miR394 modulates brassinosteroid signaling to regulate hypocotyl elongation in Arabidopsis.

The interplay between microRNAs (miRNAs) and phytohormones allows plants to integrate multiple internal and external signals to optimize their survival of different environmental conditions. Here, we report that miR394 and its target gene LEAF CURLING RESPONSIVENESS (LCR), which are transcriptionally responsive to BR, participate in BR signaling to regulate hypocotyl elongation in Arabidopsis thaliana. Phenotypic analysis of various transgenic and mutant lines revealed that miR394 negatively regulates BR signaling during hypocotyl elongation, whereas LCR positively regulates this process. Genetically, miR394 functions upstream of BRASSINOSTEROID INSENSITIVE2 (BIN2), BRASSINAZOLEs RESISTANT1 (BZR1), and BRI1-EMS-SUPPRESSOR1 (BES1), but interacts with BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1 SUPRESSOR PROTEIN (BSU1). RNA-sequencing analysis suggested that miR394 inhibits BR signaling through BIN2, as miR394 regulates a significant number of genes in common with BIN2. Additionally, miR394 increases the accumulation of BIN2 but decreases the accumulation of BZR1 and BES1, which are phosphorylated by BIN2. MiR394 also represses the transcription of PACLOBUTRAZOL RESISTANCE1/5/6 and EXPANSIN8, key genes that regulate hypocotyl elongation and are targets of BZR1/BES1. These findings reveal a new role for a miRNA in BR signaling in Arabidopsis.

Manipulating Cis-Trans Copolymer Chain Conformation to Simultaneously Improve Permittivity and DC Breakdown Strength in Polythiourea.

Polythioureas (PTUs) show great potentials for applications in the new generation of film capacitors due to their excellent dielectric properties. Herein, the cis-trans copolymer chain of PTU is successfully tailored by employing cis and trans cyclohexyl spacers. The relationship between the copolymer chain conformation, microstructure, and dielectric properties is carefully explored by a series of analysis. Compared with cis conformation, the trans with less steric hindrance can promote the formation of H-bonds. The enhanced H-bonding interactions not only reduce the molecular inter-chain spacing, but also drive the self-assembly of molecular chains to form cylindrical and droplet nano-morphologies. The phase separation between cis and trans PTUs is confirmed by combining the experimental results of TEM and DSC, and the CT64-PTU with the most two-phase interface thus obtains the highest permittivity of 5.5 (@10 Hz). The reduced molecular inter-chain spacing is accompanied by a decreased hopping distance of charges, which improves breakdown strength by 17% from 498 MV/m to 580 MV/m. Therefore, the cis-trans copolymer chain conformation in PTU provides a simultaneous high permittivity and breakdown strength. This research offers a strategy to further design high-performance dielectrics via regulation of copolymer chain conformation.

TRIM38 suppresses migration, invasion, metastasis, and proliferation in non-small cell lung cancer (NSCLC) via regulating the AMPK/NF-κB/NLRP3 pathway.

Accumulating data have revealed the pivotal function of tripartite motif protein 38 (TRIM38) in tumors. In view of this, this investigation aims to explore the function and potential mechanism of TRIM38 in non-small cell lung cancer (NSCLC). A xenotypic tumor model was established in vivo by subcutaneously injecting NSCLC cells (2 × 106 cells) in tail vein of each mouse. Relative expression of TRIM38 mRNA was detected via quantitative real-time polymerase chain reaction (qRT-PCR). For exploring the role of TRIM38 in vivo and in vitro, mice or NSCLC cells were divided into two groups: the vector group and the TRIM38 overexpression group. Also, protein expression levels of TRIM38, Vimentin, E-cadherin, and N-cadherin were determined using western blotting and immunohistochemistry staining. Tumor nodules of mouse lung tissues were assessed via performing H&E staining. Moreover, proliferation of NSCLC cells was evaluated through colony formation and CCK-8 assays. Further, migration and invasion of NSCLC cells were assessed through wound healing and transwell assays. Protein levels of pathway-related proteins including p-p65, p65, IκB, p-IκB, p-AMPK, AMPK, and NLRP3 were examined through western blotting analysis. Tumor lung tissues of mice and NSCLC cells showed low protein and mRNA expression of TRIM38. Functionally, up-regulation of TRIM38 reduced the number of tumor nodules and suppressed epithelial-to-mesenchymal transition (EMT) in lung tissues of mice. Furthermore, up-regulation of TRIM38 in NSCLC cells inhibited migration, invasion, EMT, and proliferation. With respect to the mechanism, in vivo experiments, the inhibitory effects of TRIM38 overexpression on tumor nodules, and EMT were reversed by AMPK inhibitor. In vitro experiments, TRIM38 overexpression caused down-regulation of p-IκB and p-p65 as well as up-regulation of p-AMPK. The inhibitory effects of TRIM38 overexpression on migration, proliferation, invasion, and EMT of NSCLC cells were reversed by overexpression of NLRP3. Concurrently, AMPK inhibitor enhanced the TRIM38-overexpressed NSCLC cell's abilities in migration, clone formation, invasion, and proliferation. TRIM38 regulated the AMPK/NF-κB/NLRP3 pathway to suppress the NSCLC's progression and development.

