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Abstract Colorectal cancer (CRC) ranks as one of the most common malignancies worldwide. Myeloid‐derived suppressor cells (MDSCs) represent an immunosuppressive heterogeneous population of immature monocytes and granulocytes constituting a major obstacle for CRC therapy. Previous studies demonstrated that WNT2 is enriched in tumor microenvironment (TME), promoting CRC progression. However, the role of WNT2 in regulating MDSCs to facilitate CRC progression remains largely unexplored. Our analysis of The Cancer Genome Atlas (TCGA) database and blood samples from 50 primary and recurrent CRC patients revealed a positive correlation between WNT2 expression and MDSCs abundance. Treatment with recombinant WNT2 protein significantly enhanced the accumulation and immunosuppressive function of MDSCs in vitro. Conversely, anti‐WNT2 monoclonal antibody remarkably reduced the percentage and functional activity of MDSCs in CRC tumor‐bearing mice. Mechanistic analyses further demonstrated that WNT2 mediates MDSCs activities through the p38 MAPK/Akt pathway. Collectively, our findings not only highlight the pivotal role of WNT2 in CRC progression by enhancing MDSCs activities within the TME, but also provide evidence that WNT2 levels and MDSCs abundance in peripheral blood could serve as predictive biomarkers for early diagnosis and prognosis of CRC patients.

Abstract Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Abstract Background Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. Methods The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. Results Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. Conclusion Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

Objective: Current cost-effectiveness analyses of amblyopia screening are mainly from western countries. It remains unclear whether it is cost-effective to implement a preschool amblyopia screening programme in China. Our study aimed to evaluate the cost-effectiveness of a hypothetical kindergarten-based amblyopia screening versus non-screening among 3-year-old children. Methods: We developed a decision tree combined with a Markov model to compare the cost and effectiveness of screening versus non-screening for 3-year-old children from a third-party payment perspective. The primary outcomes were quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Costs were obtained from expert opinions in different regions of China. Transition probabilities and health utilities were mainly based on published literature and open sources. Sensitivity analyses were performed to assess the impact of parameters’ uncertainty on results. Results: Base-case analysis demonstrated that the ICER of screening versus non-screening was $17,466/QALY, well below the WTP threshold ($38,223/QALY) for China. One-way sensitivity analysis showed that the prevalence of amblyopia, the transition probability per year from untreated amblyopia to healthy, and the discount rate were the top three factors. The likelihood of cost-effectiveness of screening compared with non-screening was 92.56%, according to probabilistic sensitivity analysis. Scenario analysis also indicated that ICER was lower than the WTP threshold even if the time horizon was shortened or the screening was delayed to the age of 4 or 5. Conclusions: Amblyopia screening could be considered a cost-effective strategy compared to non-screening for 3-year-old children in China. Screening for children at the age of 4 or 5 may even yield better results.

Microglia plays an important role in the production of inflammation in the central nervous system. Excessive nerve inflammation can cause neuronal damage and neurodegenerative disease. It has been shown that EPA-enriched ethanolamine plasmalogen (EPA-PlsEtn) significantly inhibited the expressions of inflammatory factors and suppressed neuronal loss in a rat model of Alzheimer's disease. However, whether EPA-PlsEtn protects against neuronal loss by inhibiting the activation of microglia is still not clear. Therefore, we examined the effect of PlsEtn on SH-SY5Y cells incubated by conditioned medium from LPS-induced BV2 cells as a neuroinflammation model. Results showed that pre-incubation of LPS-induced BV2 cells with PlsEtn significantly improved the viability of SH-SY5Y cells by reducing the early apoptosis. The increasing production of NO and TNF-α in BV2 cells was reversed by PlsEtn treatment, while the decreasing level of IL-10 was raised. Polarization toward M1 phenotype and activation of NLRP3 inflammasome pathways are attenuated significantly by pre-treatment of PlsEtn in LPS-induced BV2 cells. The study provides evidence for a positive effect of PlsEtn on neuroprotection and the inhibition of neuroinflammation, and PlsEtn may be explored as a potential functional ingredient with neuroprotection effects.

