Low Selenium and Low Protein Exacerbate Myocardial Damage in Keshan Disease by Affecting the PINK1/Parkin-mediated Mitochondrial Autophagy Pathway.

OBJECTIVE: Keshan disease (KD) is a myocardial mitochondrial disease closely related to insufficient selenium (Se) and protein intake. PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body. This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury. METHODS: A low Se and low protein animal model was established. One hundred Wistar rats were randomly divided into 5 groups (control group, low Se group, low protein group, low Se + low protein group, and corn from KD area group). The JC-1 method was used to detect the mitochondrial membrane potential (MMP). ELISA was used to detect serum creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and mitochondrial-glutamicoxalacetic transaminase (M-GOT) levels. RT-PCR and Western blot analysis were used to detect the expression of PINK1, Parkin, sequestome 1 (P62), and microtubule-associated proteins1A/1B light chain 3B (MAP1LC3B). RESULTS: The MMP was significantly decreased and the activity of CK-MB, cTnI, and M-GOT significantly increased in each experimental group (low Se group, low protein group, low Se + low protein group and corn from KD area group) compared with the control group (P<0.05 for all). The mRNA and protein expression levels of PINK1, Parkin and MAP1LC3B were profoundly increased, and those of P62 markedly decreased in the experimental groups compared with the control group (P<0.05 for all). CONCLUSION: Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.

LPI-SKMSC: Predicting LncRNA-Protein Interactions with Segmented k-mer Frequencies and Multi-space Clustering.

 Long noncoding RNAs (lncRNAs) have significant regulatory roles in gene expression. Interactions with proteins are one of the ways lncRNAs play their roles. Since experiments to determine lncRNA-protein interactions (LPIs) are expensive and time-consuming, many computational methods for predicting LPIs have been proposed as alternatives. In the LPIs prediction problem, there commonly exists the imbalance in the distribution of positive and negative samples. However, there are few existing methods that give specific consideration to this problem. In this paper, we proposed a new clustering-based LPIs prediction method using segmented k-mer frequencies and multi-space clustering (LPI-SKMSC). It was dedicated to handling the imbalance of positive and negative samples. We constructed segmented k-mer frequencies to obtain global and local features of lncRNA and protein sequences. Then, the multi-space clustering was applied to LPI-SKMSC. The convolutional neural network (CNN)-based encoders were used to map different features of a sample to different spaces. It used multiple spaces to jointly constrain the classification of samples. Finally, the distances between the output features of the encoder and the cluster center in each space were calculated. The sum of distances in all spaces was compared with the cluster radius to predict the LPIs. We performed cross-validation on 3 public datasets and LPI-SKMSC showed the best performance compared to other existing methods. Experimental results showed that LPI-SKMSC could predict LPIs more effectively when faced with imbalanced positive and negative samples. In addition, we illustrated that our model was better at uncovering potential lncRNA-protein interaction pairs.

Circ-100290 Regulates Autophagy-Mediated Angiogenesis of Human Umbilical Vein Endothelial Cells Induced by Conditioned Medium of Human Amniotic Mesenchymal Stem Cells.

BACKGROUND: Conditioned medium (CM) from human amnion-derived mesenchymal stem cells (hAMSCs) exhibits excellent pro-angiogenic capacity, and circ-100290 participates in this process. Autophagy is involved in the relevant mechanisms of angiogenesis, but it is unclear whether autophagy is related to the pro-angiogenesis effect of hAMSCs. This research sought to determine whether autophagy involved in the process of pro-angiogenesis induced by hAMSCs might be regulated by circ-100290. METHODS: Upon treatment with CM from hAMSC or 3-methyladenine (3-MA), autophagosomes in human umbilical vein endothelial cells (HUVECs) were observed by transmission electron microscopy. HUVECs' angiogenic ability was evaluated by in vitro assays (transwell, wound healing, tube formation) and an in vivo Matrigel plug assay. Specific small interfering RNAs (siRNA) or inhibitors were used to regulate circ-100290 expression. Additionally, western blot and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) were used to evaluate expression of the following indicators: Beclin-1, LC3-II, matrix metalloproteinase 2 (MMP2), MMP9, vascular endothelial growth factor (VEGF)-A, and endothelial nitric oxide synthase (eNOS). RESULTS: Incubation with hAMSC-CM increased autophagy, angiogenesis and the expressions of VEGF-A and eNOS in HUVECs, all of which were inhibited by 3-MA. Knocking down circ-100290 in hAMSC-CM-treated HUVECs reduced Beclin-1 expression and inhibited autophagy. This resulted in lower angiogenesis in the Matrigel plug assay showing that reduced angiogenesis occurred after circ-100290 silencing in hAMSC-CM-treated HUVECs. CONCLUSIONS: Circ-100290 promotes autophagy-mediated angiogenesis in hAMSC-CM-treated HUVECs.