Surprising Hydrophobic Polymer Surface with a High Content of Hydrophilic Polar Groups.

The wetting property of a solid surface has been a hotspot for centuries, and many studies suggest that the hydrophobicity is highly related to the polar components. However, the underlying mechanism of polar moieties on the hydrophobicity remains unclear. Here, we tailor the surface polar moieties of epoxy resin (EP) by ozone modification and assess their wetting properties. Our results show that, for the modified EP with more (60.54%) polar moieties, the polar effect on hydrophobicity cannot be empirically observed. To reveal the underlying mechanism, the absorption parameters, including equilibrium distance, adsorption radius, and effective adsorption sites for water on EP before and after ozone treatment, are calculated on the basis of molecular simulations. After ozone modification, the equilibrium distance (from 1.95 to 1.70 Å), adsorption radius (from 3.80 to 4.50 Å), and effective adsorption sites (from 1 to 2) change slightly and the EP surface remains hydrophobic, although the polar groups significantly increase. Therefore, it is concluded that the wetting properties of solid surfaces are dominated by the equilibrium distance, adsorption radius, and effective adsorption sites for water on solids, and the nonlinear relationship between polar groups and hydrophilicity is clarified.

Effect of industrial sludge particle size on the performance of baking-free sludge bricks.

Cement solidification is essential to reduce heavy metal leaching from industrial sludge and make it recyclable. This paper studied the effect of aggregate grading optimized by sludge containing heavy metal of different particle sizes on the performance of baking-free sludge bricks, which was mixed with industrial sludge cured by both micro-silica fume and cement. First, the gradation of fine natural aggregates was adjusted according to the Fuller curve. Fine aggregates in baking-free bricks were replaced by artificially processed sludge with particle sizes of 0.15 mm ~0.3 mm and 2.36 mm ~4.75 mm. In this case, a mixed proportion scheme was designed. Then, the strength, water absorption, porosity, and heavy metal leaching were measured. With the help of nuclear magnetic resonance (NMR) and scanning electron microscopy (SEM), the phase and pore structures were observed. The test results showed that: (1) Sludge can replace part of the fine aggregates to make baking-free bricks, resulting in the reduction of the strength of baking-free bricks, but the strength still meets the standard strength requirements of GB/T 21,144-2007. (2) When fine aggregates are partly replaced by sludge with finer particle sizes, baking-free sludge bricks exhibit higher strength, lower water absorption, better pore structures and microphase structure, and stronger solidification of heavy metals, the leaching number of heavy metals meets the standard requirements of GB5085.3-2007, which will be provided support for actual industrial production.Implications: Cement solidification is an essential means to reduce the heavy metal leaching from industrial sludge and make it recyclable. This paper studied sludge containing heavy metal of different particle sizes on the performance of baking-free sludge bricks. This paper analyzed the compressive strength, porosity and water absorption of baking-free bricks mixed with sludge of different partical sizes, and adopted the NMR to characterize the pores of baking-free bricks, and the SEM to observe the baking-free bricks resultants and the interfacial transition zone (ITZ). The heavy metal leaching test verified the environmental benefits of baking-free bricks mixed with sludge instead of aggregates. There not only make full use of solid wastes, but also thus minimizing pollution to the environment, which provide support for actual industrial production and a reference for studying industrial sludge recycling technology.

Human papillomavirus 16 E6 promotes angiogenesis of lung cancer via SNHG1.

