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Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.

Supplementary Table 1. Multivariate analysis of independent prognostic factors in breast cancer patients.

Supplementary Table 5 and 6: TRA2A expression was significantly associated with poorer survival

The gene structure view of CALU (exon2 inclusion), RSRC2 (exon4 inclusion), CEACAM1 (exon7 inclusion), LMCD1 (exon3 exclusion), PALM (exon8 exclusion) and RFWD2 (exon7 exclusion).

Table S3: Primers for qRT-PCR

Supplementary Figure 2. AURKA overexpression induced extra centrosomes, ALDH1 positivity and USP44 upregulation.

Supplementary Figure 3. USP44 KD inhibited IL-6 and IL-8 expression in breast CSCs.

Table S2: TRA2A-regulated AS events

Supplementary Figure 1. AURKA overexpression induced centrosome amplification and stemness development in MCF-7 cells.

qRT-PCR showed that MELK, CEACAM1, LMCD1 and RFWD2 AS events weren't shown during PTX treatment.

Supplementary Figure legends. Figure legends for Supplementary Figure 1-3.

Supplementary Figure legends; Table S1, S4, S7, S8, and RSRC2 minigene sequence. Table S1: The increased splicing factors expression induced by PTX treatment in MDA-MB-231 cells; Table S4. All AS events selected for validation were confirmed by VeriQuest SYBR Green qPCR; Table S7: The relationship of TRA2A, CALUl, CALUs, RSRC2l, RSRC2s, PALMl, PALMs mRNA and TRA2A protein expression with PTXR of TNBC; Table S8: The relationship of TRA2A, CALUl, CALUs, RSRC2l, RSRC2s, PALMl and PALMs mRNA with TRA2A protein expression.

Treatment of triple-negative breast cancer (TNBC) has been challenging, and paclitaxel resistance is one of the major obstacles to the better prognosis. Deregulation of alternative splicing (AS) may contribute to tumor progression and chemotherapy resistance. Human AS factor TRA2 has two separate gene paralogs encoding TRA2A and TRA2B proteins. TRA2B is associated with cancer cell survival and therapeutic sensitivity. However, the individual role of TRA2A in cancer progression has not been reported. Here we report that TRA2A facilitates proliferation and survival and migration and invasion of TNBC cells. In addition, TRA2A promotes paclitaxel resistance of TNBC by specifically controlling cancer-related splicing, which is independent of other splicing factors. TRA2A overexpression could promote AS of CALU, RSRC2, and PALM during paclitaxel treatment of TNBC cells. The isoform shift of RSRC2 from RSRC2s to RSRC2l leads to a decreased RSRC2 protein expression, which could contribute to TNBC paclitaxel resistance. TRA2A can regulate RSRC2 AS by specifically binding upstream intronic sequence of exon4. Strikingly, TRA2A expression is increased dramatically in patients with TNBC, and has a close relationship with decreased RSRC2 expression; both are associated with poor survival of TNBC. Collectively, our findings suggest that paclitaxel targets the TRA2A–RSRC2 splicing pathway, and deregulated TRA2A and RSRC2 expression may confer paclitaxel resistance. In addition to providing a novel molecular mechanism of cancer-related splicing dysregulation, our study demonstrates that expression of TRA2A in conjunction with RSRC2 may provide valuable molecular biomarker evidence for TNBC clinical treatment decisions and patient outcome. Mol Cancer Ther; 16(7); 1377–88. ©2017 AACR.

T-2 toxin is one of the most common mycotoxins found in grain foods, animal feed, and other agricultural by-products causing food contamination and health threat. The skeletal system is the main target tissue for T-2 toxin. T-2 toxin exposure is also recognized as a potential contributor to multiple types of bone diseases, including Kashin-Beck disease. However, the mechanisms of T-2 toxin-induced bone toxicity remain unclear. In this study, 60 male C57BL/6 mice were exposed T-2 toxin with 0, 0.5, 1 or 2 mg/kg body weight by intragastric administration for 28 days, respectively. Femora were collected for the detections of femur lesion, bone formation factors, oxidative stress, autophagy, apoptosis, and Wnt/β-catenin signaling. Our research showed that T-2 toxin caused bone formation disorders, presenting as the reduction of the BMD and femur length, bone structure changes and abnormal bone formation proteins expressions, along with enhanced oxidative stress. Meanwhile, T-2 toxin increased expressions of autophagy-related proteins (Beclin 1, ATG5, p62, and LC3), and promoted apoptosis in mouse femur. Moreover, T-2 toxin suppressed the Wnt/β-catenin signaling and expressions of downstream target genes. Taken together, our data indicated T-2 toxin-induced femur lesion was accompanied by autophagy and apoptosis, which was associated with Wnt/β-catenin signaling.