Bioactive secondary metabolites from endophytic strains of Neocamarosporium betae collected from desert plants.

Endophytic fungi from desert plants belong to a unique microbial community that has been scarcely investigated chemically and could be a new resource for bioactive natural products. In this study, 13 secondary metabolites (1-13) with diverse carbon skeletons, including a novel polyketide (1) with a unique 5,6-dihydro-4H,7H-2,6-methanopyrano[4,3-d][1,3]dioxocin-7-one ring system and three undescribed polyketides (2, 7, and 11), were obtained from the endophytic fungus Neocamarosporium betae isolated from two desert plant species. Different approaches, including HR-ESI-MS, UV spectroscopy, IR spectroscopy, NMR, and CD, were used to determine the planar and absolute configurations of the compounds. The possible biosynthetic pathways were proposed based on the structural characteristics of compounds 1-13. Compounds 1, 3, 4, and 9 exhibited strong cytotoxicity toward HepG2 cells compared with the positive control. Several metabolites (2, 4-5, 7-9, and 11-13) were phytotoxic to foxtail leaves. The results support the hypothesis that endophytic fungi from special environments, such as desert areas, produce novel bioactive secondary metabolites.

Mild Anemia May Affect Thyroid Function in Pregnant Chinese Women During the First Trimester.

Background: Pregnant women are often susceptible to anemia, which can damage the thyroid gland. However, compared with moderate and severe anemia, less attention has been paid to mild anemia. The purpose of this study was to evaluate the effect of mild anemia on the thyroid function in pregnant women during the first trimester. Methods: A total of 1,761 women in the first trimester of their pregnancy were enrolled from Shenyang, China, and divided into mild anemia and normal control groups based on their hemoglobin levels. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels were compared between the two groups. Results: The TSH levels of pregnant women with mild anemia were higher than those of pregnant women without mild anemia (p < 0.05). Normal control women were selected to set new reference intervals for TSH, FT3, and FT4 levels during the first trimester, which were 0.11-4.13 mIU/l, 3.45-5.47 pmol/l, and 7.96-16.54 pmol/l, respectively. The upper limit of TSH 4.13 mU/l is close to the upper limit 4.0 mU/l recommended in the 2017 American Thyroid Association (ATA) guidelines, indicating that exclusion of mild anemia may reduce the difference in reference values from different regions. Mild anemia was related to 4.40 times odds of abnormally TSH levels (95% CI: 2.84, 6.76) and 5.87 increased odds of abnormal FT3 (95% CI: 3.89, 8.85). The proportion of hypothyroidism and subclinical hypothyroidism in patients with mild anemia was higher than that in those without anemia (0.6% vs. 0, p = 0.009; 12.1% vs. 1.9%, p < 0.001). Mild anemia was related to 7.61 times increased odds of subclinical hypothyroidism (95% CI: 4.53, 12.90). Conclusions: Mild anemia may affect thyroid function during the first trimester, which highlights the importance of excluding mild anemia confounding when establishing a locally derived specific reference interval for early pregnancy.

The Diagnostic Value of Coagulation Indicators and Inflammatory Markers in Distinguishing Between Strangulated and Simple Intestinal Obstruction.

