased intracellular NAD+ level in heart from CD38-/- mice fed with HFD. In addition, in vitro knockdown of CD38 significantly attenuated OA-induced cellular injury, ROS production and lipid synthesis. Furthermore, the expression of mitochondrial deacetylase Sirt3 as well as its target genes FOXO3 and SOD2 were markedly upregulated in the H9C2 cell lines after OA stimulation. In contrast, the expressions of NOX2 and NOX4 were significantly decreased in the cells after OA stimulation. Conclusion: Our results demonstrated that CD38 deficiency protected heart from HFD-induced oxidative stress via activating Sirt3/FOXO3-mediated anti-oxidative stress pathway.

Abstract Background The Hospital for Special Surgery Hip Replacement Expectations Survey (HSS-THRES) and Knee Replacement Expectations Survey (HSS-TKRES) are widely used tools developed to assess patients’ preoperative expectations for total hip and knee arthroplasty. This study aimed to translate and adapt the HSS-THRES and HSS-TKRES into Chinese versions (SC-THRES/TKRES) and evaluate their psychometric properties in patients with osteoarthritis (OA) and ankylosing spondylitis (AS). Methods Patients scheduled for total hip (104 hip OA and 51 AS) or knee replacements (101 knee OA) were recruited in this study. Confirmatory Factor Analysis (CFA) was used to evaluate structural validity. The internal consistency was assessed by the Cronbach’s α coefficient. The intraclass correlation coefficient (ICC) was used to assess test-retest reliability. The construct validity was analyzed by evaluating the correlations between SC-THRES/TKRES and the Expectation WOMAC. The correlations with the Expectation WOMAC were tested against our hypotheses. We additionally compared preoperative expectations of AS patients to those of hip OA patients. Results The results of CFA for the SC-THRES and SC-TKRES demonstrated good fit. The results for the SC-THRES/TKRES revealed good test-retest reliability and good internal consistency (AS: ICC = 0.893, Cronbach’s α = 0.815; hip OA: ICC = 0.878, Cronbach’s α = 0.814; knee OA: ICC = 0.806, Cronbach’s α = 0.808). The correlations between the SC-THRES/TKRES and the Expectation WOMAC were moderate (0.541 for AS, 0.490 for hip OA and 0.465 for knee OA), which were consistent with the hypotheses. Conclusion The SC-THRES/TKRES are reliable, valid for the evaluation of Chinese patients with OA and AS undergoing total hip and knee arthroplasty. The surveys can be used as part of preoperative assessments. Meanwhile, additional research is needed to replicate these findings and to assess the content validity in a larger sample.

Metastasis is one of the major obstacles for successful therapy of breast tumor. To inhibit the metastasis and growth of breast tumor simultaneously, a Celastrol (Cela) loaded glucolipid-like conjugates (CSOSA/Cela) with αvβ3-ligand Tetraiodothyroacetic acid (TET) modification (TET-CSOSA/Cela) were established to block nuclear factor-kappa B (NF-κB) signaling pathway. The distribution of TET-CSOSA was remarkably increased in lung metastasis and primary tumor of 4T1 tumor-bearing mice by means of αvβ3 receptor-mediated interaction. The results demonstrated that TET-CSOSA/Cela significantly suppressed Bcl-2 activation of lung metastatic cells and reduced MMP-9 expression of 4T1 breast tumor cells by blocking NF-κB. The inhibitory rates of TET-CSOSA/Cela against lung metastasis and primary tumor were raised to 90.72 and 81.15%, compared to those of Celastrol (72.15 and 46.40%), respectively. All results demonstrated the αvβ3 receptor targeted TET-CSOSA/Cela micelles exhibited great potential in treating lung metastasis and primary tumor simultaneously via blocking NF-κB signaling pathway.

