The Brassinosteroid Receptor StBRI1 Promotes Tuber Development by Enhancing Plasma Membrane H+-ATPase Activity in Potato.

The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.

Facile Synthesis of MXene-Ti3C2/Co Nanosheet Hydrogel Sensor with the Assistance of a Smartphone for On-Site Monitoring of Glucose in Beverages.

A one-step cobaltous chloride (CoCl2) molten salt method was employed to prepare multilayer MXene-Ti3C2/Co materials with further ultrasonic treatment to acquire single-layer MXene-Ti3C2/Co nanosheets (NSs). MXene-Ti3C2/Co NSs were characterized, and their enzyme-like activities were investigated. Under the catalysis of MXene-Ti3C2/Co NSs, 3,3',5,5'-tetramethylbenzidine (TMB) could be oxidized by H2O2, with the color changing from colorless to blue. The affinity of MXene-Ti3C2/Co NSs to H2O2 and TMB was better than that of nanozymes reported in previous studies. The MXene-Ti3C2/Co NSs were used for the colorimetric determination of H2O2/glucose, with limits of detection (LODs) of 0.033 mM and 1.7 µM, respectively. MXene-Ti3C2/Co NSs embedded in sodium alginate (SA) hydrogel were used to construct a sensor platform. The digital pictures combined with a smartphone-installed app (color recognizer) could be used to analyze RGB values for colorimetric detection of glucose in beverages. This point-of-care testing platform has the advantages of cost-effectiveness and good transferability, with the potential to realize quick, intelligent and on-site detection.

Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps.

Xenotransplantation has the potential to solve the shortfall of human organ donors. Genetically modified pigs have been considered as potential animal donors for human xenotransplantation and have been widely used in preclinical research. The genetic modifications aim to prevent the major species-specific barriers, which include humoral and cellular immune responses, and physiological incompatibilities such as complement and coagulation dysfunctions. Genetically modified pigs can be created by deleting several pig genes related to the synthesis of various pig specific antigens or by inserting human complement- and coagulation-regulatory transgenes. Finally, in order to reduce the risk of infection, genes related to porcine endogenous retroviruses can be knocked down. In this review, we focus on genetically modified pigs and comprehensively summarize the immunological mechanism of xenograft rejection and recent progress in preclinical and clinical studies. Overall, both genetically engineered pig-based xenografts and technological breakthroughs in the biomedical field provide a promising foundation for pig-to-human xenotransplantation in the future.

Co(OH)2/MXene-Ti3C2 nanocomposites with triple-enzyme mimic activities as hydrogel sensing platform for on-site detection of hypoxanthine.

Novel Co(OH)2/MXene-Ti3C2 nanocomposites with oxidase (OXD)-mimic, peroxidase (POD)-mimic, and catalase (CAT)-mimic activities were prepared by a simple two-step method. The Co(OH)2/MXene-Ti3C2 nanocomposites with triple-enzyme mimic activities were embedded into sodium alginate (SA) gels for the first time to fabricate a target-responsive hydrogel-assisted assay. The catalytic mechanism and steady-state kinetics of Co(OH)2/MXene-Ti3C2 nanocomposites were investigated. Subsequently, hypoxanthine (Hx) was catalyzed by xanthine oxidase (XOD) to form H2O2, which reacts with 3,3',5,5'-tetramethyl-benzidine (TMB) in the presence of Co(OH)2/MXene-Ti3C2 nanocomposites to form a blue oxide (ox-TMB) in the hydrogel. The visible color change of the hydrogel with the increase of Hx concentration can be recognized through a smartphone App to transfer the red (R), green (G), and blue (B) values for the quantitative determination of  Hx, with a detection range from 5 to 250 µM, and detection limit of 0.2 µM. The method was applied to the determination of Hx content in different aquatic products. The spiked recoveries of the aquatic products were from 94.1 to 106.4%, and the relative standard deviations (RSD) were less than 5.4%. Our results show that the Co(OH)2/MXene-Ti3C2 nanocomposites hydrogel-assisted colorimetric biosensor is cost-effective, sensitive, and selective and has excellent application prospects for in-the-field determination of Hx.