Human papillomavirus (HPV) is a risk factor for lung cancer. However, the underlying mechanisms are not known. Long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of lung cancer due to their particular characteristics. HPV-induced lung carcinogenesis is incompletely defined. We aimed to screen and clarify the functions of lncRNAs that are differentially expressed in HPV-related lung cancer. We found that lncRNA SNHG1 is upregulated in lung cancer cells infected with HPV16 E6 by qRT‒PCR. Further results demonstrated that SNHG1 overexpression facilitates the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Our results also indicated that SNHG1 might function in lung cancer by binding with EGFR. Further studies revealed that SNHG1 overexpression could activate the nuclear factor κb (NF-κB) pathway, which increases the expression of interleukin-6 (IL-6). We also found that IL-6 can activate the STAT3 pathway, which promotes VEGF-D expression. These results expanded our understanding of SNHG1 as a new avenue for therapeutic intervention against lung cancer progression. Upregulation of SNHG1 by HPV infection might be an undefined link between lung cancer and HPV.

Integrative Analyses of Circulating mRNA and lncRNA Expression Profile in Plasma of Lung Cancer Patients.

Circulating-free RNAs (cfRNAs) have been regarded as potential biomarkers for "liquid biopsy" in cancers. However, the circulating messenger RNA (mRNA) and long noncoding RNA (lncRNA) profiles of lung cancer have not been fully characterized. In this study, we profiled circulating mRNA and lncRNA profiles of 16 lung cancer patients and 4 patients with benign pulmonary nodules. Compared with benign pulmonary nodules, 806 mRNAs and 1,762 lncRNAs were differentially expressed in plasma of lung adenocarcinoma patients. For lung squamous cell carcinomas, 256 mRNAs and 946 lncRNAs were differentially expressed. A total of 231 mRNAs and 298 lncRNAs were differentially expressed in small cell lung cancer. Eleven mRNAs, 51 lncRNAs, and 207 canonical pathways were differentially expressed in lung cancer in total. Forty-five blood samples were collected to verify our findings via performing qPCR. There are plenty of meaningful mRNAs and lncRNAs that were found. MYC, a transcription regulator associated with the stemness of cancer cells, is overexpressed in lung adenocarcinoma. Transforming growth factor beta (TGFB1), which plays pleiotropic roles in cancer progression, was found to be upregulated in lung squamous carcinoma. MALAT1, a well-known oncogenic lncRNA, was also found to be upregulated in lung squamous carcinoma. Thus, this study provided a systematic resource of mRNA and lncRNA expression profiles in lung cancer plasma.

Lung cancer scRNA-seq and lipidomics reveal aberrant lipid metabolism for early-stage diagnosis.

Lung cancer is the leading cause of cancer mortality, and early detection is key to improving survival. However, there are no reliable blood-based tests currently available for early-stage lung cancer diagnosis. Here, we performed single-cell RNA sequencing of different early-stage lung cancers and found that lipid metabolism was broadly dysregulated in different cell types, with glycerophospholipid metabolism as the most altered lipid metabolism-related pathway. Untargeted lipidomics was carried out in an exploratory cohort of 311 participants. Through support vector machine algorithm-based and mass spectrum-based feature selection, we identified nine lipids (lysophosphatidylcholines 16:0, 18:0, and 20:4; phosphatidylcholines 16:0-18:1, 16:0-18:2, 18:0-18:1, 18:0-18:2, and 16:0-22:6; and triglycerides 16:0-18:1-18:1) as the features most important for early-stage cancer detection. Using these nine features, we developed a liquid chromatography-mass spectrometry (MS)-based targeted assay using multiple reaction monitoring. This target assay achieved 100.00% specificity on an independent validation cohort. In a hospital-based lung cancer screening cohort of 1036 participants examined by low-dose computed tomography and a prospective clinical cohort containing 109 participants, the assay reached more than 90.00% sensitivity and 92.00% specificity. Accordingly, matrix-assisted laser desorption/ionization MS imaging confirmed that the selected lipids were differentially expressed in early-stage lung cancer tissues in situ. This method, designated as Lung Cancer Artificial Intelligence Detector, may be useful for early detection of lung cancer or large-scale screening of high-risk populations for cancer prevention.

Recent advances on polaprezinc for medical use (Review).