Six degree-of-freedom (6-DOF) robotic manipulators have been increasingly adopted in various applications in industries due to various advantages, such as large operation space, more degrees of freedom, low cost, easy placement, and convenient programming. However, the robotic manipulator has the problem of insufficient stiffness due to the series structures, which will cause motion errors of the manipulator end. In this paper, taking a 6-DOF robotic manipulator as an example, forward and inverse kinematics models are established, and a new modeling method for the joint angle and space stiffness of the end of the manipulator is proposed, which can establish the composite stiffness model of joint link stiffness and joint stiffness. An error compensation model is subsequently established. The experimental results indicate that the proposed error compensation method can effectively reduce the end motion error of the robotic manipulator, and hence, the working performance and accuracy of the manipulator can be improved. The proposed research is helpful for extending the application of robotic manipulators in precision machining and measurement.

Abstract Background Critically evaluation and summarization for the outcomes between autografts and artificial grafts using in anterior cruciate ligament (ACL) reconstruction have not been performed currently. The purpose of this study is to compare the clinical outcomes between artificial ligaments and autografts at a short- to mid-term follow-up. Methods A computerized search of the databases was conducted including Medline, Embase, and the Cochrane library. Only prospective or retrospective comparative studies with a minimum 2-year follow-up and a minimum sample size of 15 for each group were considered for inclusion. Two independent reviewers performed data extraction and methodological quality assessment. A Mantel-Haenszel analysis was used for pooling of results. Sensitivity analysis was performed in order to maintain the stability of results. Results Seven studies were included in this study. The total sample size was 403 (autograft group: 206 patients; synthetic graft group: 197 patients). Four studies were randomized controlled trials. Two studies were retrospective comparative studies and one study was non-randomized prospective comparative study. In terms of instrumented laxity, patient-oriented outcomes and complications, no significant difference was occurred between new artificial ligaments and autografts. But the results of IKDC grades and instrumented laxity were worsen in early artificial ligaments compared to autografts. Conclusions The outcomes of new generation of artificial ligaments are similar to autografts at a short- to mid-term follow-up. However, the early artificial ligaments are not suggested for ACL reconstruction compared to autografts.

The activation of TLR7 signaling in T cells accelerates antigen-specific responses. Such responses play an essential role in eliminating viral infections and can be anti-tumorigenic. However, the underlying mechanisms of how TLR7 can promote the optimal function of CD8+ T cells remain unclear. To investigate how TLR signaling directly contributes to CD8+ T cell functions, we examine the activation of cellular TLR7-related pathways and functional and metabolic alterations in TLR7-stimulated T cells during T cell receptor (TCR) signaling. In the present study, we investigated the activation of CD8+ T cells in response to direct stimulation by TLR7 ligands. TLR7 stimulation could promote the effector functions of purified CD8+ T cells in vitro. The TLR7-induced activation of CD8+ T cells occurs if CD8+ T cells were primed by αCD3 activation and increasingly expressed TLR7. MyD88 and AKT-mTOR signaling plays a critical role in TLR7-induced T cell activation. In addition to the upregulation of immune-related genes, metabolic alterations in CD8+ T cells, including the upregulation of glucose uptake and glycolysis, occurred by TLR7 stimulation. Glycolysis was found to be regulated by the AKT-mTOR pathway and a downstream transcription factor IRF4. Blocking glycolysis by either direct glucose deprivation or modulating the mTOR pathway and IRF4 expression was found to impair T cell activation and functions. Taken together, the activation of TLR7 signaling promotes the effector functions of CD8+ T cells by enhancing cellular glycolysis.