Cu nanoclusters decorated Ti3C2 nanosheets composite with tetraenzyme mimic activities and the application for smartphone-assisted detection of hypoxanthine.

MXene-based nanozymes have increased research enthusiasm in the field of food safety and environment monitoring. Herein, the Cu NCs/Ti3C2 NSs nanocomposites were prepared by modifying copper nanoclusters (Cu NCs) on the surface of Ti3C2 nanosheets (NSs) with a simple two-step method. The Cu NCs/Ti3C2 NSs nanocomposites had outstanding tetraenzyme mimic activities, i.e. peroxidase (POD)-mimics, catalase (CAT)-mimics, ascorbic acid oxidase (AAO)-mimics and superoxide dismutase (SOD)-mimics. Modification of Cu NCs on Ti3C2 NSs can enhance tetraenzyme mimic activities because of the synergistic catalytic effect between Cu NCs and Ti3C2 NSs. The catalytic mechanism and steady-state kinetics of Cu NCs/Ti3C2 NSs were also investigated. Based on the POD-mimic activity of Cu NCs/Ti3C2 NSs, a simple and rapid colorimetric method was established for the on-site detection of hypoxanthine (Hx), with the linear range of 5-200 µM and limit of detection (LOD) was 0.25 µM. The visible color change with the increase of Hx concentration can be recognized by a smartphone APP to transfer the red (R), green (G) and blue (B) value for the quantitative analysis of Hx, with the linear range of 10-200 µM, which provided a convenient method for the real-time detection of Hx. This work not only provides a significant route to fabricate nanocomposite with outstanding tetraenzyme mimic activities but also offers a low-cost and rapid method for monitoring the freshness of aquatic products.

Smartphone-assisted miniature device based on nitrogen and sulfur co-doped carbon dots for point-of-care testing of tetracycline.

A miniature device was design for the point-of-care testing (POCT) of tetracycline (TC) including a ratio fluorescence test strip, a sample slot, a UV lamp and a smartphone. The nitrogen and sulfur co-doped carbon dots (N, S-CDs) and Eu3+ were dropped onto the filter paper to construct the ratio fluorescence test strips for the specific detection of TC. Under the excitation at 390 nm, the fluorescence emission of N, S-CDs at 530 nm decreases through inner filter effect (IEF) after addition of Eu3+. When the further addition of TC, the emission of N, S-CDs at 530 nm kept unchanged while the emission of Eu3+ at 616 nm was obviously enhanced for the antenna effect (AE) between Eu3+ and TC. The ratio changes of the two-fluorescence emission realized the quantitative detection of TC. In addition, the test strips with different concentrations of TC showed different fluorescence color from green to red under a 365 nm UV lamp. The miniature device was designed as a fluorescence photo reader with the merits of the powerful functions of smartphones and the portability of test strips. The smartphone camera takes a fluorescent color image of the test strips and the photos are recognized by a color recognizer on the smartphone to obtain RGB (red-greenblue) values which reflect the concentrations of the analytes. Therefore, we established a fast, sensitive and efficient POCT of TC. In particular, the proposed nanomaterial-based POCT platform will open a new route towards the development of ratio fluorescence probe for TC analysis for environment samples.

Multifaceted regulation and functions of 53BP1 in NHEJ­mediated DSB repair (Review).