BACKGROUND: Intestinal obstruction with strangulation can be life-threating, and it is critical to make an accurate and timely diagnosis for emergency surgery. OBJECTIVE: This was aimed to investigate the value of coagulation indicators and inflammatory markers in distinguishing between strangulated and simple intestinal obstruction. MATERIALS AND METHODS: Fifty-four patients with intestinal obstruction were retrospectively studied. The correlation between coagulation indicators and inflammatory markers with intestinal obstruction was analyzed. Receiver operating characteristic curves were created to assess their ability in discriminative diagnosis. RESULTS: Levels of fibrinogen (Fib), C-reactive protein (CRP), neutrophil ratio, and D-Dimer were significantly greater, while thrombin time was significantly shorter in strangulated intestinal obstruction compared with simple intestinal obstruction. Furthermore, Fib levels in the necrosis subgroup of strangulated intestinal obstruction were significantly higher than those in the ischemia subgroup and simple intestinal obstruction group. The areas under the receiver operating characteristic curve were 0.58 for white blood cells, 0.78 for CRP, and 0.80 for Fib. Using the optimal cutoff values of Fib (3.71 g/L) and CRP (14.54 mg/L), the sensitivity, specificity, positive predictive value, and negative predictive value in discriminating between strangulated intestinal obstruction and simple intestinal obstruction were 51.43%, 100%, 100%, and 52.78% for Fib, and 56.25%, 94.44%, 94.74%, and 54.84% for CRP, respectively. CONCLUSIONS: Fib and CRP demonstrate good performance in predicting strangulation and are indicative of intestinal necrosis and ischemia. The combination of this coagulation indicator and inflammatory marker holds potential for better discrimination between strangulated and simple intestinal obstruction.

Determination of Toxic Pyrrolizidine Alkaloids in Traditional Chinese Herbal Medicines by UPLC-MS/MS and Accompanying Risk Assessment for Human Health.

Pyrrolizidine alkaloids (PAs) are a class of natural toxins with hepatotoxicity, genotoxicity and carcinogenicity. They are endogenous and adulterated toxic components widely found in food and herbal products. In this study, a sensitive and efficient ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was used to detect the PAs in 386 kinds of Chinese herbal medicines recorded in the Chinese Pharmacopoeia (2020). The estimated daily intake (EDI) of 0.007 µg/kg body weight (bw)/day was adopted as the safety baseline. The margin of exposure (MOE) approach was applied to evaluate the chronic exposure risk for the genotoxic and carcinogenic potential of PAs. Results showed that PAs was detected in 271 out of 386 samples with a content of 0.1-25,567.4 µg/kg, and there were 20 samples with EDI values above the baseline, 0.007 µg/kg bw/day. Beyond that, the MOE values for 10 out of 271 positive samples were below 10,000. Considering the actual situation, Haber's rule was used to assume two weeks exposure every year during lifetime, and still the MOE values for four out of 271 positive samples were under 10,000, indicating these products may have potential health risk. The developed method was successfully applied to detect the PAs-containing Chinese herbal medicines. This study provides convincing data that can support risk management actions in China and a meaningful reference for the rational and safe use of Chinese herbal medicines.

Heavy metal concentrations and associated health risks in edible tissues of marine nekton from the outer Pearl River Estuary, South China Sea.

Seven heavy metals including Hg, Cu, Pb, Cd, Zn, Cr, and As were examined in seventeen marine nekton species from the outer Pearl River Estuary (PRE), South China Sea. On the wet weight basis, the metal concentration ranges were 0.016-0.157 µg/g for Hg, 0.18-14.3 µg/g for Cu, 0.26-1.48 µg/g for Pb, 0.021-0.873 µg/g for Cd, 1.35-57.15 µg/g for Zn, 0.15-0.53 µg/g for Cr, and 0.42-7.83 µg/g for As, respectively. The levels of tested metals except for Pb in crustaceans were found to be higher than those in fish and cephalopods, suggesting that the diet and habitat played important roles on heavy metal accumulation ability of marine organism. Except for Cd in Champsodon capensis, Calappa lophos, and Portunus argentatus, all the left metal concentrations of investigated nekton species were below their permissible upper limits, indicating that consumption of examined marine nekton should be considered as safe for human health. The values of single target hazard quotient (THQ) and total THQ were all less than 1 and also suggested that there was no health risk for consumption. Even so, the local people should control their daily intake of crustacean foods from the outer PRE, since there might be potential As and Cd cumulative risks.