ObjectiveTo examine the equity in human resources allocation in centers for disease prevention and control (CDCs) and to provide evidences for optimizing resource allocation. Methods The data on human resources among CDCs in all administrative regions across China in 2014 and 2019 were collected from China′s Statistical Yearbook of Health and Family Planning – 2015 and China′s Statistical Yearbook of Health – 2020. Then, health resource agglomeration degree (HRAD) was used to evaluate the equity in human resources allocation according to population and geographical area. Results The total number of personnel in CDCs across China decreased by 2.51% from 192 397 in 2014 to 187 564 in 2019. The number of CDCs′ personnel per 10 000 population also showed a shrinking trend at all provincial levels and the number for most provincial level regions did not meet the national standard. In 2019, the proportions of CDC personnel at young age (< 35 years) and middle-aged (35 – 54 years) decreased by 3.8% and 2.4% compared with those in 2014, but the proportion of elderly personnel (≥ 55 years) increased by 6.0% contrasting to that in 2014. The number of personnel with high school/technical secondary school education or below in all CDCs in China decreased from 28.8% in 2014 to 19.4% in 2019, while the number of those with junior college education or above increased from 71.1% in 2014 to 80.6% in 2019. The results of analysis on the equity in human resources allocation showed that the spatial distribution of human resource was unbalanced. The geographical region-specific HRAD index was the highest (indicating a better equity in human resources allocation) for eastern region, followed by that for central and western region; while, the population distribution-specific HRAD index was higher for western region than that for central and eastern region. Conclusion Insufficient total number, serious turnover and unbalanced allocation are main problems in health resources allocation for CDCs in China and the situation needs to be improved for CDCs′ capability construction in China.

Abstract Background Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR. Methods We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis. Results From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1–3 times per capita GDP of Chinese in 2019). Conclusions Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China.

Background The HIV epidemic in key populations such as men who have sex with men (MSM) is a public health issue of worldwide concern. China has seen an increase in newly diagnosed HIV infections through male–male sexual contact in the past decade. In a long-term cohort, how the complex behaviour pattern of MSM changed and the association with the HIV risk are unclear at present.Methods This study was conducted from October 2011 to December 2019 in Tianjin. MSM were recruited by snowball sampling through online and offline ways. Demographic and sexual behavioural data were collected for analysis. Three indicators (condom use in last anal sex, frequency of condom use during anal sex and the number of sexual partners) were used to define the behaviour change. Participants with zero, one, and two or three risk indicators were categorised into behaviour types of ‘protective’, ‘moderate’, and ‘fragile’, respectively. Change in behaviour type between baseline and each visit was considered. Time-varying Cox models were performed to evaluate HIV infection risk.Results Of 2029 MSM included in the study, 127 were new HIV diagnoses. The overall incidence rate was 3.36 per 100 person-years. The percentage of ‘protective’ and ‘moderate’ behaviour types had a conspicuous growth trend as the follow-up. Furthermore, the HIV incidence rate in each visit among different behaviour transition types showed a general downward trend as the number of total follow-up times increased. Individuals who remained in ‘fragile’ (adjusted HR (aHR): 25.86, 95% CI: 6.92 to 96.57) or changed from ‘protective’ to ‘moderate’ (aHR: 4.79, 95% CI: 1.18 to 19.47), ‘protective’ to ‘fragile’ (aHR: 23.03, 95% CI: 6.02 to 88.13), and ‘moderate’ to ‘fragile’ (aHR: 25.48, 95% CI: 6.79 to 95.40) between baseline and the last follow-up had a higher HIV risk. Gained risk indicators were associated with the increase of HIV risk (gained one indicator, aHR: 2.67, 95% CI: 1.68 to 4.24; gained two or three indicators, aHR: 4.99, 95% CI: 3.00 to 8.31) while losing just one risk indicator could halve the risk (aHR: 0.43, 95% CI: 0.21 to 0.90).Conclusions Among MSM in Tianjin, it is necessary to get timely behaviour change for those with high-incidence behaviour patterns while sustaining for those with low-incidence patterns.Trial registration number Chinese Clinical Trials Registry (ChiCTR2000039500).

Nerve damage caused by accumulated oxidative stress is one of the characteristics and main mechanisms of Alzheimer’s disease (AD). Previous studies have shown that phosphatidylserine (PS) rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) plays a significant role in preventing and mitigating the progression of AD. However, whether DHA-PS and EPA-PS can directly protect primary hippocampal neurons against oxidative damage has not been studied. Here, the neuroprotective functions of DHA-PS and EPA-PS against H2O2/t-BHP-induced oxidative damage and the possible mechanisms were evaluated in primary hippocampal neurons. It was found that DHA-PS and EPA-PS could significantly improve cell morphology and promote the restoration of neural network structure. Further studies showed that both of them significantly alleviated oxidative stress-mediated mitochondrial dysfunction. EPA-PS significantly inhibited the phosphorylation of ERK, thus playing an anti-apoptotic role, and EPA-PS significantly increased the protein expressions of p-TrkB and p-CREB, thus playing a neuroprotective role. In addition, EPA-PS, rather than DHA-PS could enhance synaptic plasticity by increasing the expression of SYN, and both could significantly reduce the expression levels of p-GSK3β and p-Tau. These results provide a scientific basis for the use of DHA/EPA-enriched phospholipids in the treatment of neurodegenerative diseases, and also provide a reference for the development of related functional foods.