The repair of DNA double­strand breaks (DSBs) is crucial for the preservation of genomic integrity and the maintenance of cellular homeostasis. Non­homologous DNA end joining (NHEJ) is the predominant repair mechanism for any type of DNA DSB during the majority of the cell cycle. NHEJ defects regulate tumor sensitivity to ionizing radiation and anti­neoplastic agents, resulting in immunodeficiencies and developmental abnormalities in malignant cells. p53­binding protein 1 (53BP1) is a key mediator involved in DSB repair, which functions to maintain a balance in the repair pathway choices and in preserving genomic stability. 53BP1 promotes DSB repair via NHEJ and antagonizes DNA end overhang resection. At present, novel lines of evidence have revealed the molecular mechanisms underlying the recruitment of 53BP1 and DNA break­responsive effectors to DSB sites, and the promotion of NHEJ­mediated DSB repair via 53BP1, while preventing homologous recombination. In the present review article, recent advances made in the elucidation of the structural and functional characteristics of 53BP1, the mechanisms of 53BP1 recruitment and interaction with the reshaping of the chromatin architecture around DSB sites, the post­transcriptional modifications of 53BP1, and the up­ and downstream pathways of 53BP1 are discussed. The present review article also focuses on the application perspectives, current challenges and future directions of 53BP1 research.

Background-free room temperature phosphorescence and digital image colorimetry detection of melamine by carbon nitride quantum dots in cellulose matrix with smartphone-based portable device.

Carbon nitride quantum dots (CNQDs) were embedded in the sodium carboxymethyl cellulose (CMC) matrix to form CNQDs-CMC film to explore the room temperature phosphorescence (RTP) of CNQDs, which suppress the non-radiative relaxation process due to the internal hydrogen bonding interactions between CMC and CNQDs. Then, a simple, inexpensive, background-free miniature device integrating with CNQDs-CMC film and smartphone was fabricated for rapid and quantitative detection of melamine (MEL). In the present of MEL, the yellow RTP color of the CNQDs-CMC film was quenched and photographed by the smartphone. The Color Recognizer APP in the smartphone recognized the red (R) value for quantitative detection of MEL. Thus, digital image colorimetry (DIC) determination of MEL was achieved due to the visible RTP color change of CNQDs-CMC film. The smartphone-based miniature device provided a promising platform for the on-site monitoring analytes in the complex matrix including food safety, environmental screening, health monitoring, and disease prevention.

Long-term outcomes of refractory esophageal strictures after endoscopic submucosal dissection of superficial esophageal neoplasms.

BACKGROUND: Many studies have focused on prophylactic therapy for post-endoscopic submucosal dissection (ESD) of esophageal strictures. However, various strategies cannot prevent the occurrence of postoperative strictures after extensive ESD. Postoperative strictures often inevitably occur, and endoscopic dilation is still a temporarily effective therapy. METHODS: This study included patients with post-ESD refractory esophageal strictures (RESs) from January 2014 to November 2019. Clinical effectiveness was assessed using univariate analysis and multivariate logistic regression. Hierarchical linear models were used to identify factors that predicted the dysphagia-free period. RESULTS: A total of 50 patients fulfilled the inclusion criteria and entered the study. Twenty-seven (54%) patients had a history of prophylactic oral steroid therapy. Forty-six patients (92%) underwent ≥ 75% circumferential resection, including 32 (64%) cases involving entire circumferential ESD. The mean dysphagia-free period of 50 patients was 2.9 months (95% CI 2.3-3.5). The dysphagia-free period had a linear growth trend over time, increasing by 6.9 days per endoscopic therapy, and the estimated last dysphagia-free period was 85.9 days. Old and female patients had shorter dysphagia-free periods compared with young and male patients. Endoscopic therapy success was achieved in 30 (60%) patients. Multivariate analysis revealed that circumferential lesions (OR 6.106, 95% CI 1.013-36.785, P = 0.048) were significant predictive factors for poor clinical outcome. CONCLUSION: Endoscopic dilation seemed effective in patients with post-ESD RESs by increasing the dysphagia-free period. After approximately 10 continuous dilations, 60% of patients achieved endoscopic success, and the remission rate of obstruction was increased. Prophylactic oral steroid therapy could reduce the occurrence of RESs. However, once a RES had occurred, prophylactic steroid therapy could not reduce the frequency of dilations or change the long-term outcomes. TRIAL REGISTRATION: This study was prospectively registered and approved by the Ethics Committee of West China Hospital of Sichuan University (IRB number: ChiCTR-ONN-17012382) on 2015.