Residual lesions in the tumor bed have been a challenge for conventional white-light breast-conserving surgery. Meanwhile, lung micro-metastasis also requires improved detection methods. Intraoperative accurate identification and elimination of microscopic cancer can improve surgery prognosis. In this study, a smart fibronectin-targeting and metalloproteinase-activatable imaging probe CREKA-GK8-QC is developed. CREKA-GK8-QC possesses an average diameter of 21.7 ± 2.5 nm, excellent MMP-9 protein responsiveness and no obvious cytotoxicity. In vivo experiments demonstrate that NIR-I fluorescence imaging of CREKA-GK8-QC precisely detects orthotopic breast cancer and micro-metastatic lesions (nearly 1 mm) of lungs with excellent imaging contrast ratio and spatial resolution. More notably, fluorescence image-guided surgery facilitates complete resection and avoids residual lesions in the tumor bed, improving survival outcomes. We envision that our newly developed imaging probe shows superior capacity for specific and sensitive targeted imaging, as well as providing guidance for accurate surgical resection of breast cancer. Graphical Abstract

As the worldwide spreading epidemic of SARS-CoV-2, quick inspection and quarantine of passengers for SARS-CoV-2 infection are essential for controlling the spread of SARS-CoV-2, especially the cross-border transmission. This study reports a SARS-CoV-2 genome sequencing method based on a re-sequencing tiling array successfully used in border inspection and quarantine. The tiling array chip has four cores, with one core of 240,000 probes dedicated to the whole genome sequencing of the SAR-CoV-2 genome. The assay protocol has been improved to reduce the detection time to within one day and can detect 96 samples in parallel. The detection accuracy has been validated. This fast and simple procedure is also of low cost and high accuracy, and it is particularly suitable for the rapid tracking of viral genetic variants in custom inspection applications. Combining these properties means this method has significant application potential in the clinical investigation and quarantine of SARS-CoV-2. We used this SARS-CoV-2 genome re-sequencing tiling array to inspect and quarantine China's entry and exit ports in the Zhejiang Province. From November 2020 to January 2022, we observed the gradual shift of SARS-CoV-2 variants from the D614G type to the Delta Variant, and then to the dominance of the Omicron variant recently, consistently with the global emergency pattern of the new SARS-CoV-2 variant.

Sulfur mustard (SM) is a notorious blistering chemical warfare agent. Rapid field screening for trace SM is of vital significance for the detection of antiterrorism and timely treatment. Here, a visual assay for SM was constructed on the basis of its inhibition for the G-quadruplexes/hemin DNAzyme. Specifically, multiple guanine (G)-rich single stranded oligonucleotides (ssODN) named S1 (80% of G in the total bases), i.e., the precursor for G-quadruplex, which could oxide tetramethylbenzidine (TMB) to its green product, were conjugated on the nonfouling polymer brush grafted magnetic beads (MB@P(C-H)). SM could specifically alkylate the N7 and O6 sites of G in the S1; thus, it failed to form the DNAzyme based signal reporter. It was demonstrated that the nonfouling P(C-H) interface on the magnetic bead (MB) could protect the conjugated ssODN from nuclease degradation, thus ensuring its well sensing performance in complex samples. Under the optimized conditions, this method achieved good sensitivity and selectivity with a limit of detection (LOD) as low as 0.26 μmol L

Objectives: An empirical study is carried out based on Plague, Inc. to explore whether the game has raised awareness of public health and urged players to make a better choice about health. Materials and Methods: Twenty-six college students from 24 cities in 11 provinces of China were investigated for a week-long survey. According to grounded theory principles, we coded original records from 69 diary reports using qualitative analysis tools. Results: We constructed nine core categories from participants' journals and drew the mechanism chart of the game as a means of health communication. The results showed that participants had experienced (1) an iterative learning process based on the authenticity and multiperspective features of the game and obtained specific learning outcomes; (2) deep thinking through the association between the game and the real world. And we extracted variables that are highly predictive of behavior change, including cognition of seriousness, cognition of susceptibility, action clue, and self-efficacy. Furthermore, noncore categories (including emotions and gameplay) directly and indirectly impacted players' learning and behavior change. Conclusion: The study shows Plague, Inc. has played a positive role in health communication (mainly reflected in the improvement of players' cognitive level, the establishment of health belief, and behavior changes). Moreover, it is concluded that reflection plays an important role in health communication interventions. However, careful consideration should be given to the use of this game as a means of health intervention due to its limitations and certain deficiencies.