SCALPEL3: A scalable open-source library for healthcare claims databases.

OBJECTIVE: This article introduces SCALPEL3 (Scalable Pipeline for Health Data), a scalable open-source framework for studies involving Large Observational Databases (LODs). It focuses on scalable medical concept extraction, easy interactive analysis, and helpers for data flow analysis to accelerate studies performed on LODs. MATERIALS AND METHODS: Inspired from web analytics, SCALPEL3 relies on distributed computing, data denormalization and columnar storage. It was compared to the existing SAS-Oracle SNDS infrastructure by performing several queries on a dataset containing a three years-long history of healthcare claims of 13.7 million patients. RESULTS AND DISCUSSION: SCALPEL3 horizontal scalability allows handling large tasks quicker than the existing infrastructure while it has comparable performance when using only a few executors. SCALPEL3 provides a sharp interactive control of data processing through legible code, which helps to build studies with full reproducibility, leading to improved maintainability and audit of studies performed on LODs. CONCLUSION: SCALPEL3 makes studies based on SNDS much easier and more scalable than the existing framework [1]. It is now used at the agency collecting SNDS data, at the French Ministry of Health and soon at the National Health Data Hub in France [2].

Evacuate or Stay? A Typhoon Evacuation Decision Model in China Based on the Evolutionary Game Theory in Complex Networks.

The Chinese Government has played an important role in organizing the evacuation of typhoon disasters, and in-depth analysis of individual behavioral decisions is a prerequisite for adopting an effective emergency organization plan. Existing evacuation plans only consider how the Government issues the early warning and organizes the mandatory evacuation, but does not formulate effective policies to improve the efficiency of self-evacuation of evacuees and lacks the understanding of individual evacuation decision-making. Using game-based theory in a small-world network context, we build an evolutionary game model of evacuation decision diffusion between evacuees in the context of a complex network. The model simulates the effects of guaranteeing the evacuation order and providing material supplies on the evacuation decision diffusion in a small-world network in China. The results showed that various levels of policy-implementation led to different rates of evacuation. As the cost-reduction of the evacuation process increased, the evacuation response rate in the social system increased. In contrast, as the rate of reducing the non-evacuation cost decreased or the cost-reduction rate of non-evacuation increased, the evacuation response rate in the social system decreased. The study findings provided insights on emergency planning and the effectiveness of their implementation in social networks, which can be used to improve evacuation policy.

Occurrence of microplastics in gastrointestinal tracts and gills of fish from Beibu Gulf, South China Sea.

Microplastics are widespread across the global oceans, yet the potential risks of the ubiquitous environmental contaminant to marine organisms has been less known. Accumulation of microplastics and associated contaminants in marine fish, may pose adverse impacts to human health via seafood consumption. This study evaluated microplastic contamination in 24 fish species collected from Beibu Gulf, one of the world's largest fishing grounds in South China Sea. Microplastics were detected in 12 fish species at an abundance of 0.027-1.000 items individual-1 and found in fish stomach, intestines and gills with the count percentage of 57.7%, 34.6% and 7.7%, respectively. Transparent fibers were observed as the predominant microplastics, which might be ingested accidently by fish or transferred through other animals at lower trophic levels. Majority of microplastics were identified as polyester (44%) and nylon (38%), whereas polypropylene (6%), polyethylene (6%), and acrylics (6%) were also found. Relatively, higher microplastic abundances were found in demersal fish compared to the pelagic species. Overall, the abundance of microplastics was documented as relatively low in the commercial fish collected from the open water of Beibu Gulf, South China Sea.

Construction of a replication-competent hepatitis B virus vector carrying secreted luciferase transgene and establishment of new hepatitis B virus replication and expression cell lines.