Summary: Dysregulated axonal trafficking of mitochondria is linked to neurodegenerative disorders. We report a high-content screen for small-molecule regulators of the axonal transport of mitochondria. Six compounds enhanced mitochondrial transport in the sub-micromolar range, acting via three cellular targets: F-actin, Tripeptidyl peptidase 1 (TPP1), or Aurora Kinase B (AurKB). Pharmacological inhibition or small hairpin RNA (shRNA) knockdown of each target promotes mitochondrial axonal transport in rat hippocampal neurons and induced pluripotent stem cell (iPSC)-derived human cortical neurons and enhances mitochondrial transport in iPSC-derived motor neurons from an amyotrophic lateral sclerosis (ALS) patient bearing one copy of SOD1A4V mutation. Our work identifies druggable regulators of axonal transport of mitochondria, provides broadly applicable methods for similar image-based screens, and suggests that restoration of proper axonal trafficking of mitochondria can be achieved in human ALS neurons. : Shlevkov et al. establish a high-content screen for enhancers of axonal mitochondrial trafficking. Identified compounds act through three cellular targets: F-Actin, Tripeptidyl peptidase 1, and Aurora Kinase B. Motor neurons derived from a SOD1+/A4VALS patient have decreased mitochondrial motility, which can be reversed by inhibitors of these targets. Keywords: mitochondria, high-content screening, Aurora B, TPP1, F-actin, ALS, axonal transport

Background Few well-designed studies have investigated water exchange colonoscopy (WE). We performed a meta-analysis to comprehensively evaluate the clinical utility of WE based on high-quality randomized controlled trials (RCTs) and to compare the impacts of WE, water immersion colonoscopy (WI), and gas-insufflation colonoscopy. Methods We searched the Cochrane Library, MEDLINE, Embase, PubMed, Elsevier, CNKI, VIP, and Wan Fang Data for RCTs on WE. We analyzed the results using fixed- or random-effect models according to the presence of heterogeneity. Publication bias was assessed by funnel plots. Results Thirteen studies were eligible for this meta-analysis. The colonoscopic techniques included WE as the study group, and WI and air- or CO 2 -insufflation colonoscopy as control groups. WE was significantly superior to the control procedures in terms of adenoma detection rate, proportion of painless unsedated colonoscopy procedures, and cecal intubation rate according to odds ratios. WE was also significantly better in terms of maximal pain score and patient satisfaction score according to mean difference. Conclusions WE can remarkably improve the adenoma detection rate, proportion of painless unsedated colonoscopy procedures, patient satisfaction, and cecal intubation rate, as well as reducing the maximal pain score in patients undergoing colonoscopy.

In this paper, a new chaotic system is proposed based on mixing three-dimensional Chen chaotic system with a chaotic tactics. This new system is proved to be chaotic under Wiggins’ chaos definition and can generate chaotic sequences with high complexity. Furthermore, we propose a new pseudorandom bit generator (PRBG) based on this new system. A coding algorithm is used to make the sequences uniform. Both statistical and security tests are provided to show the generated sequences are with good randomness and high complexity to withstand attacks.

Folic acid (FA) is an important vitamin for human growth, especially for pregnant women. FA deficiency is associated with megaloblastic anemia, neural tube defects, cardiovascular diseases, irritability, diarrhea, and psychiatric disorders. Normally, FA molecules bind to folate-binding protein (FBP) in the serum as complex. Before quantify the FA concentration, a releasing procedure should be conducted. Alkaline condition and tris(2-carboxyethyl)phosphine (TCEP) are used to release binding FA to freeing state. In this work, a chemiluminescence immunoassay (CLIA) for human serum FA was established by competition model. Streptavidin (SA) was labeled to magnetic beads by an 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDAC/NHS) method. Activated biotin molecules were labeled to FBP molecules purified from milk. FA was labeled to horseradish peroxidase (HRP) by EDAC to activate the FA molecules. The pretreated samples or standards were added into the reaction tube with biotin-FBP and FA-horseradish peroxidase (HRP), FA in the sample compete with FA-HRP for binding to biotin-FBP, the signal is inversely proportional to the FA concentration. The method established shows good thermostability and performance. The limitation of detection (LOD) is 0.44 ng/mL. The intra-assay coefficient of variation (CV) is 3.6%–7.1%, the interassay CV is 4.2%–7.5%, and the recovery rate is 92.1%–103.5%. Cross reactivity (CR) was remarkably low with aminopterin, folinic acid, and methotrexate. The method shows good correlation with the FA CLIA product from Beckman Coulter; the equation is y = 0.9618x−0.1434 while the R2 value is 0.9224. The established method is sensitive, rapid, and accurate which can fully satisfy for the clinical requirement.

