A novel ratiometric sensor for fluorimetric and visual dual-mode detection of Al3+ in environmental water based on the target-regulated formation of Eu MOFs.

Herein, a novel ratiometric sensor for fluorimetric and smartphone-assisted visual detection of Al3+ in environmental water was developed based on the target-regulated formation of Eu metal-organic frameworks (Eu MOFs). By employing 2-[4-(2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid (Hepes), Eu3+ and tetracycline (TC) as raw materials, Eu MOFs with red emission were facilely synthesized through the coordination of Eu3+ with Hepes and TC. However, upon the introduction of Al3+, a higher affinity of TC towards Al3+ resulted in the formation of a TC-Al3+ complex with green fluorescence and inhibited the generation of Eu MOFs. This led to an increase in green fluorescence and a decrease in red fluorescence accompanied by the fluorescence color of the solution changing from red to green under the illumination of the UV lamp. Thus, a ratiometric sensor for fluorimetric and the smartphone-assisted visual detection of Al3+ was established. The ratiometric sensor exhibited high sensitivity for Al3+ detection with a detection limit of 0.14 µM for fluorescence detection and 1.21 µM for visual detection. Additionally, the proposed strategy was successfully applied to detect Al3+ in the environmental water samples with satisfactory results, indicating great application prospects for environmental monitoring.

Cerebral endothelial cells mediated enhancement of brain pericyte number and migration in oxygen-glucose deprivation involves the HIF-1α/PDGF-ß signaling.

The present study focused on whether hypoxia-inducible factor-1alpha (HIF-1α) and platelet-derived factor-beta (PDGF-ß) are involved in the crosstalk between brain microvascular endothelial cells (BMECs) and brain vascular pericytes (BVPs) under ischaemic-hypoxic conditions. Mono-cultures or co-cultures of BVPs and BMECs were made for the construction of the blood-brain barrier (BBB) model in vitro and then exposed to control and oxygen-glucose deprivation (OGD) conditions. BBB injury was determined by assessing the ability, apoptosis, and migration of BVPs and the transendothelial electrical resistance and horseradish peroxidase permeation of BMECs. Relative mRNA and protein levels of HIF-1α and PDGF-ß, as well as tight junction proteins ZO-1 and claudin-5 were analyzed by western blotting, reverse transcription quantitative PCR, and/or immunofluorescence staining. Dual-luciferase reporter assays assessed the relationship between PDGF-ß and HIF-1α. Co-culturing with BMECs alleviated OGD-induced reduction in BVP viability, elevation in BVP apoptosis, and repression in BVP migration. Co-culturing with BVPs protected against OGD-induced impairment on BMEC permeability. OGD-induced HIF-1α upregulation enhanced PDGF-ß expression in mono-cultured BMECs and co-cultured BMECs with BVPs. Knockdown of HIF-1α impaired the effect of BMECs on BVPs under OGD conditions, and PDGFR-ß silencing in BVPs blocked the crosstalk between BMECs and BVPs under OGD conditions. The crosstalk between BMECs and BVPs was implicated in OGD-induced BBB injury through the HIF-1α/PDGF-ß signaling.

In Situ Growth Strategy to Construct "Four-In-One" Separators with Functionalized Polyphosphazene Coatings for Safe and Stable Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LSBs) are facing many challenges, such as the inadequate conductivity of sulfur, the shuttle effect caused by lithium polysulfide (LiPSs), lithium dendrites, and the flammability, which have hindered their commercial applications. Herein, a "four-in-one" functionalized coating is fabricated on the surface of polypropylene (PP) separator by using a novel flame-retardant namely InC-HCTB to meet these challenges. InC-HCTB is obtained by cultivating polyphosphazene on the surface of carbon nanotubes with an in situ growth strategy. First, this unique architecture fosters an enhanced conductive network, bolstering the bidirectional enhancement of both ionic and electronic conductivities. Furthermore, InC-HCTB effectively inhibits the shuttle effect of LiPSs. LSBs exhibit a remarkable capacity of 1170.7 mA h g-1 at 0.2 C, and the capacity degradation is a mere 0.0436% over 800 cycles at 1 C. Third, InC-HCTB coating serves as an ion migration network, hindering the growth of lithium dendrites. More importantly, InC-HCTB exhibits notable flame retardancy. The radical trapping action in the gas phase and the protective effect of the shielded char layer in the condensed phase are simulated and verified. This facile in situ growth strategy constructs a "four-in-one" functional separator coating, rendering InC-HCTB a promising additive for the large-scale production of safe and stable LSBs.