The present study described the chemical and biological properties of zinc complex of L-carnosine (L-CAZ; generic name, polaprezinc; chemical name, catena-(S)-[µ-[N(α)-(3-aminopropionyl) histidinato (2-) N1, N2, O: N(τ)]-zinc], molecular formula, C9H14N4O3Zn; molecular weight, 291.6404; CAS registry number, 107667-60-7). Characterized as a white or yellowish white crystalline powder, this drug is insoluble in glacial acetic acid and almost insoluble in water, methanol, ethanol and ether. It is soluble in dilute hydrochloric acid, dilute nitric acid and sodium hydroxide solution, and its melting point is 260-270˚C. Polaprezinc is an anti-ulcer drug that was jointly studied and developed by Hamari Chemicals Co., Ltd. and Zeria Pharmaceutical Co., Ltd., and was first approved in Japan in 1994. This review article summarizes the research advances of polaprezinc, including the patents, preparations, synthetic routes, pharmacokinetics, pharmacological effects and application in clinical research.

Assessment of an Exhaled Breath Test Using High-Pressure Photon Ionization Time-of-Flight Mass Spectrometry to Detect Lung Cancer.

Importance: Exhaled breath is an attractive option for cancer detection. A sensitive and reliable breath test has the potential to greatly facilitate diagnoses and therapeutic monitoring of lung cancer. Objective: To investigate whether the breath test is able to detect lung cancer using the highly sensitive high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Design, Setting, and Participants: This diagnostic study was conducted with a prospective-specimen collection, retrospective-blinded evaluation design. Exhaled breath samples were collected before surgery and detected by HPPI-TOFMS. The detection model was constructed by support vector machine (SVM) algorithm. Patients with pathologically confirmed lung cancer were recruited from Peking University People's Hospital, and healthy adults without pulmonary noncalcified nodules were recruited from Aerospace 731 Hospital. Data analysis was performed from August to October 2020. Exposures: Breath testing and SVM algorithm. Main Outcomes and Measures: The detection performance of the breath test was measured by sensitivity, specificity, accuracy, and area under the receiver-operating characteristic curve (AUC). Results: Exhaled breath samples were from 139 patients with lung cancer and 289 healthy adults, and all breath samples were collected and tested. Of all participants, 228 (53.27%) were women and the mean (SD) age was 57.0 (11.4) years. After clinical outcomes were ascertained, all participants were randomly assigned into the discovery data set (381 participants) and the blinded validation data set (47 participants). The discovery data set was further broken into a training set (286 participants) and a test set (95 participants) to construct and test the detection model. The detection model reached a mean (SD) of 92.97% (4.64%) for sensitivity, 96.68% (2.21%) for specificity, and 95.51% (1.93%) for accuracy in the test set after 500 iterations. In the blinded validation data set (47 participants), the model revealed a sensitivity of 100%, a specificity of 92.86%, an accuracy of 95.74%, and an AUC of 0.9586. Conclusions and Relevance: This diagnostic study's results suggest that a breath test with HPPI-TOFMS is feasible and accurate for lung cancer detection, which may be useful for future lung cancer screenings.

Development and Validation of Machine Learning-based Model for the Prediction of Malignancy in Multiple Pulmonary Nodules: Analysis from Multicentric Cohorts.

PURPOSE: Nodule evaluation is challenging and critical to diagnose multiple pulmonary nodules (MPNs). We aimed to develop and validate a machine learning-based model to estimate the malignant probability of MPNs to guide decision-making. EXPERIMENTAL DESIGN: A boosted ensemble algorithm (XGBoost) was used to predict malignancy using the clinicoradiologic variables of 1,739 nodules from 520 patients with MPNs at a Chinese center. The model (PKU-M model) was trained using 10-fold cross-validation in which hyperparameters were selected and fine-tuned. The model was validated and compared with solitary pulmonary nodule (SPN) models, clinicians, and a computer-aided diagnosis (CADx) system in an independent transnational cohort and a prospective multicentric cohort. RESULTS: The PKU-M model showed excellent discrimination [area under the curve; AUC (95% confidence interval (95% CI)), 0.909 (0.854-0.946)] and calibration (Brier score, 0.122) in the development cohort. External validation (583 nodules) revealed that the AUC of the PKU-M model was 0.890 (0.859-0.916), higher than those of the Brock model [0.806 (0.771-0.838)], PKU model [0.780 (0.743-0.817)], Mayo model [0.739 (0.697-0.776)], and VA model [0.682 (0.640-0.722)]. Prospective comparison (200 nodules) showed that the AUC of the PKU-M model [0.871 (0.815-0.915)] was higher than that of surgeons [0.790 (0.711-0.852), 0.741 (0.662-0.804), and 0.727 (0.650-0.788)], radiologist [0.748 (0.671-0.814)], and the CADx system [0.757 (0.682-0.818)]. Furthermore, the model outperformed the clinicians with an increase of 14.3% in sensitivity and 7.8% in specificity. CONCLUSIONS: After its development using machine learning algorithms, validation using transnational multicentric cohorts, and prospective comparison with clinicians and the CADx system, this novel prediction model for MPNs presented solid performance as a convenient reference to help decision-making.