It is theoretically plausible that social anxiety (SA) and social relationships (SR) can influence each other. However, the available empirical evidence is inconsistent, leading to substantial uncertainty regarding the cross-lagged relations between SA and SR. This meta-analysis systematically integrates data from 107 longitudinal studies, comprising 110 independent samples and involving a total of 115,133 participants from childhood to adulthood. Four types of SR were assessed: family-related, school-related, romantic, and general relationships. One-stage meta-analytic structural equation modeling was applied to fit four cross-lagged panel models and to test potential moderators. No significant publication bias was detected. Effect size analyses revealed that prior SA significantly and negatively predicted quality of all types of SR. Family-related and general relationships each predicted prospective SA symptoms, but school-related and romantic relationships did not. No moderators were identified in analyses of family-related and romantic relationships. However, the publication year, sample age, gender, reporter, and time lag played a moderating role in analyses of school-related and general relationships. These findings suggest that SA is a crucial factor undermining SR and that dysfunctional family and general relationships also contribute to the exacerbation of SA symptoms. The strengths, limitations, and future directions of this study are discussed.

The law of pollutant emission and diffusion in stratified waters is a common issue. In this paper, numerical study on the interaction between vertical turbulent jets and the pycnocline is carried out to study the problems of jet’s emission through the large eddy simulation (LES). A trigonometric function disturbance (TFD) method is developed to ensure the velocity distribution of the jet in the horizontal plane yield to Gaussian profile. Numerical simulations are carried out in the range of 1.11 < Frp < 4.77, corresponding to 1393 < Rep < 5979, where the Froude number Frp and the Reynolds number Rep are defined at the entrance of pycnocline. The coherent structure and internal waves are observed at the pycnocline during the process of jets impinging. After the impingement, the destratification effects can be found. It can be found that Frp = 3 is a threshold value for the interaction between jets and the pycnocline. When Frp > 3, the interaction becomes intensely. Furthermore, the fitting formula of the radial momentum flux dissipation rate that is used to describe the decay of energy contained by the jets during the impinging process, is established through the dimensionless analysis. As a result, the influence range of the jet on the horizontal plane can be evaluated by Rep. It is also found that the destratification of jets is mainly affected by the velocity of the internal wave induced by jets. In addition, by employing the dimensionless time T related to that velocity, the law of destratification varies with dimensionless time is obtained, which can be summarized as follows: Due to the influence of the first internal wave, the thickness of the pycnocline increases rapidly and reaches a critical value at T = 1.4, after that, the increase of the thickness of the pycnocline becomes linear.

Antifibrinolytic site-specific pharmaco-laser therapy (SSPLT) is an experimental treatment modality for refractory port wine stains (PWS). Conceptually, antifibrinolytic drugs encapsulated in thermosensitive liposomes are delivered to thrombi that form in semi-photocoagulated PWS blood vessels after conventional laser treatment. Local release of antifibrinolytics is induced by mild hyperthermia, resulting in hyperthrombosis and complete occlusion of the target blood vessel (clinical endpoint). In this study, 20 thermosensitive liposomal formulations containing tranexamic acid (TA) were assayed for physicochemical properties, TA:lipid ratio, encapsulation efficiency, and endovesicular TA concentration. Two candidate formulations (DPPC:DSPE-PEG, DPPC:MPPC:DSPE-PEG) were selected based on optimal properties and analyzed for heat-induced TA release at body temperature (T), phase transition temperature (Tm), and at T > Tm. The effect of plasma on liposomal stability at 37 °C was determined, and the association of liposomes with platelets was examined by flow cytometry. The accumulation of PEGylated phosphocholine liposomes in laser-induced thrombi was investigated in a hamster dorsal skinfold model and intravital fluorescence microscopy. Both formulations did not release TA at 37 °C. Near-complete TA release was achieved at Tm within 2.0–2.5 min of heating, which was accelerated at T > Tm. Plasma exerted a stabilizing effect on both formulations. Liposomes showed mild association with platelets. Despite positive in vitro results, fluorescently labeled liposomes did not sufficiently accumulate in laser-induced thrombi in hamsters to warrant their use in antifibrinolytic SSPLT, which can be solved by coupling thrombus-targeting ligands to the liposomes.