The most common mutations in gastrointestinal stromal tumors (GISTs) are

Non-targeted analysis of chemical hazards in foods plays a crucial role in controlling food safety. However, because it brings forward high demand for sample pretreatment, materials suitable for the pretreatment of foods, especially animal foods, are rare. Herein, covalent organic frameworks (COF)-based monolithic materials were constructed by three successive steps: preparation of polydimethylsiloxane (PDMS) sponge using sugar cube as a sacrificial template, loading of a heteroporous COF on PDMS sponge via ultrasonic or in-situ growth method, coating of the obtained PDMS@COF by polydopamine (PDA) network. As-prepared PDMS@COF@PDA sponges were demonstrated to work well in sample pretreatment of animal foods for non-targeted analysis of chemical hazards. After a simple vortex treatment for about 2 min, more than 98% triglycerides, the main interfering matrix components in animal foods, could be removed from lard and pork samples, accompanied by "full recovery" (recovery efficiencies: ≥63%) of 44 chemical hazards with different physicochemical properties. Besides providing promising sample pretreatment materials for non-targeted food safety analysis, this work also paves a feasible way to improve COF-based monolithic materials and thus promote their practical applications, because we found that the introduction of PDA network on COF-based monolithic material surface could play a role in "killing three birds with one stone": enhancing the stability of the materials by overcoming the detachment of COF during operations; controllably adjusting hydrophobic and hydrogen-bonding interactions on the material surface to promote the removal of triglycerides; weakening the hydrophobic and π-π interactions between COF and chemical hazards to increase the recoveries of chemical hazards.

Rapid screening monofluoroacetic acid (FAcOH) is responsible for preventing chemical poisoning and food safety events. Whereas surface enhanced Raman scattering (SERS) spectra is an effective tool for detecting forbidden chemicals, it is difficult to directly detect FAcOH due to its small Raman scattering cross section as well as weak adsorption on SERS substrates. In this work, the metal phenolic supramolecular networks (MPNs, i.e., the tannic acid and Fe3+ complex) were fabricated on the commercial nanoanodic aluminum oxide film (NAAO) for assisting in situ chemical deposition highly uniform Ag nanostructure over large areas (the NAAO@AgNS). The low cost and simple fabrication process made the NAAO@AgNS a single-use consumable. For FAcOH detection, a specific derivative reaction between FAcOH and thiosalicylic acid (TSA) was introduced. By taking TSA as the Raman probe, its SERS signal attenuated constantly with the increasing amount of FAcOH. For improving quantitative accuracy, thiocyanate (SCN-) was introduced on the NAAO@AgNS as an internal standard; thus, the characteristic peak intensity ratios associated with TSA and SCN- (I1035/I2125) were fitted to the concentration of FAcOH. It was demonstrated that the SERS assay achieved good sensitivity and selection toward FAcOH with the limit of quantitation (LOD) as low as 50 nmol L-1. The NAAO@AgNS featured with highly sensitive, uniform, and consistent SERS performances could easily extend to wide SERS applications.

The pollution of aluminum (Al) in agricultural production and its wide application in food processing greatly increase the chance of human and animal exposure. Al can accumulate in bone and cause bone diseases by inducing oxidative stress. Mitophagy can maintain normal cell function by degrading damaged mitochondria and scavenging reactive oxygen species. However, the role of mitophagy in the bone impairment caused by Al is unknown. In this study, we demonstrated that PTEN induced putative kinase 1 (PINK1)/ E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy was activated in the bone impairment caused by Al in vivo. Then, the Al-induced mitophagy in Parkin-deficient mice and MC3T3-E1 cells were decreased. Meanwhile, Parkin deficiency exacerbated the bone impairment, mitochondrial damage, and oxidative stress under Al exposure, both in vivo and in vitro. In general, the results reveal that Al exposure can activate PINK1/Parkin-mediated mitophagy, and the PINK1/Parkin-mediated mitophagy plays a protective role in the bone impairment caused by Al.