BACKGROUND: Previously, we have successfully constructed replication-competent hepatitis B virus (HBV) vectors by uncoupling the P open reading frame (ORF) from the preC/C ORF to carefully design the transgene insertion site to overcome the compact organization of the HBV genome and maintain HBV replication competence. Consequently, the replication-competent HBV vectors carrying foreign genes, including pCH-BsdR, carrying blasticidin resistance gene (399 bp), and pCH-hrGFP, carrying humanized renilla green fluorescent protein gene (720 bp), were successfully obtained. However, the replication efficiency of the former is higher but it is tedious to use, while that of the latter is poor and cannot be quantified. Hence, we need to search for a new reporter gene that is convenient and quantifiable for further research. AIM: To establish a helpful tool for intracellular HBV replication and anti-viral drugs screening studies. METHODS: We utilized the replication-competent HBV viral vectors constructed by our laboratory, combined with the secreted luciferase reporter gene, to construct replication-competent HBV vectors expressing the reporter gene secretory Nanoluc Luciferase (SecNluc). HepG2.TA2-7 cells were transfected with this vector to obtain cell lines with stably secreted HBV particles carrying secNluc reporter gene. RESULTS: The replication-competent HBV vector carrying the SecNluc reporter gene pCH-sNLuc could produce all major viral RNAs and a full set of envelope proteins and achieve high-level secreted luciferase expression. HBV replication intermediates could be produced from this vector. Via transfection with pTRE-sNLuc and selection by hygromycin, we obtained isolated cell clones, named HBV-NLuc-35 cells, which could secrete secNLuc recombinant viruses, and were sensitive to existing anti-HBV drugs. Using differentiated HepaRG cells, it was verified that recombinant HBV possessed infectivity. CONCLUSION: Our research demonstrated that a replication-competent HBV vector carrying a secreted luciferase transgene possesses replication and expression ability, and the established HBV replication and expression cell lines could stably secrete viral particles carrying secNluc reporter gene. More importantly, the cell line and the secreted recombinant viral particles could be used to trace HBV replication or infection.

Thermally Activated Delayed Fluorescence Carbonyl Derivatives for Organic Light-Emitting Diodes with Extremely Narrow Full Width at Half-Maximum.

Two novel thermally activated delayed fluorescence (TADF) emitters, 3-phenylquinolino[3,2,1- de]acridine-5,9-dione (3-PhQAD) and 7-phenylquinolino[3,2,1- de]acridine-5,9-dione (7-PhQAD), were designed and synthesized based on a rigid quinolino[3,2,1- de]acridine-5,9-dione (QAD) framework. With the effective superimposed resonance effect from electron-deficient carbonyls and electron-rich nitrogen atom, both emitters realize significant TADF characteristics with small Δ ESTs of 0.18 and 0.19 eV, respectively. And, molecular relaxations were dramatically suppressed for both emitters because of their conjugated structure. In the devices, 3-PhQAD realizes superior performance with a maximum external quantum efficiency (EQE) of 19.1% and a narrow full width at half-maximum (FWHM) of 44 nm, whereas a maximum EQE of 18.7% and an extremely narrow FWHM of 34 nm are realized for 7-PhQAD. These superior results reveal that apart from nitrogen and boron-aromatic systems, QAD framework can also act as a TADF matrix with effective resonance effect, and QAD derivatives are ideal candidates to develop TADF emitters with narrow FWHMs for practical applications.

Simultaneous Determination and Risk Assessment of Pyrrolizidine Alkaloids in Artemisia capillaris Thunb. by UPLC-MS/MS Together with Chemometrics.

Pyrrolizidine alkaloids (PAs) are natural toxins found in some genera of the family Asteraceae. However, it has not been reported whether PAs are present in the widely used Asteraceae plant Artemisia capillaris Thunb. (A. capillaris). The purpose of this study was to establish a sensitive and rapid UPLC-MS/MS method together with chemometrics analysis for simultaneous determination and risk assessment of PAs in A. capillaris. The developed UPLC-MS/MS method was validated and was confirmed to display desirable high selectivity, precision and accuracy. Risk assessment was conducted according to the European Medicines Agency (EMA) guideline. Chemometrics analysis was performed with hierarchical clustering analysis and principal component analysis to characterize the differences between PAs of A. capillaris. Finally, PAs were found in 29 out of 30 samples and at least two were detected in each sample, besides, more than half of the samples exceeded the EMA baseline. Nevertheless, the chemometrics results suggested that the PAs contents of A. capillaris from different sources varied significantly. The method was successfully applied to the detection and risk evaluation of PAs-containing A. capillaris for the first time. This study should provide a meaningful reference for the rational and safe use of A. capillaris.