Intrarectally administered polaprezinc attenuates the development of dextran sodium sulfate-induced ulcerative colitis in mice.

Polaprezinc (PZ), a chelate of zinc and L-carnosine, has been widely used in the treatment of gastric ulcers since 1994. In recent years, researchers have found PZ to have a beneficial effect on various experimentally induced models of colitis in mice. In the present study, 6% dextran sodium sulfate (DSS) was used to induce a model of ulcerative colitis (UC) in Institute of Cancer Research mice. The therapeutic effect and mechanism of PZ action in a model of UC was studied in order to provide an experimental basis for the clinical application of PZ in UC treatment. The effect of PZ on UC was evaluated in five groups of mice: A vehicle control only group, a DSS model control group (DSS, 6%), a validated treatment control group (DSS 6% + Mesalamine), a low-dose PZ treatment group (DSS 6% + PZ 60 mg/kg) and a high-dose PZ group (DSS 6% + PZ 120 mg/kg). After the animals were sacrificed, blood was collected and the serum levels of NF-κB and tumor necrosis factor-α (TNF-α) were measured. Changes in histology were observed by light microscopy. The protein levels of AKT, phosphorylated AKT and heat shock protein 70 (HSP70) were determined by western blot analysis. The results suggested that PZ reduced the DSS-induced increase in the inflammatory proteins TNF-α and NF-κB in the UC model. The high-dose of PZ also increased the HSP70 protein level, inhibited AKT phosphorylation in a DSS-induced UC animal model, and decreased white blood cell and neutrophil % counts compared to levels in an untreated DSS control group. Histopathology indicated that the mice of the DSS model group had irregular colonic villi, a large number of inflammatory cells and mucosal damage, whereas mice of the group treated with PZ had small intestinal villus morphology and their villi showed signs of recovery from the damage of UC. The results of the present study indicated that PZ significantly alleviates DSS-induced UC in mice, relieves diarrhea, and inhibits the phosphorylation of inflammatory factors and the inflammatory AKT signaling pathway.

Oral Administration of Polaprezinc Attenuates Fluorouracil-induced Intestinal Mucositis in a Mouse Model.

5-Fluorouracil (5-FU) has broadly been applied to treat colorectal cancer as one of the most effective chemotherapeutic agents. However, it frequently causes intestinal mucosal injury and related side effects, such as abdominal pain and diarrhoea, which limit the use of 5-FU in a clinic setting. Polaprezinc has gradually become known as a mucosal protective agent for the management of gastric ulcer. This study aimed to investigate the prophylactic efficacy of Polaprezinc administered orally against intestinal mucositis induced by 5-FU in mice on the condition that the antitumour effect could not be compromised. We induced intestinal mucositis in SPF-grade ICR mice with 5-FU, and evaluated intestinal damage in the absence or presence of Polaprezinc. We examined the score of diarrhoea and the loss of weight after the 5-FU treatment and assessed the integrity of villus and the proliferation of small intestine crypt cells by haematoxylin and eosin staining and PCNA immunohistochemical detection. The antitumour effect of 5-FU on colorectal cancer was assessed with or without Polaprezinc in a xenograft model. The result showed that Polaprezinc significantly reduced the elevated diarrhoea score and the body-weight loss caused by 5-FU abolished histological abnormality and crypt cell hypoproliferation in a dose-dependent manner, without affecting 5-FU efficacy on colon xenograft tumour in mice. We conclude that Polaprezinc could inhibit 5-FU-induced diarrhoea and alleviate the weight loss during 5-FU chemotherapy, as a possible candidate for treatment and prevention of intestinal mucositis, through protecting intestinal mucosa and improving the quality of life after chemotherapy.