The growth and development of the fetus and newborn throughout pregnancy and lactation are directly related to the nutritional status of the mother, which has a significant impact on the health of the offspring. The purpose of this experiment was to investigate the susceptibility of n-3 polyunsaturated fatty acid deficiency in early life to seizures in adulthood. The n-3 PUFAs-deficient mice’s offspring were established and then fed with α-LNA diet, DHA-enriched ethyl ester, and DHA-enriched phospholipid-containing diets for 17 days at the age of eight weeks. During this period, animals received intraperitoneal injections of 35 mg/kg of pentylenetetrazol (PTZ) every other day for eight days. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate PTZ-induced epileptic seizures and brain disorders. Notably, nutritional supplementation with n-3 PUFAs in adulthood for 17 days could significantly recover the brain n-3 fatty acid and alleviate the epilepsy susceptibility as well as raise seizure threshold to different levels by mediating the neurotransmitter disturbance and mitochondria-dependent apoptosis, demyelination, and neuroinflammation status of the hippocampus. DHA-enriched phospholipid possessed a superior effect on alleviating the seizure compared to α-LNA and DHA-enriched ethyl ester. Dietary n-3 PUFA deficiency in early life increases the susceptibility to PTZ-induced epilepsy in adult offspring, and nutritional supplementation with n-3 PUFAs enhances the tolerance to the epileptic seizure.

Abstract Background Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been reported that dietary DHA-enriched phosphatidylcholine (DHA-PC) and phosphatidylserine (DHA-PS) could improve brain function. However, it was unclear that whether supplementation of DHA-PC and DHA-PS could change lipid profiles in the brain of dementia animals. Methods SAMP8 mice was fed with different diet patterns for 2 months, including high-fat diet and low-fat diet. After intervention with DHA-PC and DHA-PS for another 2 months, the lipid profile in cerebral cortex was determined by lipidomics in dementia mice. Results High-fat diet could significantly decrease the levels of DHA-containing PS/pPE, DPA-containing PS, and AA-containing PE, which might exhibit the potential of lipid biomarkers for the prevention and diagnosis of AD. Notably, DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice. These might provide a potential novel therapy strategy and direction of dietary intervention for patients with cognitive decline. Conclusions DHA-PC and DHA-PS could recover the content of brain DHA-containing PS and pPE in SAMP8 mice fed with high-fat diet. Abstract graphical

Background: Angiogenesis plays an important role in the development of rheumatoid arthritis (RA), which increases the supply of nutrients, cytokines, and inflammatory cells to the synovial membrane. Genistein (GEN), a soy-derived isoflavone, has been validated that can effectively inhibit the angiogenesis of several tumours. We thus carried out a study in vitro to investigate the effect of GEN in vascular endothelial growth factor (VEGF) expression and angiogenesis induced by the inflammatory environment of RA. Methods: MH7A cells were used to verify whether GEN can inhibit the expression of VEGF in MH7A cells under inflammatory conditions and demonstrate the mechanism. EA.hy926 ​cells were used to verify whether GEN can inhibit the migration and tube formation of vascular endothelial cells in inflammatory environment. Results: GEN dose-dependently inhibited the expression and secretion of interleukin (IL)-6 and VEGF, as well as the nucleus translocation of Signal transducer and activator of transcription 3 (STAT3) in MH7A. Furthermore, GEN inhibited IL-6–induced vascular endothelial cell migration and tube formation in vitro. Conclusion: GEN inhibits IL-6–induced VEGF expression and angiogenesis partially through the Janus kinase 2 (JAK2)/STAT3 pathway in RA, which has provided a novel insight into the antiangiogenic activity of GEN in RA. The translational potential of this article: Our study provides scientific guidance for the clinical translational research of GEN in the RA treatment.

Abstract Background Pembrolizumab (Pembro) in combination with chemotherapy has been approved for the treatment of pretreated advanced NSCLC in the United States and China for its significant efficacy. However, the cost‐effectiveness is unknown considering Pembro's high price. The impact of programmed death ligand 1 (PD‐L1) test on the cost‐effectiveness is also unknown. The current study assessed the cost‐effectiveness of combination therapy for nonsquamous NSCLC from the United States and China public payers’ perspective. Materials and Methods A literature‐based Markov model was conducted using KEYNOTE‐189 trial data to compare cost and quality‐adjusted life years (QALYs) of three treatment strategies for nonsquamous NSCLC: Pembro‐chemotherapy combination and chemotherapy strategy without PD‐L1 test, and treatment strategy according to their PD‐L1 status. Results In base case analysis, the combination strategy generated an additional 0.78 QALYs and 0.59 QALYs over chemotherapy in the United States and China respectively, resulting in an ICER of $132 392/QALY in the United States and $92 533/QALY in China. In the PD‐L1 ≥1% base case, the ICERs were $77 754/QALY and $56 768/QALY respectively in the United States and China for PD‐L1 test strategy. In the PD‐L1 ≥50% base case, the ICERs were $44 731/QALY and $34 388/QALY respectively in the United States and China for PD‐L1 test strategy. Lowering Pembro price can also partly decrease the ICERs. Conclusion Compared with chemotherapy, the combination strategy is not cost‐effective for the treatment of NSCLC in the American and Chinese health care system at WTP threshold of $100 000/QALY for the United States and $27 351/QALY for China. Using PD‐L1 test for patient selection and price reduction could improve the cost‐effective probabilities of immunotherapy for nonsquamous NSCLC.