Since urban open spaces provide various benefits to the citizens, it is necessary to improve the outdoor thermal comfort in urban open spaces. However, global warming increases heat stress and at the same time decrease cold stress of outdoor spaces. The final impact of climate change on outdoor thermal comfort is not evident, and depends on the climate characteristics. This study investigated the influence of climate change on outdoor thermal comfort conditions of five selected cities (Minneapolis, New York City, San Francisco, Miami, and Las Vegas) with distinctive climate patterns in the United States. It is found that all cities suffered from deterioration in thermal comfort. This is because the increases in the heat stress rate were greater than the decreases in cold stress rate. In the 2080s, the greatest reduction in acceptable thermal stress rate happened in Miami from 44.7% to 21.3% under high emission scenario.

The inhibitor of apoptosis protein (IAP) genes are frequently overexpressed in malignancies. Second mitochondria-derived activator of caspase (SMAC) mimetics, which target IAPs, have potential to trigger cancer cell death and sensitize tumor cells to cytotoxic therapy. The aim of this study was to investigate the anti-tumor potential of a novel bivalent SMAC mimetic, APG-1387, in hepatocellular carcinoma (HCC). The mRNA and protein expressions of IAPs, including cellular IAPs (cIAP1 and cIAP2) and X chromosome-linked IAP (XIAP), were increased in HCC tumors compared with normal liver tissue. APG-1387 treatment alone significantly reduced the protein levels of IAPs, but had only a modest effect on the viability and apoptosis of HCC cells in vitro. However, APG-1387 in combination with tumor necrosis factor-alpha (TNF-α) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly reduced cell viability and proliferation, and induced apoptosis in HepG2 cells, as well as in HCCLM3 cells that harbors cancer stem cell-like properties. These synergistic killing effects were caspase-dependent and partially dependent on RIPK1 kinase activity. Furthermore, APG-1387 also promoted the killing effect of Natural Killer cells on HCC cells in vitro and the combination therapy significantly inhibited tumor growth by inducing cell apoptosis in xenograft mice model. In conclusion, our study clarified that APG-1387 could sensitize HCC cells to cytokines or immune cells mediated cell killing and implied that potential of SMAC mimetic based combination immunotherapy for HCC treatment.

ABSTRACT Spiders, as predators of insects and other invertebrates, are an important part of the natural enemies, and they are recognized as an important biological control agent. Plutella xylostella (Linnaeus, 1758), the diamondback moth (DBM), is a well-known and destructive insect pest of brassicaceous crops worldwide. Here, we analyzed the functional responses of four spiders (Araneae) - Ebrechtella tricuspidata (Fabricius, 1775) (Thomisidae), Pardosa laura (Karsch, 1879) (Lycosidae), Pardosa astrigera (Koch, 1878) (Lycosidae), and Pardosa pseudoannulata (Bösenberg & Strand, 1906) (Lycosidae) - on P. xylostella larvae. We also analyzed intraspecific disturbances in the predation reaction and the intensity of scrambling competition of the spiders to P. xylostella larvae. Our results demonstrated that the functional responses of four spiders of different genera were in line with the Holling II model. Two Lycosidae spiders (P. astrigera and P. pseudoannulata) had the potential to control P. xylostella, and female and male spiders that belonged to the same species had different functional responses to P. xylostella. The functional responses of female predation of P. astrigena, P. laura, and P. pseudoannulata was stronger than the males, but male E. tricuspidatus had stronger functional responses to predation than females. We used the Hassell model to describe the intraspecific disturbance experiments of four spiders. There were intraspecific disturbances in the predation reactions of spiders, indicating that the predation ratio of spiders decreased in relation to the increase of its density, and with the increase of spider density, the intensity of scrambling competition of the spider increased.

Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-α and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection.

Sichuan white goose (SCW) is one of the famous indigenous breeds in China. It is the first time that the complete mitochondrial genome sequence of the SCW has been reported. The total length of the mtDNA is 16,741 bp. It contains the typical structure, including 22 transfer RNA genes, 2 ribosomal RNA genes, 13 protein-coding genes, and 1 non-coding control region (D-loop region). The overall composition of the mtDNA was estimated to be 30.27% for A, 22.62% for T, 32.09% for C, and 15.02% for G. Phylogenetic analyses using N-J computational algorithms showed that the analyzed 18 Anseriform species are divided into four major clades: Anatinae, Anserinae, Dendrocygninae and Anseranatidae. In addition, our work confirmed that SCW has a close genetic relationship with Anser albifrons. This work will provide an important dataset for studying the genetic mechanism of goose in China.

Landes goose (LG) is a famous fatty liver breed in the world. It is the first time that the complete mitochondrial genome sequence of the LG was reported. The total length of the mtDNA is 16,743 bp, it contains the typical structure, including 22 transfer RNA genes, two ribosomal RNA genes, 13 protein-coding genes, and one non-coding control region (D-loop region). The overall composition of the mtDNA was estimated to be 30.10% for A, 22.57% for T, 32.19% for C, and 15.14% for G. Phylogenetic analyses using N-J computational algorithms showed that the analyzed 18 Anseriform species are divided into four major clades: Anatinae, Anserinae, Dendrocygninae, and Anseranatidae. In addition, our work confirmed that LG and Anser anser have a close genetic relationship with fellow tribal members Anser fabalis.

We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with febrile seizures plus (GEFS+), and N79S was found in a single patient with generalized tonic–clonic seizures (GTCS). Although all three mutations were located in an N-terminal loop that contributes to the γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(N79S) subunits were efficiently assembled into GABAA receptors with only minimally altered receptor trafficking, suggesting that N79S was a rare or susceptibility variant rather than an epilepsy mutation. Increased structural variability at assembly motifs was predicted by R82Q and P83S, but not N79S, substitution, suggesting that R82Q and P83S substitutions were less tolerated. Membrane proteins with missense mutations that impair folding and assembly often can be “rescued” by decreased temperatures. We coexpressed wildtype or mutant γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, suggesting that lower temperatures increased GABAA receptor stability. Thus epilepsy-associated mutations N79S, R82Q and P83S disrupted GABAA receptor assembly to different extents, an effect that could be potentially rescued by facilitating protein folding and assembly.

The circadian clock in plants synchronizes biological processes that display cyclic 24-h oscillation based on metabolic and physiological reactions. This clock is a precise timekeeping system, that helps anticipate diurnal changes; e.g., expression levels of clock-related genes move in synchrony with changes in pathogen infection and help prepare appropriate defense responses in advance. Salicylic acid (SA) is a plant hormone and immune signal involved in systemic acquired resistance (SAR)-mediated defense responses. SA signaling induces cellular redox changes, and degradation and rhythmic nuclear translocation of the non-expresser of PR genes 1 (NPR1) protein. Recent studies demonstrate the ability of the circadian clock to predict various potential attackers, and of redox signaling to determine appropriate defense against pathogen infection. Interaction of the circadian clock with redox rhythm promotes the balance between immunity and growth. We review here a variety of recent evidence for the intricate relationship between circadian clock and plant immune response, with a focus on the roles of redox rhythm and NPR1 in the circadian clock and plant immunity.