Hydrophilic 1T-WS2 Nanosheet Arrays toward Conductive Textiles for High-Efficient and Continuous Hydroelectric Generation and Storage.

Flexible hydroelectric generators (HEGs) are promising self-powered devices that spontaneously derive electrical power from moisture. However, achieving the desired compatibility between a continuous operating voltage and superior current density remains a significant challenge. Herein, a textile-based van der Waals heterostructure is rationally designed between conductive 1T phase tungsten disulfide@carbonized silk (1T-WS2 @CSilk) and carbon black@cotton (CB@Cotton) fabrics with an asymmetric distribution of oxygen-containing functional groups, which enhances the proton concentration gradients toward high-performance wearable HEGs. The vertically staggered 1T-WS2 nanosheet arrays on the CSilk fabric provide abundant hydrophilic nanochannels for rapid carrier transport. Furthermore, the moisture-induced primary battery formed between the active aluminum (Al) electrode and the conductive textiles introduces the desired electric field to facilitate charge separation and compensate for the decreased streaming potential. These devices exhibit a power density of 21.6 µW cm-2 , an open-circuit voltage (Voc ) of 0.65 V sustained for over 10 000 s, and a current density of 0.17 mA cm-2 . This performance makes them capable of supplying power to commercial electronics and human respiratory monitoring. This study presents a promising strategy for the refined design of wearable electronics.

A facile fluorescence Eu MOF sensor for ascorbic acid and ascorbate oxidase detection.

In this work, a facile fluorescence Eu3+-based metal-organic framework (Eu MOF) sensor for ascorbic acid (AA) and ascorbate oxidase (AAO) detection was developed. The fluorescence of the Eu MOF could be effectively quenched by Ce3+ but not by Ce4+ at an appropriate concentration, and thus, when the reductant AA was added into the solution containing Ce4+, Ce4+ was chemically reduced to Ce3+, which induced the decreased fluorescence signal of the Eu MOF. However, when AAO was introduced, AA was effectively oxidized to dehydroascorbic acid (DHAA) under the catalysis of AAO, and thus, Ce4+ could not be reduced, resulting in the fluorescence restoration of the Eu MOF. Hence, the concentration of AA and AAO could be determined by the fluorescence decrease and restoration of the Eu MOF. The fluorescent platform showed high sensitivity with a limit of detection of 0.32 µM for AA and 1.18 U L-1 for AAO, respectively. Moreover, the proposed method was successfully applied for AA and AAO determination in real samples, indicating great potential for biomedical application in complex matrices.

Adverse childhood experiences and human immunodeficiency virus testing among adults with human immunodeficiency virus risk behaviours.

Adverse childhood experiences (ACEs) have been associated with poor HIV testing in adulthood yet, they have not been extensively described in those at increased risk for HIV. Cross-sectional analysis data (n = 204,231) on ACEs and HIV testing were obtained from the 2019-2020 Behavioural Risk Factor Surveillance Survey. Weighted logistic regression models were used to access the association of ACEs exposure, ACEs score, and ACEs type with HIV testing among adults with HIV risk behaviours, and stratified analysis was also performed to examine gender differences. The results indicated the overall rate of HIV testing was 38.8% and was higher among those with HIV risk behaviours (64.6%) than those without (37.2%). In populations with HIV risk behaviours, the negative association of HIV testing with ACEs exposure, ACEs score, and ACEs type was identified. Relative to those without ACEs, adults who were exposed to ACEs might decrease the rate of HIV testing, participants with ≥4 ACEs scores were less likely to have HIV testing, and childhood exposure to sexual abuse had the greatest impact on HIV testing. For both males and females, childhood exposure to ACEs was associated with lower odds of HIV testing and ACEs score ≥4 had the most robust associations with HIV testing. For males, those who experienced witnessed domestic violence had the lowest odds of HIV testing but the odds of engaging in HIV testing for females were the lowest among those who experienced childhood sexual abuse.