Two new echinocystic acid derivatives catalyzed by filamentous fungus Gliocladium roseum CGMCC 3.3657.

Biotransformation of Echinocystic acid (EA,1) using G. roseum CGMCC 3.3657 has been investigated, which leads to the isolation and identification of two novel Echinocystic acid derivatives, 4, 16α-dihydroxy-3,4-seco-olean-12-en-3,28-dioic acid (2) and 16α-hydroxy, A-homo-3α-oxa-olean-12-en-3-one-28-oic acid (3). Their structures have been elucidated by analysis of spectroscopic data. This biocatalysis could serve as an efficient tool complementary to classical chemical methods for the transformation of EA.

Microbe-mediate transformation of echinocystic acid by whole cells of filamentous fungus Cunninghamella blakesleana CGMCC 3.910.

Structural modification of echinocystic acid (EA), a pentacyclic triterpenoid with wide spread biological activities was investigated by microbial transformation. Microbe-mediate transformation of EA was carried out by filamentous fungus Cunninghamella blakesleana CGMCC 3.910. Four metabolites 3ß, 7ß, 16α-trihydroxy-olean-12-en-28-oic acid (EA-2); 3ß, 7ß, 16ß,19ß-tetrahydroxy-olean-12-en-28-oic acid (EA-3); 3ß, 7ß, 16α, 21ß-tetrahydroxy-olean-12-en-28-oic acid (EA-4); 3ß, 7ß, 16α-trihydroxy-olean-11, 13(18)-dien-28-oic acid (EA-5) were produced. Structures of transformed products were elucidated by 1D and 2D NMR and HR-MS data. EA-3 and EA-4 were new compounds.

Microbial transformation of pseudoprotodioscin by Gibberella fujikuroi.

Three new (6, 9, and 12) and nine known steroidal saponins were obtained from the fermentation broth of pseudoprotodioscin (PPD) incubated with a fungus Gibberella fujikuroi CGMCC 3.4663. Structures of the metabolites were elucidated by 1-D (1H, 13C), 2-D (HMBC, HSQC, NOESY) NMR, and HR-MS analyses. The biotransformation pathway of pseudoprotodioscin by Gibberella fujikuroi CGMCC 3.4663 was proposed. Compounds 1-11 were tested in vitro for their cytotoxic activities against two human cancer cell lines (HepG2 and Hela). Compounds 1, 6, 9, and 10 exhibited cytotoxic activity against HepG2 cells. Compound 10 exhibited cytotoxicity to Hela cells.

MiR-29c reduces the cisplatin resistance of non-small cell lung cancer cells by negatively regulating the PI3K/Akt pathway.

In previous studies, miR-29s showed tumor suppressor properties against lung cancer, which improved the survival of patients upon the administration of chemotherapy via an unknown mechanism. Here, we investigated the regulatory effects of miR-29s on the cisplatin resistance of NSCLC cells. The expression of miR-29s was assessed in 130 clinical patients and in cisplatin-treated NSCLS cell lines. MiR-29c expression was decreased in 77% of NSCLC patients. Cisplatin treatment increased the expression of miR-29c and decreased the expression of its oncogenic target AKT2 in NSCLC cell lines. A Kaplan-Meier survival analysis indicated that higher miR-29c levels led to a longer disease-free survival. In particular, patients who experienced cancer recurrences after cisplatin chemotherapy exhibited a lower level of miR-29c expression, suggesting that miR-29c activation may contribute to the chemotherapeutic efficiency of cisplatin. The enforced expression of miR-29c enhanced the cisplatin sensitivity of NSCLC cells, while the knocking down of miR-29c led to cisplatin resistance. MiR-29c amplified the therapeutic effects of cisplatin in vivo. Rescue experiments suggested that miR-29c regulates the cisplatin resistance of NSCLS cells by negatively regulating the PI3K/Akt pathway. Overall, our results demonstrated that miR-29c enhances the sensitivity of NSCLC cells to cisplatin by targeting the PI3K/Akt pathway.