Effectiveness and safety of REBACIN as a non-invasive intervention for persistent high-risk human papillomavirus infection: A real-world prospective multicenter cohort study.

BACKGROUND: We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. METHODS: According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. RESULTS: The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. CONCLUSION: This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry Registration Number: ChiCTR1800015617 http://www.chictr.org.cn/showproj.aspx?proj=26529 Date of Registration: 2018-04-11.

Mixed-Linker Strategy for the Construction of Metal-Organic Framework Combined with Dyes toward Alcohol Detection.

Herein, a N-rich metal-organic framework (MOF) with four kinds of cages, Zn4(ade)2(TCA)2(H2O) (NENU-1000, Hade = adenine, H3TCA = 4,4',4″-tricarboxytriphenylamine, NENU = Northeast Normal University), was prepared by the mixed-ligand strategy. Cationic dyes can be selectively absorbed by NENU-1000 at proper concentrations, but not neutral and anionic dyes, which perhaps can be assigned to the N-rich neutral framework of NENU-1000. When NENU-1000 was introduced to a relatively lower concentration of cationic dye solutions (e.g., rhodamine B or basic red 2), the colors of these systems faded quickly. Furthermore, the faded solutions can be used for the detection of methanol and other small alcohol molecules with either the naked eye or common UV-vis spectra. The effect of the length of carbon chain, the position of the -OH group, and the number of the hydroxyl group of the alcohols was explored for the color development rate. In addition, the performance of NENU-1000 in iodine sorption and release was also studied.

Linking oxidative DNA lesion 8-OxoG to tumor development and progression.

Cells of the aerobic metabolic organism are inevitably subjected to the damage from reactive oxygen species (ROS). ROS cause multiple forms of DNA damage, among which the oxidation product of guanine G 8-hydroxyguanine (8-oxoG) is the most frequent DNA oxidative damage, recognized by the specific glycosidase OGG1 that initiates the base excision repair pathway. If left unrepaired, 8-oxoG may pair with A instead of C, leading to a mutation of G: C to T: A during replication. Thus, the accumulation of 8-oxoG or the abnormal OGG1 repair is thought to affect gene function, which in turn leads to the development of tumor or aging-related diseases. However, a series of recent studies have shown that 8-oxoG tends to be produced in regulatory regions of the genome. 8-oxoG can be regarded as an epigenetic modification, while OGG1 is a specific reader of this information. Substrate recognition, binding or resection by OGG1 can cause DNA conformation changes or affect histone modifications, causing up-regulation or down-regulation of genes with different properties. Thus, in addition to the potential genotoxicity, the association of guanine oxidative damage with development of tumors is closely related to its aberrant initiation of gene expression through epigenetic mechanisms. In this review, we summarize the underlying mechanism of 8-oxoG and repair enzyme OGG1 in tumor development and progression, with aims to interpret the relationship between DNA oxidative damage and tumor from a new perspective, and provide new ideas and targets for tumor treatment.

Real-time fluorometric monitoring of monophenolase activity using a matrix-matched calibration curve.

Tyrosinase is the key enzyme for the metabolism of tyrosine and inherently comprises both monophenolase activity and diphenolase activity. A real-time fluorometric assay method was established to exclusively monitor the monophenolase activity by eliminating interference from diphenolase reactions through a combination of borate and hydroxylamine. Synthetic matrices comprised of tyrosine and DOPA (L-3,4-dihydroxyphenylalanine) preincubated with tyrosinase with the consistent sum concentration of 70 µM to mimic the monophenolase reaction mixture in borate buffer according to law of mass conservation. A matrix-matched calibration curve for determination of tyrosine was established using the synthetic matrices as standard sample to eliminate spectral interference from DOPA. The limit of detection (LOD) for tyrosine was 0.61 µM. The time course for consumption of tyrosine was established to measure the initial velocity through real-time reading out the tyrosine fluorescence intensity of the reaction mixture in a cuvette in situ. The assay worked in the monophenolase activity range from 0.2839 to 1.7308 U mL-1 with LOD of 0.0851 U mL-1. The proposal sensing system successfully afforded a prospective potential for application in enzyme kinetics and screening of inhibitor. Graphical abstract.