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional β-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA β-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA β-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet β-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.

B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that mediates the escape of tumor cells from immunosurveillance. Consequently, BTLA and its ligand herpesvirus entry mediator (HVEM) are potentially immunotherapeutic targets. However, the potential effects of BTLA on tumor cells remain incompletely unknown. Here, we show that BTLA is expressed across a broad range of tumor cells. The depletion of BTLA or HVEM promotes cell proliferation and colony formation, which is reversed by the overexpression of BTLA in BTLA knockout cells. In contrast, overexpression of BTLA or HVEM inhibits tumor cell proliferation and colony formation. Furthermore, the proliferation of a subpopulation with high BTLA was also significantly slower than that of the low BTLA subpopulation. Mechanistically, the coordination of BTLA and HVEM inhibits its major downstream extracellular regulated protein kinase (ERK1/2) signaling pathway, thus preventing tumor cell growth. This study demonstrates that tumor cell-intrinsic BTLA/HVEM is a potential tumor suppressor and is likely to have a potential antagonist for immunotherapy, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

Abstract Background The tick Haemaphysalis longicornis exhibits two separate reproductive populations: bisexual and parthenogenetic, which have diploid and triploid karyotypes, respectively. The parthenogenetic population can undergo engorgement without copulation and produce viable female-only offspring with a longer incubation period than the bisexual population. Three enzymes, cathepsin B, cathepsin D and acid phosphatase, were found to be involved in vitellin degradation during the embryonic development of bisexual H. longicornis. However, the expression and activity profiles of these enzymes during the embryonic development of parthenogenetic ticks remain unknown. In the present study, the transcriptional expression profile, enzyme activity and roles in embryogenesis of the three enzymes during the embryonic development of parthenogenetic H. longicornis were investigated. Methods Quantitative real-time polymerase chain reaction (qPCR) and fluorescence detection were used to analyze the dynamic changes in the three enzymes during embryogenesis. The roles of the three enzymes during embryogenesis were also explored using RNA interference (RNAi). Results The three enzymes were all expressed during embryonic development in parthenogenetic H. longicornis. The expression of cathepsin B was highest on day 15, whereas that of cathepsin D was highest on day 3 and the peak of acid phosphatase expression occurred on day 9. The activity of cathepsin B was highest on day 3 and lowest on day 5, then gradually increased and remained stable. Cathepsin D activity was highest on day 1 and showed a gradually decreasing trend, whereas acid phosphatase showed the opposite trend and reached a peak on day 23. RNA interference experiments in engorged female ticks revealed that there was no significant difference in the number of eggs laid, but the hatching rate of the eggs was significantly decreased. Conclusion The three enzymes all play important roles in embryonic development of H. longicornis, but the expression patterns and changes in the activity of the enzymes in the bisexual and parthenogenetic populations are different. The results will help a better understanding of the similarities and differences underlying embryonic development in the bisexual and parthenogenetic populations and contribute to the future exploration of the development of the parthenogenetic population of H. longicornis.

Abstract Background Three main enzymes including cathepsin B, cathepsin D and acid phosphatase are involved in vitellin degradation, which is a major biochemical event of the embryonic development and can provide nutrients and metabolites for tick embryos. In the present study, the mRNA expression profiles and enzymatic activity of cathepsin B, cathepsin D and acid phosphatase were investigated during embryonic development in the tick Haemaphysalis longicornis. Results The results revealed that all three enzymes were expressed throughout embryonic development. Both cathepsin B and acid phosphatase transcripts were accumulated during the first four days. Cathepsin B reached its highest expression on day 5, whereas the peak expression of acid phosphatase and cathepsin D occurred on day 11. The highest activity of cathepsin B was observed on the first day of egg development, whereas cathepsin D reached its highest activity on day 13. Acid phosphatase activity increased gradually during the first five days and then remained stable until the end of egg development. Conclusions Three enzymes were expressed and activated in eggs, and also presented different dynamic changes with the development of embryos. The profiles of both mRNA expression and enzymatic activity of these enzymes indicate that they are controlled orderly and play multiple roles during embryonic development in ticks.