PtrABR1 Increases Tolerance to Drought Stress by Enhancing Lateral Root Formation in Populus trichocarpa.

Roots are the main organ for water uptake and the earliest part of a plant's response to drought, making them of great importance to our understanding of the root system's response to drought. However, little is known about the underlying molecular mechanisms that control root responses to drought stress. Here, we identified and functionally characterized the AP2/ERF family transcription factor (TF) PtrABR1 and the upstream target gene zinc-finger protein TF PtrYY1, which respond to drought stress by promoting the growth and development of lateral roots in Populus trichocarpa. A root-specific induction of PtrABR1 under drought stress was explored. The overexpression of PtrABR1 (PtrABR1-OE) promoted root growth and development, thereby increasing tolerance to drought stress. In addition, PtrYY1 is directly bound to the promoter of PtrABR1 under drought stress, and the overexpression of PtrYY1 (PtrYY1-OE) promoted lateral root growth and development and increased tolerance to drought stress. An RNA-seq analysis of PtrABR1-OE with wild-type (WT) poplar identified PtrGH3.6 and PtrPP2C44, which share the same pattern of expression changes as PtrABR1. A qRT-PCR and cis-element analysis further suggested that PtrGH3.6 and PtrPP2C44 may act as potential downstream targets of PtrABR1 genes in the root response pathway to drought stress. In conclusion, these results reveal a novel drought regulatory pathway in which PtrABR1 regulates the network through the upstream target gene PtrYY1 and the potential downstream target genes PtrGH3.6 and PtrPP2C44, thereby promoting root growth and development and improving tolerance to drought stress.

Significance of ypTNM stage in determining the prognosis and therapy after surgery for locally advanced rectal cancer.

BACKGROUND: In the current NCCN guidelines, the prognosis and adjuvant chemotherapy of patients who underwent neoadjuvant chemoradiotherapy (nCRT) are based on pre-radiotherapy clinical TNM (cTNM) stage. However, the value of neoadjuvant pathologic TNM (ypTNM) stage is not clearly described. METHODS: This retrospective study investigated the prognosis and adjuvant chemotherapy which based on ypTNM stage compared to cTNM stage. Between 2010 and 2015, a total of 316 rectal cancer patients who underwent nCRT, followed by total mesorectal excision (TME), were included for analysis. RESULTS: Our findings revealed that cTNM stage was the only significant independent factor in the pCR group (HR = 6.917, 95% CI: 1.133-42.216, P = 0.038). In the non-pCR group, ypTNM stage was more important than cTNM stage in prognosis (HR = 2.704, 95% CI: 1.811-4.038, P < 0.001). In ypTNM III stage group, there was a statistically significant difference in prognosis between the patients with and without adjuvant chemotherapy (HR = 1.943, 95% CI: 1.015-3.722, P = 0.040), but there was no significant difference in cTNM III stage group (HR = 1.430, 95% CI: 0.728-2.806, P = 0.294). CONCLUSIONS: We concluded that ypTNM stage, rather than cTNM stage, might be a more important factor in the prognosis and adjuvant chemotherapy of patients with rectal cancer who underwent nCRT.

Tetrahydroberberrubine prevents peritoneal adhesion by suppressing inflammation and extracellular matrix accumulation.