Discovery of Potent and Isoform-selective Histone Deacetylase Inhibitors Using Structure-based Virtual Screening and Biological Evaluation.

Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC-27, AGS, MDA-MB-231, A549, MCF-7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC-27 cells-derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC-targeting inhibitor for solid tumor therapy.

A BCNO QDs-MnO2 nanosheets based fluorescence "off-on-off" and colorimetric sensor with smartphone detector for the detection of organophosphorus pesticides.

In this work, boron carbon oxynitride quantum dots (BCNO QDs) were prepared by a one-step hydrothermal process of ethanolamine and boric acid. BCNO QDs exhibited blue fluorescence with the optimal excitation/emission fluorescence peak at 335 and 420 nm, respectively. As an efficient fluorescence quencher, manganese dioxide (MnO2) nanosheets can effectively quench the fluorescence of BCNO QDs via the inner filter effect (IFE). Acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylcholine (ATCh) to produce thiocholine (TCh). TCh can reductively degrade MnO2 nanosheets to generate Mn2+, thereby recovering the fluorescence of BCNO QDs. Organophosphorus pesticides (OPs) can inhibit the activity of AChE enzymes, thereby preventing the production of TCh and the decomposition of MnO2 nanosheets, resulting in the fluorescence "turn-off". Therefore, the concentration of OPs can be detected by measuring the fluorescence intensity change of AChE-ATCh-MnO2-BCNO-QDs system. Under optimal experimental conditions, the dynamic detection range of paraoxon is 0.1-250 ng mL-1, and the detection limit is 0.03 ng mL-1. Meanwhile, the reaction system also showed concentration-dependent visual color changes from colorless to brownish. Furthermore, we prepared a portable BCNO QDs test paper. By using a smartphone to identify the RGB values of the reaction solution and the corresponding test paper, we carried out the digital image chromaticity analysis, which can shorten the detection time and reduce the detection cost, and provide an effective solution for the rapid detection of OPs on site.

Pivotal role of video-assisted thoracoscopic surgery in improving survival outcome of stage I non-small cell lung cancer in day surgery patients.

BACKGROUND: Lung cancer, the leading cause of cancer-related deaths worldwide, has high morbidity rates. Video-assisted thoracoscopic surgery (VATS) as day surgery makes surgical treatment ideally in time with the same quality of medical care. This study aimed to assess the safety of stage I NSCLC patients who underwent VATS at a day surgery center. METHODS: We retrospectively analyzed the clinical characteristics and tumor features of VATS patients at a single center, West China Hospital, from June 1, 2019, to December 31, 2020. Patients fulfilled all inclusion criteria, did not meet any exclusion criteria and underwent wedge resection, segmentectomy, or lobectomy with systematic lymph node dissection. RESULTS: The median patient age was 43 (range, 19-67) years. Of the 209 patients, most were women. A total of 108 (51.7%) patients underwent segmentectomy, 87 (41.6%) lobectomy, and 14 (6.7%) wedge resection with systematic lymph node dissection. According to the AJCC/UICC eighth edition of lung cancer stage grouping, stages IA, IA1, IA2, and IA3 were 195 (93.3%), 122 (58.4%), 50 (23.9%), and one (0.5%), respectively. A total of 36 (17.2%) patients were stage 0. Adenocarcinoma was predominantly the postoperative pathological diagnosis, as only 14 (6.7%) were benign. A total of 201 (96.17%) patients were discharged without a chest tube. The most common chief complaints were cough, incisional pain, and shortness of breath. No severe complications or life-threatening emergencies were observed. CONCLUSIONS: The day surgery mode of VATS for stage I NSCLC is safe and feasible, which makes surgical treatment ideally in time for stage I NSCLC patients with the same quality of medical care.