Aspergillus flavus and the produced aflatoxins cause great hazards to food security and human health across all countries. The control of A. flavus and aflatoxins in grains during storage is of great significance to humans. In the current study, bacteria strain YM6 isolated from sea sediment was demonstrated effective in controlling A. flavus by the production of anti-fungal volatiles. According to morphological characteristics and phylogenetic analysis, strain YM6 was identified as Pseudomonas stutzeri. YM6 can produce abundant volatile compounds which could inhibit mycelial growth and conidial germination of A. flavus. Moreover, it greatly prevented fungal infection and aflatoxin production on maize and peanuts during storage. The inhibition rate was 100%. Scanning electron microscopy further supported that the volatiles could destroy the cell structure of A. flavus and prevent conidia germination on the grain surface. Gas chromatography/mass spectrometry revealed that dimethyl trisulfide (DMTS) with a relative abundance of 13% is the most abundant fraction in the volatiles from strain YM6. The minimal inhibitory concentration of DMTS to A. flavus conidia is 200 µL/L (compound volume/airspace volume). Thus, we concluded that Pseudomonas stutzeri YM6 and the produced DMTS showed great inhibition to A. flavus, which could be considered as effective biocontrol agents in further application.

Dietary supplementation of sea cucumber saponins and calorie restriction have been proved to be effective in alleviating obesity, but the differences of anti-obesity effects between sea cucumber saponins and energy restriction during weight loss and weight regain are still unknown. In the present study, high-fat-induced obesity mice were randomly divided into three groups, including a high-fat diet group (HF), an energy restriction by 40% group (HF-L), and a sea cucumber saponins group (HF-S), to compare the effects of dietary sea cucumber saponins and energy restriction on the weight, glucose, and lipid metabolism of obese mice during weight loss and weight regain. The results showed that dietary 0.06% sea cucumber saponins and limiting energy intake by 40% had the same weight loss effect. Interestingly, sea cucumber saponins could alleviate impaired glucose tolerance and insulin resistance caused by obesity. In addition, the inhibited SREBP-1c mediated lipogenesis might lead to the alleviation of weight regain after resuming the high-fat diet even when sea cucumber saponins were no longer supplemented. In contrast, limiting energy intake tended to promote lipid synthesis in the liver and white adipose tissue after restoring a high-fat diet, and inflammation was also induced. The findings indicated that sea cucumber saponins could replace calorie restriction to prevent obesity and might be used as a functional food or drug to resist obesity and related diseases caused by obesity.

The purpose of this paper is to examine how feedback seeking impact safety performance through feedback environment and the moderating role of consideration of future consequence. Correlation data were collected from 202 participants in three industries of China. Results indicate that feedback seeking is positively associated with feedback environment and safety performance, the feedback environment mediated the relationship between feedback seeking and safety performance. However, the positive effect of feedback environment on safety performance is more significant when consideration of future consequence is high. Overall, the findings highlight the critical importance of individual features in the research on safety performance. The conclusion is conducive to a more detailed understanding of the antecedents that affect safety performance and provides a new perspective for the improvement of safety performance.

In this work, we consider the chiral nonlinear Schrödinger equation in (2 + 1)-dimensions, which describes the envelope of amplitude in many physical media. We employ the Lie symmetry analysis method to study the vector field and the optimal system of the equation. The similarity reductions are analyzed by considering the optimal system. Furthermore, we find the power series solution of the equation with convergence analysis. Based on a new conservation law, we construct the conservation laws of the equation by using the resulting symmetries.

Eicosapentaenoic acid (EPA) enriched phospholipids (EPA-PL) are widely distributed in marine products. It has been reported that the protective effects of the mixture of EPA and docosahexaenoic acid (DHA) on Parkinson’s disease (PD), however, it is hard to confirm the improvement of EPA alone on PD. In the present study, EPA-PL was extracted from the sea cucumber (Cucumaria frondosa) to compare the effects of EPA-PL and commercial EPA in the form of ethyl ester (EPA-EE) on PD mice induced by 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP). Results showed that dietary EPA-PL instead of EPA-EE notably improved MPTP-induced behavioral deficiency. Further research showed that EPA-PL suppressed MPTP-induced oxidative stress and apoptosis, thereby alleviating the loss of dopaminergic neurons via mitochondria – mediated pathway and mitogen-activated protein kinase pathway. These findings firstly confirmed that EPA-PL could improve MPTP-induced symptoms and pathology of PD, providing a reference for the prevention and treatment of neurodegenerative diseases.

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. The present study was conducted to evaluate the efficacy of the saponins of sea cucumber (SSC) on reversing atherosclerosis. Results showed that SSC treatment reduced serum lipid levels in a dose-dependent manner in rats fed with cholesterol-rich diet. Notably, 0.07% SSC treatment for 8 weeks significantly promoted plaque regression by 56.9% in ApoE−/− mice. Mechanistically, SSC significantly decreased serum total cholesterol (19.5%) and hepatic free cholesterol level (49.2%), by mediating mRNA and protein levels of genes related to hepatic cholesterol reserve transport. Moreover, dietary SSC dramatically inhibited inflammation by down-regulating the expression of pro-inflammatory cytokines in vascular and peritoneal macrophage. The obtained results indicated that SSC might serve as a novel functional ingredient with anti-atherosclerotic activity.

Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin–angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-β and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1β and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.