TWIST1 transcriptionally regulates glycolytic genes to promote the Warburg metabolism in pancreatic cancer.

Reprogrammed glucose metabolism is essential for tumor initiation and development, especially for pancreatic ductal adenocarcinoma (PDAC). Most cancer cells rely on aerobic glycolysis, a phenomenon termed "the Warburg effect", to support uncontrolled proliferation and evade apoptosis. However, the direct regulators of the Warburg effect remain areas of active investigation. In this study, we found that the highly conserved transcription factor, TWIST1, is a crucial regulator of aerobic glycolysis in PDAC. Genetic silencing of TWIST1 significantly inhibited the glycolytic phenotypes of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate, which can be restored by re-expression of siRNA-resistant TWIST1. Moreover, tamoxifen-inducible expression of TWIST1 promoted the Warburg metabolism of PDAC cells. Mechanistically, by luciferase reporter assay and chromatin immunoprecipitation experiment, we showed that TWIST1 can directly increase the expression of several glycolytic genes, including SLC2A1, HK2, ENO1, and PKM2. Of note, the transcriptional regulation by TWIST1 was not dependent on HIF1α or c-Myc. In The Cancer Genome Atlas and Gene Expression Omnibus accession GSE15471, we confirmed that TWIST1 was closely associated with the glycolysis pathway. Collectively, our findings indicate that TWIST1 is likely to act as important regulator of the Warburg effect in PDAC.

Multi-Output Monitoring of High-Speed Laser Welding State Based on Deep Learning.

In order to ensure the production quality of high-speed laser welding, it is necessary to simultaneously monitor multiple state properties. Monitoring methods combining vision sensing and deep learning models are popular but most models used can only make predictions on single welding state property. In this contribution, we propose a multi-output model based on a lightweight convolutional neural network (CNN) architecture and introduce the particle swarm optimization (PSO) technique to optimize the loss function of the model, to simultaneously monitor multiple state properties of high-speed laser welding of AISI 304 austenitic stainless steel. High-speed imaging is performed to capture images of the melt pool and the dataset is built. Test results of different models show that the proposed model can achieve monitoring of multiple welding state properties accurately and efficiently. In addition, we make an interpretation and discussion on the prediction of the model through a visualization method, which can help to deepen our understanding of the relationship between the melt pool appearance and welding state. The proposed method can not only be applied to the monitoring of high-speed laser welding but also has the potential to be used in other procedures of welding state monitoring.

Continuous Fluorometric Method for Determining the Monophenolase Activity of Tyrosinase on L-Tyrosine, through Quenching L-DOPA Fluorescence by Borate.

Tyrosinase is the key enzyme in melanin biosynthesis and inherently involves both monophenolase activity and diphenolase activity. A continuous fluorometric assay method was developed for the first time to directly monitor the real monophenolase activity without the interference of diphenolase reactions through exclusively quenching the native fluorescence of DOPA by borate. Complexation with borate at pH 8.0 allowed for selective quantitation of tyrosine in a binary mixture of tyrosine and DOPA at 335 nm. The time course for consumption of tyrosine was established to measure the initial velocity by recording the tyrosine fluorescence intensity at discrete intervals. The assay worked in the monophenolase activity range from 0.13 to 2.01 U mL-1 with the limit of detection (LOD) of 0.10 U mL-1. The assay method exhibited a promising prospect in application in kinetics of monophenolase and high throughput screening for monophenolase inhibitors.

Spectrofluorometric method for the determination of ascorbic acid in pharmaceutical preparation using l-tyrosine as fluorescence probe.