Lipophilic shellfish toxins pose significant threats to the health of seafood consumers and public health. The symptoms of these kinds of toxins include severe diarrhea, abdominal cramps, nausea and gastrointestinal disorders. These symptoms could be hardly distinguished with many other symptoms of food poisoning and diseases. Therefore, a fast and accurate determination method in human biological samples is urgently needed for the accurate judgement of food poisoning incident, which is important for the investigation of public health emergencies and clinical treatment of poisoned patients. However, there were several flaws of the previous studies reported on the analysis of lipophilic shellfish toxins: (1) limited target compounds were covered; (2) the pre-treatment process was complex; (3) the sensitivity of the compound was low. In this study, a simple extraction method coupled with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of 12 lipophilic shellfish toxins, including azaspir acid 1 (AZA1), azaspir acid 2 (AZA2), azaspir acid 3 (AZA3), dinophysistoxin 1 (DTX1), dinophysistoxin 2 (DTX2), gymnodimine (GYM), hyessotoxin (HYTX), okadaic acid (OA), pinnatoxin (Pntx), pectenotoxins 2 (PTX2), spirolides 1 (SPX1), yessotoxin (YTX), in plasma and urine. Firstly, the instrument conditions were optimized. Different additions in mobile phase were compared and 0.05% (v/v) ammonia solution was selected since it can improve the peak shape of YTX and HYTX, and increase the respondence by four times. Secondly, the volume of acetonitrile (0.2, 0.4, 0.6, 0.8, 1.0 mL) use for the extraction of the target compounds in plasma was optimized. Satisfactory recoveries were obtained when 0.6 mL of acetonitrile was used. At the same time, satisfactory recoveries were obtained when 0.9 mL of acetonitrile was used in urine samples. Finally, under the optimized conditions, the 12 compounds in plasma and urine samples were ultrasonically extracted with acetonitrile. Chromatographic separation was performed on a Phenomenex Kinetex C18 column (50 mm×3 mm, 2.6 μm) with 90% (v/v) acetonitrile aqueous solution and water containing 0.05% (v/v) ammonia as mobile phases. Gradient elution with a flow rate of 0.40 mL/min was employed. The 12 compounds were monitored in the multiple reactions monitoring (MRM) mode with electrospray ionization (ESI) under both positive and negative conditions. The matrix effects of the 12 compounds ranged from 0.8 to 1.1. Therefore, external standard calibration curves were used for the quantification. The 12 shellfish toxins showed good linear relationship in the range of 0.03-36.25 μg/L with the correlation coefficients greater than 0.995. The limits of detection (LODs, S/N=3) were 0.08-0.21 ng/mL for the urine samples and 0.10-0.28 μg/L for the plasma samples, respectively. The limit of quantitations (LOQs, S/N=10) were 0.23-0.63 μg/L for the urine samples and 0.31-0.84 μg/L for the plasma samples, respectively. The recoveries of the 12 compounds were in the range of 72.7%-124.1% at three spiked levels (i. e., LOQ, three times LOQ, and ten times LOQ). The intra-day and inter-day precisions were 2.1%-20.0% and 2.1%-15.3%, respectively. The method was applied in the detection of the 12 lipophilic shellfish toxins in the urine and plasma samples of healthy humans and mice previously injected with the 12 shellfish toxins intraperitoneally. None of the 12 toxins were found in the samples from healthy human, while all of the 12 lipophilic shellfish toxins were found in the urine and plasma samples collected from the poisoned mice in the range of 1.14-2.35 μg/L and 1.01-1.17 μg/L, respectively. The established method has the advantages of sensitive, quick, easy to operate, and of low sample volume. It can be used for the simultaneous determination of 12 lipophilic shellfish toxins in urine and plasma samples.

T-2 toxin is produced by the Fusarium genus. Ingestion of food or feed contaminated by T-2 toxin will cause damage to kidney. Selenium (Se), an essential trace element, showed the significant protective effects against kidney and renal cell damage induced by toxic substances. To explore the protective effects and mechanisms of Se against T-2-induced renal lesions, forty-eight male Kunming mice were exposed to T-2 toxin (1.0 mg/kg) and/or Se (0.2 mg/kg) for 28 days. In this study, we found that Se alleviated T-2-induced nephrotoxicity, presenting as increasing the body weight and kidney coefficient, relieving the renal structure injury, decreasing the contents of renal function-related biomarkers, decreasing the levels of reactive oxygen species (ROS), and increasing the mitochondrial membrane potential in T-2 toxin-treated mice. In addition, inhibition of renal cell apoptosis by Se was associated with blocking the mitochondrial pathway in T-2 toxin-treated mice, presenting as decreasing the protein expression of cytochrome-c, activities of caspase-3/9, as well as regulating the protein and mRNA expressions of Bax and Bcl-2. These results documented that the alleviating effect of Se on T-2-induced nephrotoxicity is related to the inhibition of ROS-mediated renal apoptosis.

Concentrations of bisphenol A (BPA) and its analogues (together with their chlorinated derivatives are referred to as BPs) were measured in 181 breastmilk samples collected from 9 provinces in China in 2014. Twelve BP types were found. The BP concentrations ranged from not detected to 5.912 μg/L. BPA was the predominant BP, followed by bisphenol F (BPF) and bisphenol S (BPS). The mean BPA, BPF, and BPS levels were 0.444, 0.107, and 0.027 μg/L, respectively. Other BPs were sporadically detected in breastmilk samples. There were no differences (p > 0.05) in BPA, BPF, BPS, or total BP levels in the urban and rural regions or the northern and southern regions. BPA accounted for approximately 70% of the BPs and BPF accounted for more than 20% of the BPs in breast milk samples. The high contribution of BPF indicated that BPA analogues, not only BPA, should receive attention. The upper-bound daily intakes of BPs for infants 0-6 months old were 0.044-1.291 μg/kg bw/day. Despite the absence of tolerable daily intake data, attention should be paid not only on BPA but also BPF.