Chiral vicinal amino alcohols are found in many bioactive compounds and may serve as chiral ligands. Here, the authors report a photocatalytic enantioselective cross-coupling of nitrones with aromatic aldehydes with a chiral ligand-coordinated rare earth ion synergistically producing enantiopure vicinal amino alcohols.

Finding meaningful clustering patterns in data can be very challenging when the clusters are of arbitrary shapes, different sizes, or densities, and especially when the data set contains high percentage (e.g., 80%) of noise. Unfortunately, most existing clustering techniques cannot properly handle this tough situation and often result in dramatically deteriorating performance. In this paper, a purposefully designed clustering algorithm called Density-Based Multiscale Analysis for Clustering (DBMAC)-II is proposed, which is an improved version of the latest strong-noise clustering algorithm DBMAC. DBMAC is proposed under the assumption that all clusters are homogeneous and cannot work well when the data set contains clusters of varying densities. DBMAC-II overcomes the limitation of DBMAC by executing the multiscale analysis iteratively and can conduct strong noise-robust clustering without any strict assumption on the shapes and densities of clusters. In DBMAC-II, each data point or object is mapped into a feature space using its r-neighborhood statistics with different r (radius) values, which is similar to DBMAC. In general, the higher the value of r-neighborhood statistics, the more likely the object is considered as a “clustered”object. Instead of trying to find a single optimal r value, a set of radius values appropriate for separating “clustered”objects and “noisy”objects is identified, using a formal statistical method for multimodality test, referred to as multiscale analysis. For clusters with varying densities, multiscale analysis is applied to extract the clusters with the highest density from the current data set iteratively. Moreover, a statistical uniformity test for measuring clustering tendency is used as the self-adaptive stopping criterion of the iteration. Comprehensive experimental studies on a series of challenging benchmark data sets demonstrate that DBMAC-II is not only superior to classical density-based clustering approaches, including DBSCAN, OPTICS, and HDBSCAN, but also can consistently outperform the latest strong-noise robust clustering techniques, such as Skinny-dip.

Abstract Background Docosahexaenoic acid (DHA) is important for optimal neurodevelopment and brain function during the childhood when the brain is still under development. Methods The effects of DHA-Phosphatidylcholine (DHA-PC) and the recombination of DHA-Triglyceride with egg PC (DHA-TG + PC) or α-Glycerylphosphorylcholine (DHA-TG + α-GPC) were comparatively analyzed on DHA recovery and the DHA accumulation kinetics in tissues including cerebral cortex, erythrocyte, liver, and testis were evaluated in the weaning n-3 deficient mice. Results The concentration of DHA in weaning n-3 deficient mice could be recovered rapidly by dietary DHA supplementation, in which DHA-PC exhibited the better efficacy than the recombination of DHA-Triglyceride with egg PC or α-GPC. Interestingly, DHA-TG + α-GPC exhibited the greater effect on DHA accumulation than DHA-TG + PC in cerebral cortex and erythrocyte (p

Abstract Background Haemaphysalis longicornis is a blood-sucking ectoparasite that can cause diseases by transmitting some pathogens to humans and animals. Paramyosin (Pmy) is an immunomodulatory protein, which plays an important role in immune reactions against parasites. In this study, we evaluated the immune protection elicited by recombinant plasmids encoding H. longicornis Pmy in rabbits. Results Rabbits vaccinated with pcDNA3.1(+)-Pmy developed high level of IgG compared to control group, suggesting that humoral immune response was induced by vaccination. On the fourth day after fed on the rabbit, some female adults died and the mortality rate from pcDNA3.1(+)-Pmy group (27.31%) was significantly higher than that of the control group (P

Prevention of acute kidney injury caused by drugs is still a clinical problem to be solved urgently. Astaxanthin (AST) and docosahexaenoic acid (DHA) are important marine-derived active ingredients, and they are reported to exhibit renal protective activity. It is noteworthy that the existing forms of AST in nature are mainly fatty acid-acylated AST monoesters and diesters, as well as unesterified AST, in which DHA is an esterified fatty acid. However, no reports focus on the different bioactivities of unesterified AST, monoesters and diesters, as well as the recombination of DHA and unesterified AST on nephrotoxicity. In the present study, vancomycin-treated mice were used to evaluate the effects of DHA-acylated AST monoesters, DHA-acylated AST diesters, unesterified AST, and the recombination of AST and DHA in alleviating nephrotoxicity by determining serum biochemical index, histopathological changes, and the enzyme activity related to oxidative stress. Results found that the intervention of DHA-acylated AST diesters significantly ameliorated kidney dysfunction by decreasing the levels of urea nitrogen and creatinine, alleviating pathological damage and oxidative stress compared to AST monoester, unesterified AST, and the recombination of AST and DHA. Further studies revealed that dietary DHA-acylated AST esters could inhibit the activation of the caspase cascade and MAPKs signaling pathway, and reduce the levels of pro-inflammatory cytokines. These findings indicated that the administration of DHA-acylated AST esters could alleviate vancomycin-induced nephrotoxicity, which represented a potentially novel candidate or therapeutic adjuvant for alleviating acute kidney injury.