Ascorbic acid is a vital nutrient and antioxidant that is commonly used as an additive in commercial products. Quantitation of ascorbic acid is highly desired in the medical, food, and cosmetic industries. A spectrofluorometric assay for sensitive determination of ascorbic acid was developed using l-tyrosine as a fluorescent probe. The native fluorescence intensity of tyrosine was quenched using ascorbic acid. The linear range was 0.03-30.00 µM, and the limit of detection was 0.01 µM. The method exhibited excellent precision, accuracy, specificity, and robustness. Components of pharmaceutical preparations that are commonly found with ascorbic acid did not interfere with detection. The procedure was successfully employed for determination of ascorbic acid content in pharmaceutical tablets, injections, and nutrient supplements with satisfactory results. A Stern-Volmer plot and fluorescence lifetime revealed that quenching was attributed to the inner filter effect and static quenching. Isothermal titration calorimetry confirmed the formation of a complex between tyrosine and ascorbic acid, with a binding constant of 1.68 × 103 M-1 and reaction stoichiometry of 0.94. Thermodynamic parameters suggested spontaneous complexation via hydrophobic interactions as the dominant binding force. This method is promising for the simple and rapid determination of ascorbic in the pharmaceutical industry.

Research on the Weld Position Detection for the T-Joints in Web-Core Sandwich Panels Based on Eddy Current Technology.

Web-core sandwich panels have gained the popularity in various fields, especially aviation and shipbuilding, etc. Penetration welding was considered as an effective process to manufacture such a structure through a T-joint. To ensure the formation quality and mechanical properties of weld, the welding torch needs to be aligned with the T-joint position. However, it is difficult to locate the T-joint position (i.e., the position of core panel) because of the shielding of the face panels. This paper investigated the detection of T-joint position from the face panel side in web-core sandwich panels based on eddy current technology. First, we designed an experimental system for the weld position detection of T-joints from the face panel side. The relationships are investigated between the characteristics of the eddy current detection signal and the primary parameters of the detection system (including excitation frequency, coil outer diameter, and lift off distance) and the T-joint (including thickness of the core panel, gap distance, and thickness of the cover panel). Corresponding experiments were carried out with variable primary parameters, and the influence mechanism of the primary parameters on the detection results in terms of sensitivity and dynamic performance was elaborated to set up the theoretical basis for the detection. Finally, weld position detection experiments were carried out on TC4 titanium alloy T-joint specimens with 3 mm-thick face panel and 5 mm-thick core panel. Results showed that the maximum detection error was 0.482 mm, and the average error was 0.234 mm. This paper provided a possible technical solution to the automatic tracking problem for the welding of T-joints in the web-core sandwich panels.

Closed-Loop Control of Droplet Transfer in Electron-Beam Freeform Fabrication.

In the process of electron-beam freeform fabrication deposition, the surface of the deposit layer becomes rough because of the instability of the feeding wire and the changing of the thermal diffusion condition. This will make the droplet transfer distance change in the deposition process, and the droplet transfer cannot always be stable in the liquid bridge transfer state. It is easy to form a large droplet or make wire and substrate stick together, which makes the deposition quality worsen or even interrupts the deposition process. The current electron-beam freeform fabrication deposition is mostly open-loop control, so it is urgent to realize the real-time and closed-loop control of the droplet transfer and to make it stable in the liquid bridge transfer state. In this paper, a real-time monitoring method based on machine vision is proposed for the droplet transfer of electron-beam freeform fabrication. The detection accuracy is up to ± 0.08 mm. Based on this method, the measured droplet transfer distance is fed back to the platform control system in real time. This closed-loop control system can stabilize the droplet transfer distance within ± 0.14 mm. In order to improve the detection stability of the whole system, a droplet transfer detection algorithm suitable for this scenario has been written, which improves the adaptability of the droplet transfer distance detection method by means of dilatation/erosion, local minimum value suppression, and image segmentation. This algorithm can resist multiple disturbances, such as spatter, large droplet occlusion and so on.