Peritoneal adhesion is a common abdominal surgical complication that induces abdominal haemorrhage, intestinal obstruction, infertility, and so forth. The high morbidity and recurrence rate of this disease indicate the need for novel therapeutic approaches. Here, we revealed the protective roles of tetrahydroberberrubine (THBru), a novel derivative of berberine (BBR), in preventing peritoneal adhesion and identified its underlying mechanism in vivo and in vitro. Abrasive surgery was used to create a peritoneal adhesion rat model. We found that THBru administration markedly ameliorated peritoneal adhesion, as indicated by a lowered adhesion score and ameliorated caecal tissue damage. By comparison, THBru exhibited more potent anti-adhesion effects than BBR at the same dose. Mechanistically, THBru inhibited inflammation and extracellular matrix (ECM) accumulation in the microenvironment of adhesion tissue. THBru suppressed the expression of inflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1), by regulating the transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factor κB (NF-κB) signaling pathways. However, THBru promoted the activation of MMP-3 by directly blocking the TIMP-1 activation core and subsequently decreased collagen deposition. Taken together, this study identifies THBru as an effective anti-adhesion agent that regulates diverse mechanisms, thereby outlining its potential therapeutic implications for the treatment of peritoneal adhesion.

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer.

Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI, 1.334-8.713; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.

Adverse childhood experiences and sleep duration among U.S. 65 years and older: results from the 2020 BRFSS.

BACKGROUND: Adverse childhood experiences (ACEs) are a risk factor for many chronic diseases and health behaviors. This study explores the relationship between ACEs and sleep duration in elderly populations in 22 U.S. states in 2020. METHODS: This study is a cross-sectional analysis of aged 65 years or older in the 2020 Behavioral Risk Factor Database (BRFSS). The weighted multivariate logistic regression was used to assess the association of ACEs status, ACEs type, and ACE scores with sleep duration. Subgroup analysis was used to estimate differences based on covariates. RESULTS: Among the 42,786 participants (55.8 % female) included in this analysis, 50.5 % reported at least one ACE, and 7.3 % reported 4 or more ACEs. Adjusting for confounding factors, experiencing ACEs was associated with short and long sleep duration (Odds Ratio (OR): 2.03, 95 % Confidence Interval (CI): 1.51,2.73; OR:1.78, 95%CI:1.34,2.36). Older adults who experienced sexual abuse in children were 146 % more likely to short sleep (OR:2.46,95%CI:1.84,3.31) and 99 % more likely to long sleep (OR:1.99, 95%CI:1.35,2.92). There was a dose-response gradient between ACEs scores and sleep duration, reporting ≥ 4 ACEs had 3.10 (OR:3.10,95%CI:2.12,4.53) and 2.13 (OR:2.13, 95%CI:1.33,3.40) times the risk for short-sleep and long-sleep duration compared to respondents reporting no ACEs. CONCLUSIONS: This study showed the association between ACEs and a high risk of sleep duration, which increased with increasing ACEs scores.

Brominated flame retardants coated separators for high-safety lithium-sulfur batteries.

Lithium-sulfur batteries (LSBs) have become highly promising next-generation secondary lithium batteries owing to their high theoretical energy density and abundance of sulfur. Nevertheless, the large-scale application of LSBs is still restricted by the shuttle effect of lithium polysulfide (LiPSs) and the potential fire hazard caused by flammable electrolytes. Herein, three electrolyte-insoluble brominated flame retardants (BFRs) are selected and coated on both sides of commercial polypropylene separators by a facile slurry coating method. The effects of the three BFRs on the safety and electrochemical properties of LSBs are characterized and compared. The coating modification separators greatly improves the flame retardancy of LSBs through radical elimination mechanism. The self-extinguishing time of the electrolyte is reduced from 0.66 s/mg to 0.20 s/mg. Moreover, it is demonstrated that the oxygen (O)-containing BFRs exert a significant adsorption capacity and are more advantageous than O-free BFRs in LSBs. In addition, octabromoether (BDDP) coated separator is more effective in trapping LiPSs than decabromodiphenyl ether (DBDPO) due to higher O content, which can mitigate the shuttle effect and enhance the cycle and rate performance of LSBs. This simple coating strategy for separators with BFRs offers a strongly competitive option for the large-scale production of high-safety LSBs.

Neuroendocrine differentiation: a risk fellow in colorectal cancer.