Genome-wide identification and expression analysis of the GSK gene family in Solanum tuberosum L. under abiotic stress and phytohormone treatments and functional characterization of StSK21 involvement in salt stress.

Plant Glycogen Synthase Kinase 3 (GSK3)/SHAGGY-like kinase (GSK) proteins play important roles in modulating growth, development, and stress responses in several plant species. However, little is known about the members of the potato GSK (StGSK) family. Here, nine StGSK genes were identified and phylogenetically grouped into four clades. Gene duplication analysis revealed that segmental duplication contributed to the expansion of the StGSK family. Gene structure and motif pattern analyses indicated that similar exon/intron and motif organizations were found in StGSKs from the same clade. Conserved motif and kinase activity analyses indicated that the StGSKs encode active protein kinases, and they were shown to be distributed throughout whole cells. Cis-acting regulatory element analysis revealed the presence of many growth-, hormone-, and stress-responsive elements within the promoter regions of the StGSKs, which is consistent with their expression in different organs, and their altered expression in response to hormone and stress treatments. Association network analysis indicated that various proteins, including two confirmed BES1 family transcription factors, potentially interact with StGSKs. Overexpression of StSK21 provides enhanced sensitivity to salt stress in Arabidopsis thaliana plants. Overall, these results reveal that StGSK proteins are active protein kinases with purported functions in regulating growth, development, and stress responses.

Low-dose combined exposure of carboxylated black carbon and heavy metal lead induced potentiation of oxidative stress, DNA damage, inflammation, and apoptosis in BEAS-2B cells.

Black carbon (BC) and heavy metal lead (Pb), as typical components of atmospheric PM2.5, have been shown to cause a variety of adverse health effects. However, co-exposure to BC and Pb may induce pulmonary damage by aggravating toxicity via an unknown mechanism. This study aimed to investigate the combined toxicity of carboxylated black carbon (c-BC) and lead acetate (Pb) on human bronchial epithelial cells (BEAS-2B) at the no-observed-adverse-effect level (NOAEL). Cells were exposed to c-BC (6.25 µg/mL) and Pb (4 µg/mL) alone or their combination, and their combined toxicity was investigated by focusing on cell viability, oxidative stress, DNA damage, mitochondrial membrane potential (MMP), apoptosis, and cellular inflammation. Factorial analyses were also used to determine the potential interactions between c-BC and Pb. The results suggested that the combination of c-BC and Pb could significantly increase the production of reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase leakage (LDH) and decrease the activities of glutathione (GSH) and superoxide dismutase (SOD). The excessive oxidative stress could increase the levels of inflammatory cytokine IL-6 and TNF-α, and induce oxidative DNA damage and dissipation of MMP. Moreover, the results also suggested that the combined group could enhance the cellular apoptotic rate and the activation of apoptotic markers like caspase-3, caspase-8, and caspase-9. The factorial analysis further demonstrated that synergistic interaction was responsible for the combined toxicity of c-BC and Pb co-exposure. Most noticeably, the co-exposure of c-BC and Pb could induce some unexpected toxicity, even beyond the known toxicities of the individual compounds in BEAS-2B cells at the NOAEL.

Glycogen synthase kinase 3ß in tumorigenesis and oncotherapy (Review).

Glycogen synthase kinase 3ß (GSK 3ß), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. Therefore, aberrant regulation of GSK 3ß results in a broad range of human diseases, such as tumors, diabetes, inflammation and neurodegenerative diseases. Accumulating evidence has suggested that GSK 3ß is correlated with tumorigenesis and progression. However, GSK 3ß is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3ß is involved in tumor growth, whereas it contributes to the cell sensitivity to chemotherapy. However, the underlying regulatory mechanisms of GSK 3ß in tumorigenesis remain obscure and require further in­depth investigation. In this review, we comprehensively summarize the roles of GSK 3ß in tumorigenesis and oncotherapy, and focus on its potentials as an available target in oncotherapy.