Face-Sharing Archimedean Solids Stacking for the Construction of Mixed-Ligand Metal-Organic Frameworks.

Reticular chemistry has been an important guiding principle for the design of metal-organic frameworks (MOFs). This approach utilizes discrete building units (molecules and clusters) that are connected through strong bonds into extended networks assisted by topological considerations. Although the simple design principle of connecting points and lines has proved successful, new design strategies are still needed to further explore the structures and functions of MOFs. Herein, we report the design and synthesis of two mixed-ligand MOFs, [(CH3)2NH2]4[Zn4O]4[Zn(TCPP)]5[BTB]8/3 (PCN-137) and [Zr6(µ3-O)4(µ3-OH)4][TCPP][TBTB]8/3 (PCN-138) (BTB = 1,3,5-benzene(tris)benzoate, TBTB = 4,4',4″-(2,4,6-trimethylbenzene-1,3,5-triyl)tribenzoate, and TCPP = tetrakis(4-carboxyphenyl)porphyrin) by the stacking of face-sharing Archimedean solids. In these two MOFs, high-symmetrical metal clusters serve as vertices, and tritopic or tetratopic carboxylate ligands function as triangular and square faces, leading to the formation of two kinds of Archimedean solids (rhombicuboctahedron and cuboctahedron). Furthermore, the ordered accumulation of Archimedean solids successfully gives rise to 3D structures through face-sharing, highlighting the polyhedron-based approach for the design and preparation of MOFs. In addition, PCN-138 was utilized as a heterogeneous catalyst toward CO2 photoreduction under visible-light irradiation. This structure shows high photocatalytic activity, which can be attributed to the coexistence of photosensitizing porphyrin fragments and Zr-oxo centers within the PCN-138 scaffold.

Creating Well-Defined Hexabenzocoronene in Zirconium Metal-Organic Framework by Postsynthetic Annulation.

The incorporation of large π-conjugated ligands into metal-organic frameworks (MOFs) can introduce intriguing photophysical and electrochemical properties into the framework. However, these effects are often hindered by the strong π-π interaction and the low solubility of the arylated ligands. Herein, we report the synthesis of a porous zirconium-based MOF, Zr6(µ3-O)4(µ3-OH)4(OH)6(H2O)6(HCHC) (PCN-136, HCHC = hexakis(4-carboxyphenyl)hexabenzocoronene), which is composed of a hexacarboxylate linker with a π-conjugated hexabenzocoronene moiety. Direct assembly of the Zr4+ metal centers and the HCHC ligands was unsuccessful due to the low solubility and the unfavorable conformation of the arylated HCHC ligand. Therefore, PCN-136 was obtained from aromatization-driven postsynthetic annulation of the hexaphenylbenzene fragment in a preformed framework (pbz-MOF-1) to avoid π-π stacking. This postsynthetic modification was done through a single-crystal-to-single-crystal transformation and was clearly observable utilizing single -crystal X-ray crystallography. The formation of large π-conjugated systems on the organic linker dramatically enhanced the photoresponsive properties of PCN-136. With isolated hexabenzocoronene moieties as photosensitizers and Zr-oxo clusters as catalytic sites, PCN-136 was employed as an inherent photocatalytic system for CO2 reduction under visible-light irradiation, which showed increased activity compared with pbz-MOF-1.

Research on the Weld Position Detection Method for Sandwich Structures from Face-Panel Side Based on Backscattered X-ray.