BACKGROUND: Neuroendocrine differentiation (NED) is often found in colorectal cancer (CRC) and may have unique biological behavior, which has not been previously delineated. Here, we explore the relationship between CRC, NED, and clinicopathological factors. We also offer a preliminary explanation of the mechanism underlying the malignant biological behavior of NED in CRC. METHODS: Between 2013 and 2015, 394 CRC patients who underwent radical operations were selected for analysis. The relationship between NED and clinicopathological factors was analyzed. To further clarify the pivotal role of NED in CRC, we performed bioinformatic analyses and identified genes that may be involved in NED, which were obtained from in silico data from The Cancer Genome Atlas (TCGA) database. Then, we conducted functional enrichment analyses and confirmed the critical pathways for intensive study. Moreover, we detected the expression of key proteins by immunohistochemistry and analyzed the correlation of their expression with NED. RESULTS: The statistical analysis showed that CRC with NED was positively correlated with lymph node metastasis. Through bioinformatic analysis, we found that chromogranin A (CgA) was positively correlated with invasion and lymph node metastasis. ErbB2 and PIK3R1, which are key proteins in the PI3K-Akt signaling pathway, were closely related to NED. Furthermore, we determined that the PI3K-Akt signaling pathway likely plays a critical role in the NED of CRC. CONCLUSIONS: CRC with NED is associated with lymph node metastasis. The PI3K-Akt signaling pathway, which is closely related to CRC, may be the mechanism promoting the malignant biological behavior of CRC with NED.

Epidemiological Characteristics of Norovirus Outbreaks in Shenyang from 2017 to 2021.

Norovirus is one of the leading causes of acute gastroenteritis outbreaks worldwide. This study aimed to identify the epidemiological characteristics of norovirus outbreaks and to provide evidence for public health entities. Specimens and epidemiological survey data were collected to determine if there were differences in the attack rate of norovirus in terms of the year, season, transmission route, exposure setting, and region and to determine whether there were relationships between the reporting interval, the number of illnesses in a single outbreak and the duration of the outbreak. Norovirus outbreaks were reported throughout the year, with seasonal characteristics (i.e., high rates in spring and winter). Among all regions in Shenyang with the exception of Huanggu and Liaozhong, norovirus outbreaks had been reported, and the primary genotype was GII.2[P16]. Vomiting was the most common symptom. The main places of occurrence were childcare institutions and schools. The person-to-person route was the main transmission route. The median duration of norovirus was 3 days (IQR [interquartile range]: 2-6 days), the median reporting interval was 2 days (IQR: 1-4 days), the median number of illnesses in a single outbreak was 16 (IQR: 10-25); there was a positive correlation between these parameters. Norovirus surveillance and genotyping studies still need to be further strengthened to increase knowledge regarding the pathogens and their variant characteristics, to better characterize the patterns of norovirus outbreaks and to provide information for outbreak prevention. Norovirus outbreaks should be detected, reported and handled early. Public health entities and the government should develop corresponding measures for different seasons, transmission routes, exposure settings, and regions.

Monitoring reduced accumulation and risk evaluation of Cry1Ca during food chain transfer from genetically engineered plant to endoparasitoid.

BACKGROUND: The potential risk of insecticidal proteins produced by genetically engineered (GE) plants to nontarget organisms have long been an ecotoxicological concern. Apanteles chilonis, an important endoparasitoid of rice pest Chilo suppressalis, potentially is exposed to Bacillus thuringiensis (Bt) endotoxins through a food chain of transgenic Bt rice - C. suppressalis - A. chilonis, and thus, a rigorous risk assessment is urgently needed. Here, we combined a tri-trophic bioassay system with high-dose exposure approach using C. suppressalis hemolymph as the carrier of insecticidal protein to evaluate the biosafety of Cry1Ca to A. chilonis. RESULTS: Cry1Ca protein could be transmitted and retained along the food chain and remains bioactive in the hemolymph of C. suppressalis during the pre-adult duration of A. chilonis. No significant differences in pre-adult period, male and female longevity, adult fecundity and weight, emergence rate nor sex ratio were observed when A. chilonis parasitized C. suppressalis feeding on cry1Ca rice compared with control treatment. However, the pupal period and weight were significantly prolonged and decreased. When A. chilonis parasitized C. suppressalis injected with a high dosage of Cry1Ca protein, no adverse effects on the life-history parameters, peroxidase (POD), superoxide dismutase (SOD) or glutathione reductase (GR) of A. chilonis were observed, demonstrating that the host quality mediates adverse effects during the food chain. CONCLUSIONS: We confirmed that Cry1Ca posed no ecological risk to the nontarget endoparasitoid A. chilonis. This study may serve as an example for future risk assessment of transgenic crops to nontarget endoparasitoids. © 2023 Society of Chemical Industry.