Diacylglycerol acyltransferase (DGAT) is the only enzyme that catalyzes the acyl-CoA-dependent acylation of sn-1, 2-diacylglycerol (DAG) to form triacylglycerol (TAG). The two main types of DGAT enzymes in the woody perennial biofuel plant Jatropha curcas, JcDGAT1 and JcDGAT2, were previously characterized only in heterologous systems. In this study, we investigated the functions of JcDGAT1 and JcDGAT2 in J. curcas.JcDGAT1 and JcDGAT2 were found to be predominantly expressed during the late stages of J. curcas seed development, in which large amounts of oil accumulated. As expected, overexpression of JcDGAT1 or JcDGAT2 under the control of the CaMV35S promoter gave rise to an increase in seed kernel oil production, reaching a content of 53.7% and 55.7% of the seed kernel dry weight, respectively, which were respectively 25% and 29.6% higher than that of control plants. The increase in seed oil content was accompanied by decreases in the contents of protein and soluble sugars in the seeds. Simultaneously, there was a two- to four-fold higher leaf TAG content in transgenic plants than in control plants. Moreover, by analysis of the fatty acid (FA) profiles, we found that JcDGAT1 and JcDGAT2 had the same substrate specificity with preferences for C18:2 in seed TAGs, and C16:0, C18:0, and C18:1 in leaf TAGs. Therefore, our study confirms the important role of JcDGAT1 and JcDGAT2 in regulating oil production in J. curcas.

Lymphoma rarely occurs during pregnancy, making this condition difficult to define. Lymphomas that occur in reproductive organs during pregnancy exhibit unique clinical characteristics. Among the limited cases, non-Hodgkin's lymphoma (NHL) shows a considerably higher incidence rate than Hodgkin's lymphoma (HL); NHL also displays clinical characteristics, such as high aggressiveness, advanced stage, and poor outcome. This study reports on four cases of lymphomas in non-gonadal organs (HL, n=2; NHL, n=2) during pregnancy. The tumors rapidly progressed in all patients during pregnancy but remitted at the end of pregnancy and/or therapy. The two HL cases were nodular sclerosis classical HL and treated with chemotherapy after terminating the pregnancy. One of the NHL cases was primary cutaneous follicular center lymphoma, a B cell-derived indolent lymphoma. The patient was followed up without any therapy after terminating her pregnancy. The other case was a follicular lymphoma grade 3B, which was treated with chemotherapy after delivery. We also conducted a literature review of 165 lymphoma cases occurring during pregnancy reported from 1976 to 2013 to reveal the correlation between pregnancy and lymphoma progression. Immunohistochemistry studies were performed to determine the expression of estrogen/progesterone receptors (ER/PR), and ER was weakly positive and sporadic. We concluded that lymphomas occurring during pregnancy should be managed with a prompt and reasonable treatment. High estrogen level in maternal body may affect lymphoma progression.

The large deformation problem of the wing with high aspect ratio cannot be avoided due to the large bending moment and poor torsional stiffness. The wing design follows the following procedure; firstly, the design indexes of high aspect ratio wing are preliminarily formulated referring to some parameters of the Predator UAV. Then, the aerodynamic analysis of the wing is performed, and the stress cloud diagram is obtained. Next, the finite element model of the wing is designed, and the static analysis is conducted in the ANSYS ACP module, and the unreasonable component size is changed. An appropriate thickness which is 12 mm is selected as the final thickness of the wing. Then, the analysis of laying methods of skin structure is conducted. Finally, the composite structure is proved to reduce the maximum deformation and maximum stress effectively compared with the metal wing.

Tormentic acid (TA) is a triterpenoid saponin widely distributed in natural plant foods with various bioactivities. However, the underlying pathways through which TA exerts the bioactivities remain unclear. Here, experiments were carried out to elucidate the molecular mechanisms accounting for the antiproliferation of TA using MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry, quantitative real-time polymerase chain reaction and Western blotting analysis. TA exhibited a dose-dependent inhibitory effect on MCF-7 cells, which was caused by apoptosis and G0/G1 phase arrest. Reactive oxygen species (ROS) acts as an upstream mediator in TA-induced MCF-7 cell growth inhibition and intracellular ROS levels induced mitochondrial dysfunction, thereby resulting in the release of apoptogenic factors into cytosol, and then activating caspase-3 and caspase-9. TA induced cell cycle arrest via changing the cyclin D1 and cyclin-dependent kinase 4 messenger ribonucleic acid expression levels. Moreover, TA significantly down-regulated the NF-kappa-B cell survival pathway and the expression level of phosphorylated ERK.