Web-core sandwich panels are a typical lightweight structure utilized in a variety of fields, such as naval, aviation, aerospace, etc. Welding is considered as an effective process to join the face panel to the core panel from the face panel side. However, it is difficult to locate the joint position (i.e., the position of core panel) due to the shielding of the face panel. This paper studies a weld position detection method based on X-ray from the face panel side for aluminum web-core sandwich panels used in aviation and naval structures. First, an experimental system was designed for weld position detection, able to quickly acquire the X-ray intensity signal backscattered by the specimen. An effective signal processing method was developed to accurately extract the characteristic value of X-ray intensity signals representing the center of the joint. Secondly, an analytical model was established to calculate and optimize the detection parameters required for detection of the weld position of a given specimen by analyzing the relationship between the backscattered X-ray intensity signal detected by the detector and the parameters of the detection system and specimen during the detection process. Finally, several experiments were carried out on a 6061 aluminum alloy specimen with a thickness of 3 mm. The experimental results demonstrate that the maximum absolute error of the detection was 0.340 mm, which is sufficiently accurate for locating the position of the joint. This paper aims to provide the technical basis for the automatic tracking of weld joints from the face panel side, required for the high-reliability manufacturing of curved sandwich structures.

Online Measurement of Deposit Surface in Electron Beam Freeform Fabrication.

In the process of electron beam freeform fabrication (EBF3), due to the continuous change of thermal conditions and variability in wire feeding in the deposition process, geometric deviations are generated in the deposition of each layer. In order to prevent the layer-by-layer accumulation of the deviation, it is necessary to perform online geometry measurement for each deposition layer, based on which the error compensation can be done for the previous deposition layer in the next deposition layer. However, the traditional three-dimensional reconstruction method that employs structured laser cannot meet the requirements of long-term stable operation in the manufacturing process of EBF3. Therefore, this paper proposes a method to measure the deposit surfaces based on the position information of electron beam speckle, in which an electron beam is used to bombard the surface of the deposit to generate the speckle. Based on the structured information of the electron beam in the vacuum chamber, the three-dimensional reconstruction of the surface of the deposited parts is realized without need of additional structured laser sensor. In order to improve the detection accuracy, the detection error is theoretically analyzed and compensated. The absolute error after compensation is smaller than 0.1 mm, and the precision can reach 0.1%, which satisfies the requirements of 3D reconstruction of the deposited parts. An online measurement system is built for the surface of deposited parts in the process of electron beam freeform fabrication, which realizes the online 3D reconstruction of the surface of the deposited layer. In addition, in order to improve the detection stability of the whole system, the image processing algorithm suitable for this scene is designed. The reliability and speed of the algorithm are improved by ROI extraction, threshold segmentation, and expansion corrosion. In addition, the speckle size information can also reflect the thermal conditions of the surface of the deposited parts. Hence, it can be used for online detection of defects such as infusion and voids.

A Vision Based Detection Method for Narrow Butt Joints and a Robotic Seam Tracking System.

Automatic joint detection is of vital importance for the teaching of robots before welding and the seam tracking during welding. For narrow butt joints, the traditional structured light method may be ineffective, and many existing detection methods designed for narrow butt joints can only detect their 2D position. However, for butt joints with narrow gaps and 3D trajectories, their 3D position and orientation of the workpiece surface are required. In this paper, a vision based detection method for narrow butt joints is proposed. A crosshair laser is projected onto the workpiece surface and an auxiliary light source is used to illuminate the workpiece surface continuously. Then, images with an appropriate grayscale distribution are grabbed with the auto exposure function of the camera. The 3D position of the joint and the normal vector of the workpiece surface are calculated by the combination of the 2D and 3D information in the images. In addition, the detection method is applied in a robotic seam tracking system for GTAW (gas tungsten arc welding). Different filtering methods are used to smooth the detection results, and compared with the moving average method, the Kalman filter can reduce the dithering of the robot and improve the tracking accuracy significantly.

Regulation of Hedgehog signaling Offers A Novel Perspective for Bone Homeostasis Disorder Treatment.