MXene-Decorated Smart Textiles with the Desired Mid-Infrared Emissivity for Passive Personal Thermal Management.

Multifunctional and long-term stable wearable heating systems have attracted extensive attention from experts, yet smart textiles that only rely on harvesting the body's heat without additional energy still face huge challenges in practical applications. Herein, we rationally prepared the monolayer MXene Ti3C2Tx nanosheets via an in situ hydrofluoric acid generation method, which was further employed to construct a wearable heating system of MXene @ polyester polyurethane blend fabrics (MP textile) for the passive personal thermal management through a simple spraying process. Owing to the unique two-dimensional (2D) structure, the MP textile presents the desired mid-infrared emissivity, which could efficiently suppress the thermal radiation loss from the human body. Notably, the MP textile with an MXene concentration of 28 mg/mL exhibits a low mid-infrared emissivity of 19.53% at 7-14 µm. Significantly, these prepared MP textiles demonstrate an enhanced temperature of more than 6.83 °C compared with those of favorably traditional fabrics, involving the black polyester fabric, pristine polyester polyurethane blend fabric (PU/PET), and cotton, suggesting a charming indoor passive radiative heating performance. The temperature of real human skin covered by MP textile is 2.68 °C higher than that covered by cotton fabric. Impressively, these prepared MP textiles simultaneously possess attractive breathability, moisture permeability, mechanical strength, and washability, which provide new insight into human body temperature regulation and physical health.

Association of Calcium, Magnesium, Zinc, and Copper Intakes with Diabetic Retinopathy in Diabetics: National Health and Nutrition Examination Survey, 2007-2018.

PURPOSE: To evaluate the associations between calcium, magnesium, zinc, and copper intakes and the risk of diabetic retinopathy (DR) in US diabetes adults. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Multivariable logistic regression models and restricted cubic spline models were applied to examine the associations between total calcium, magnesium, zinc, and copper intakes and diabetic retinopathy. RESULTS: A total of 3794 adults aged 40 years or older were included. Higher quartile intake of calcium, magnesium, zinc, and copper was associated with a lower occurrence of DR, the multivariate adjusted ORs (95% CI) were 0.57 (0.38-0.86), 0.48 (0.32-0.73), 0.58 (0.39-0.88), and 0.48 (0.30-0.77), respectively. U-shaped dose-response relationships were found between calcium, magnesium, zinc, copper intake, and the risk of DR. CONCLUSION: Higher total calcium, magnesium, zinc, and copper intake were inversely associated with the risk of DR in US diabetes adults.

Uncovering the Pathogenesis of Orofacial Clefts Using Bioinformatics Analysis.

OBJECTIVE: Many genes have been found to be associated with the occurrence of the orofacial clefts (OFC). The links between these pathogenic genes are rarely studied. In this study, bioinformatics analysis were performed in order to find associations between OFC- related genes and provide new ideas for etiology study of OFCs. METHODS: Orofacial clefts-related genes were searched and identified from the Online Mendelian Inheritance of Man (OMIM.org). These genes were then analyzed by bioinformatics methods, including protein-protein interaction network, functional enrichment analysis, module analysis, and hub genes analysis. RESULTS: After searching the database of OMIM.org and removing duplicate results, 279 genes were finally obtained. These genes were involved to 369 pathways in biological process, 56 in cell component, 64 in molecular function, and 45 in the Kyoto Encyclopedia of Genes and Genomes. Most identified genes were significantly enriched in embryonic appendage morphogenesis (29.17%), embryonic limb morphogenesis (6.06%), and limb development (4.33%) for biological process ( Fig. 5A ); ciliary tip (42.86%), MKS complex (28.57%), ciliary basal body (14.29%), and ciliary membrane (14.29%) for cell component. The top 10 hub genes were identified, including SHH, GLI2, PTCH1, SMAD4, FGFR1, BMP4, SOX9, SOX2, RUNX2 , and CDH1. CONCLUSIONS: Bioinformatics methods were used to analyze OFC- related genes in this study, including hub gene identifying and analysis, protein - protein interaction network construction, and functional enrichment analysis. Several potential mechanisms related to occurrence of OFCs were also discussed. These results may be helpful for further studies of the etiology of OFC.