This research was aimed to isolate the active compounds with antioxidant and anti-tumour properties from Amomum tsaoko Crevost et Lemaire, a traditional health food in China. Ethanol (95%) extract and ethyl acetate fraction was found to have significant DPPH radical scavenging activities and cytotoxicities against cervical cancer cell Hela, hepatoma cells HepG-2 and SMMC-7721, and lung cancer cell A549. Four compounds were isolated from ethyl acetate fraction, and compounds III and IV are identified as new compounds. Compounds III and IV showed high DPPH radical scavenging activities. Compound II, III and IV exhibited good anti-tumour activity against HepG-2, SMMC-7721, Hela and A549 cell lines. Compound I showed a strong anti-tumour activity only against Hela cell lines. Compounds III and IV were concluded to be the active compositions responsible for potent antioxidant and anti-tumour properties of A. tsaoko, whose molecular mechanism and pathways of inhibiting tumour cell need to be further studied.

Rubus chingii Hu has been used as a functional food for a long time. This work was aimed to identify the anti-inflammatory ingredients from R. chingii by an activity-guided isolation. The ethanol extracts of R. chingii were partitioned into petroleum ether, ethyl acetate, butanol and water fractions, and the ethyl acetate fraction exhibited excellent anti-inflammatory activity. Five flavonoid glycosides were isolated from the ethyl acetate fraction based on anti-inflammatory assay-guided purification, which were identified as quercitrin, hyperoside, tiliroside, astragalin and kaempferol 3-rutinoside. The inhibitory effects of extract fractions and compounds on NO production in LPS-stimulated macrophage RAW 264.7 cells were evaluated. The five flavonoid glycosides displayed different degrees of anti-inflammatory activity, among which tiliroside showed stronger activity than others. Further analysis showed that the anti-inflammatory activity of tiliroside might be exerted through inhibiting the activation of ERK and JNK to decrease NO and pro-inflammatory cytokines (TNF-α, iNOS and IL-6) production.

Ormosia hosiei is a critically Endangered and important economic plant which is endemic in southern, eastern and central China. The complete chloroplast (cp) genome sequence of O. hosiei was determined by Next-generation sequencing technology. Total length of the cp genome is 172,210 bp, which contained a large single-copy (LSC) and a small single copy (SSC), separated by the inverted repeats (IR) of 40,377 bp. The cpDNA is structured with 144 genes, comprising 98 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Phylogenetic analysis suggested that Ormosia is closely related to the genus Styphnolobium within the Fabaceae.

The gene encoding the GroEL chaperonin is duplicated in nearly 30% of bacterial genomes; and although duplicated groEL genes have been comprehensively determined to have distinct physiological functions in different species, the mechanisms involved have not been characterized to date. Myxococcus xanthus DK1622 has two copies of the groEL gene, each of which can be deleted without affecting cell viability; however, the deletion of either gene does result in distinct defects in the cellular heat-shock response, predation, and development. In this study, we show that, from the expression levels of different groELs, the distinct functions of groEL1 and groEL2 in predation and development are probably the result of the substrate selectivity of the paralogous GroEL chaperonins, whereas the lethal effect of heat shock due to the deletion of groEL1 is caused by a decrease in the total groEL expression level. Following a bioinformatics analysis of the composition characteristics of GroELs from different bacteria, we performed region-swapping assays in M. xanthus, demonstrating that the differences in the apical and the C-terminal equatorial regions determine the substrate specificity of the two GroELs. Site-directed mutagenesis experiments indicated that the GGM repeat sequence at the C-terminus of GroEL1 plays an important role in functional divergence. Divergent functions of duplicated GroELs, which have similar patterns of variation in different bacterial species, have thus evolved mainly via alteration of the apical and the C-terminal equatorial regions. We identified the specific substrates of strain DK1622's GroEL1 and GroEL2 using immunoprecipitation and mass spectrometry techniques. Although 68 proteins bound to both GroEL1 and GroEL2, 83 and 46 proteins bound exclusively to GroEL1 or GroEL2, respectively. The GroEL-specific substrates exhibited distinct molecular sizes and secondary structures, providing an encouraging indication for GroEL evolution for functional divergence.

In this brief, a dual-band filtering power divider (FPD) with high selectivity and independently controllable passbands is designed. The proposed FPD consists of asymmetric folded F-type resonators (AFFRs) and quarter-wavelength three parallel-coupled lines (TPCLs). The center frequencies of the dual bands can be determined by adjusting the physical lengths of AFFRs. Meanwhile, TPCLs can increase the transmission paths and introduce multiple transmission zeros (TZs) to achieve high selectivity. For demonstration, the proposed FPD is designed, fabricated, and measured. The center frequencies are 2.59/3.63 GHz with the 3-dB fractional bandwidths (FBWs) of 12.95% and 7.88%, and the isolation between port 2 and port 3 is better than 12.56/21.03 dB. The minimum insertion losses are better than 0.54/0.32 dB in each passband. The simulated results are compared with measured ones, and good agreement is realized. [ABSTRACT FROM AUTHOR]