The hedgehog (HH) signaling pathway is central to the regulation of bone development and homeostasis. HH signaling is not only involved in osteoblast differentiation from bone marrow mesenchymal stem cells (BM-MSCs), but also acts upstream within osteoblasts via the OPG/RANK/RANKL axis to control the expression of RANKL. HH signaling has been found to up-regulate parathyroid hormone related protein (PTHrP) expression in osteoblasts, which in turn activates its downstream targets nuclear factor of activated T cells (NFAT) and cAMP responsive element binding protein (CREB), and as a result CREB and NFAT cooperatively increase RANKL expression and osteoclastogenesis. Osteoblasts must remain in balance with osteoclasts in order to avoid excessive bone formation or resorption, thereby maintaining bone homeostasis. This review systemically summarizes the mechanisms whereby HH signaling induces osteoblast development and controls RANKL expression through PTHrP in osteoblasts. Proper targeting of HH signaling may offer a therapeutic option for treating bone homeostasis disorders.

In-Process Monitoring of Lack of Fusion in Ultra-Thin Sheets Edge Welding Using Machine Vision.

Lack of fusion can often occur during ultra-thin sheets edge welding process, severely destroying joint quality and leading to seal failure. This paper presents a vision-based weld pool monitoring method for detecting a lack of fusion during micro plasma arc welding (MPAW) of ultra-thin sheets edge welds. A passive micro-vision sensor is developed to acquire clear images of the mesoscale weld pool under MPAW conditions, continuously and stably. Then, an image processing algorithm has been proposed to extract the characteristics of weld pool geometry from the acquired images in real time. The relations between the presence of a lack of fusion in edge weld and dynamic changes in weld pool characteristic parameters are investigated. The experimental results indicate that the abrupt changes of extracted weld pool centroid position along the weld length are highly correlated with the occurrences of lack of fusion. By using such weld pool characteristic information, the lack of fusion in MPAW of ultra-thin sheets edge welds can be detected in real time. The proposed in-process monitoring method makes the early warning possible. It also can provide feedback for real-time control and can serve as a basis for intelligent defect identification.

A Weld Position Recognition Method Based on Directional and Structured Light Information Fusion in Multi-Layer/Multi-Pass Welding.

Multi-layer/multi-pass welding (MLMPW) technology is widely used in the energy industry to join thick components. During automatic welding using robots or other actuators, it is very important to recognize the actual weld pass position using visual methods, which can then be used not only to perform reasonable path planning for actuators, but also to correct any deviations between the welding torch and the weld pass position in real time. However, due to the small geometrical differences between adjacent weld passes, existing weld position recognition technologies such as structured light methods are not suitable for weld position detection in MLMPW. This paper proposes a novel method for weld position detection, which fuses various kinds of information in MLMPW. First, a synchronous acquisition method is developed to obtain various kinds of visual information when directional light and structured light sources are on, respectively. Then, interferences are eliminated by fusing adjacent images. Finally, the information from directional and structured light images is fused to obtain the 3D positions of the weld passes. Experiment results show that each process can be done in 30 ms and the deviation is less than 0.6 mm. The proposed method can be used for automatic path planning and seam tracking in the robotic MLMPW process as well as electron beam freeform fabrication process.

A Vision-Aided 3D Path Teaching Method before Narrow Butt Joint Welding.

For better welding quality, accurate path teaching for actuators must be achieved before welding. Due to machining errors, assembly errors, deformations, etc., the actual groove position may be different from the predetermined path. Therefore, it is significant to recognize the actual groove position using machine vision methods and perform an accurate path teaching process. However, during the teaching process of a narrow butt joint, the existing machine vision methods may fail because of poor adaptability, low resolution, and lack of 3D information. This paper proposes a 3D path teaching method for narrow butt joint welding. This method obtains two kinds of visual information nearly at the same time, namely 2D pixel coordinates of the groove in uniform lighting condition and 3D point cloud data of the workpiece surface in cross-line laser lighting condition. The 3D position and pose between the welding torch and groove can be calculated after information fusion. The image resolution can reach 12.5 µm. Experiments are carried out at an actuator speed of 2300 mm/min and groove width of less than 0.1 mm. The results show that this method is suitable for groove recognition before narrow butt joint welding and can be applied in path teaching fields of 3D complex components.