Isolation and identification of the components in Cybister chinensis Motschulsky against inflammation and their mechanisms of action based on network pharmacology and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Cybister chinensis Motschulsky belongs to the family Dytiscidae. As a traditional Chinese medicine, the insect is called Longshi in the folk and is commonly used to treat enuresis in children and frequent urination in the elderly. AIM OF THE STUDY: Inflammation is involved in chronic kidney disease. The previous study proved ethanol extract of C. chinensis exhibited anti-inflammation effects in the Doxorubicin-induced kidney disease. However, the material basis and their possible mechanism of the insect were still unclear. Thus, we aimed to separate the active compounds of the ethanol extract from C. chinensis and to investigate their possible mechanism of anti-inflammation by network pharmacology and molecular docking. MATERIALS AND METHODS: The insect was extracted with 75% ethanol to produce ethanol extracts and then were extracted by petroleum ether, ethyl acetate and n-butanol respectively. Silica gel column chromatography and preparative HPLC were applied to separate the compounds of the extract. The compounds were characterized and identified by NMR and mass. The compound associated genes were collected by BATMAN-TCM database and the inflammation associated genes were obtained through DigSee database. The protein-protein interaction (PPI) network was carried out via Search Tool for the Retrieval of Interacting Genes/Protein (STRING) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) target pathway analysis was performed in Database for Annotation, Visualization and Integrated Discovery (DAVID). The possible mechanism of compounds against inflammation was investigated by molecular docking. Finally, the anti-inflammatory effect of the representative compound was verified by the LPS-induced Raw 264.7 cell inflammatory model. TNF-α, IL-1ß and IL-6 of the cell supernatants were analyzed via using ELISA kits and the key proteins in JAK2/STAT3 signaling pathway were verified via the Western blot assays. RESULTS: Among crude extracts from C. chinensis, ethyl acetate extract showed the obvious anti-inflammatory effects. Nine compounds were isolated from ethyl acetate extract of Cybister chinensis for the first time, including benzoic acid (1), hydroxytyrosol (2), protocatechualdehyde (3), N-[2-(4-hydroxyphenyl)ethyl]acetamide (4), (2E)-3-phenylprop-2-enoic acid (5), 3-phenylpropionic acid (6), methyl 3,4-dihydroxybenzoate (7), 1,4-diphenyl butane-2,3-diol (8) and p-N,N-dimethylaminobenzaldehyde (9). After searching in the database, 1079 compound associated genes and 467 inflammation associated genes were found. The 137 common targets covered 77 signaling pathways, in which HIF-1 signaling pathway, TNF signaling pathway, influenza A, PI3K/Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway and Jak-STAT signaling pathway were important for inflammation. Molecular docking studies showed compound 1, 4, 5, 6, 7 and 8 were the potential inhibitors of JAK2 protein. In addition, the in vitro test showed compound 5 reduced the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in a dose-dependent manner. Furthermore, it was found that compound 5 inhibited the expression of p-JAK2 and p-STAT3 in LPS-induced RAW264.7 cells in a dose-dependent manner. CONCLUSIONS: Based on the network pharmacology and molecular docking, the study suggested that C. chinensis could relieve the inflammation based on the multi-compounds and multi-pathways, which provided the foundation for the medicinal application of C. chinensis.