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ObjectiveRheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model.MethodsMice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21.ResultsAfter administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (PConclusionThe results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways.

Periodontitis is a multifactorial chronic inflammatory disease that can lead to the irreversible destruction of dental support tissues. As an epigenetic factor, the expression of circRNA is tissue-dependent and disease-dependent. This study aimed to identify novel periodontitis-associated circRNAs and predict relevant circRNA-periodontitis regulatory network by using recently developed bioinformatic tools and integrating sequencing profiling with clinical information for getting a better and more thorough image of periodontitis pathogenesis, from gene to clinic.High-throughput sequencing and RT-qPCR were conducted to identify differentially expressed circRNAs in gingival tissues from periodontitis patients. The relationship between upregulated circRNAs expression and probing depth (PD) was performed using Spearman's correlation analysis. Bioinformatic analyses including GO analysis, circRNA-disease association prediction, and circRNA-miRNA-mRNA network prediction were performed to clarify potential regulatory functions of identified circRNAs in periodontitis. A receiver-operating characteristic (ROC) curve was established to assess the diagnostic significance of identified circRNAs.High-throughput sequencing identified 70 differentially expressed circRNAs (68 upregulated and 2 downregulated circRNAs) in human periodontitis (fold change2.0 and p .05). The top five upregulated circRNAs were validated by RT-qPCR that had strong associations with multiple human diseases, including periodontitis. The upregulation of circRNAs were positively correlated with PD (R = .40-.69, p .05, moderate). A circRNA-miRNA-mRNA network with the top five upregulated circRNAs, differentially expressed mRNAs, and overlapped predicted miRNAs indicated potential roles of circRNAs in immune response, cell apoptosis, migration, adhesion, and reaction to oxidative stress. The ROC curve showed that circRNAs had potential value in periodontitis diagnosis (AUC = 0.7321-0.8667, p .05).CircRNA-disease associations were predicted by online bioinformatic tools. Positive correlation between upregulated circRNAs, circPTP4A2, chr22:23101560-23135351+, circARHGEF28, circBARD1 and circRASA2, and PD suggested function of circRNAs in periodontitis. Network prediction further focused on downstream targets regulated by circRNAs during periodontitis pathogenesis.

Efforts to understand the morphogenesis of complex craniofacial structures have largely focused on the role of chondrocytes and osteoblasts. Along with these bone–creating cells, bone–resorbing osteoclasts are critical in homeostasis of adult skeletal structures, but there is currently limited information on their role in the complex morphogenetic events of craniofacial development. Fundamental aspects of skull formation and general skeletal development are conserved from zebrafish to mammals. Using a cathepsinK reporter, we documented osteoclast location in the developing zebrafish skull over several weeks, from 5.18 mm to 9.6 mm standard length (approximately 15 to 34 days post fertilization). While broad distribution of osteoclasts is consistent across individuals, they are sparse and the exact locations vary among fish and across developmental time points. Interestingly, we observed osteoclasts concentrating at areas associated with neuromasts and their associated nerves, in particular the hyomandibular foramina and around the supraorbital lateral line. These are areas of active remodeling. In contrast, other areas of rapid bone growth, such as the osteogenic fronts of the frontal and parietal bones, show no particular concentration of osteoclasts, suggesting that they play a special role in shaping bone near neuromasts and nerves. In csf1ra mutants lacking functional osteoclasts, the morphology of the cranial bone was disrupted in both areas. The hyomandibular foramen is present in the initial cartilage template, but after the initiation of ossification, the diameter of the canal is significantly smaller in the absence of osteoclasts. The diameter of the supraorbital lateral line canals was also reduced in the mutants, as was the number of pores associated with neuromasts, which allow for the passage of associated nerves through the bone. Our findings define important and previously unappreciated roles for osteoclast activity in shaping craniofacial skeletal structures with a particular role in bone modeling around peripheral cranial nerves, providing a scaffold for wiring the sensioneural system during craniofacial development. This has important implications for the formation of the evolutionarily diverse lateral line system, as well understanding the mechanism of neurologic sequelae of congenital osteoclast dysfunction in human craniofacial development.

Remote sensing course is a general disciplinary required course of human geography and urban-rural planning major. Its class hour is 48, including theoretical classes and experimental classes. Rapid technological developments is remote sensing area demand quick and steady changes in the education programme and its realization, especially in experimental classes. Experimental classes include: introduction to remote sensing software and basic operations, remote sensing data pre-processing (input, output, 2D and 3D terrain display, image cut, image mosaic, and projection transformation), remote sensing image enhancement, remote sensing image transformation, computer aided classification, image interpretation, and remote sensing image terrain analysis. There are two difficulties in the remote sensing experimental classes. First, it cost a lot of time to prepare the remote sensing software and the remote sensing images. Second, some students just want to use the remote sensing as a tool to investigate environment changing, some other students may want to study more remote sensing image processing technologies. A web-based learning environment of remote sensing is developed to facilitate the application of remote sensing experimental teaching. To make the learning more effective, there are eight modules including four optional modules. The Python programming language is chosen to implement the web-based remote sensing learning environment. The web-based learning environment is implemented in a local network server, including the remote sensing data processing algorithms and many satellite image data. Students can easily exercise the remote sensing experimental courses by connecting to the local network server. It is developed mainly for remote sensing experimental course, and also can be adopted by digital image processing or other courses. The feature of web-based learning may be very useful as the online education adopted because of Corona Virus Disease 2019. The results are encouraging and some recommendations will be extracted for the future.

Jumping with controllable elevation is significant for insect-scale robots to improve terrain adaptability and to escape from risks. However, jumping robots based on soft materials with low stiffness cannot transmit displacement precisely, exhibiting poor control of jumping. Here, we propose a modified two-bars catapult mechanism combined with an asynchronous sequential releasing strategy to realize elevation controllable jumping. In this work, an 80 mg prototype robot, 56 (long) × 29 mm (wide) × 3 mm (high) mm in size, is designed with the controllable elevation range from 63° to 112°. The soft robot is mainly composed of a shape memory alloy actuator and four electrostatic pads acting as the lock/release structures. Elevation control is realized by asynchronously releasing the electrostatic pads in a small time interval (about 10 ms). A maximum jump height of 62 mm and a maximum half-distance of 41 mm are also achieved.

The future of improved immunotherapy against cancer depends on an in-depth understanding of the dynamic interactions between the immune system and tumors. Over the past two decades, the zebrafish has served as a valuable model system to provide fresh insights into both the development of the immune system and the etiologies of many different cancers. This well-established foundation of knowledge combined with the imaging and genetic capacities of the zebrafish provides a new frontier in cancer immunology research. In this review, we provide an overview of the development of the zebrafish immune system along with a side-by-side comparison of its human counterpart. We then introduce components of the adaptive immune system with a focus on their roles in the tumor microenvironment (TME) of teleosts. In addition, we summarize zebrafish models developed for the study of cancer and adaptive immunity along with other available tools and technology afforded by this experimental system. Finally, we discuss some recent research conducted using the zebrafish to investigate adaptive immune cell-tumor interactions. Without a doubt, the zebrafish will arise as one of the driving forces to help expand the knowledge of tumor immunity and facilitate the development of improved anti-cancer immunotherapy in the foreseeable future.

This study aimed to determine the impact of

The Single-hidden Layer Feed-forward Neural Network has been widely applied in the fields such as pattern recognition, automatic control and data mining. However, the speed of the tradition...

The motional Stark effect (MSE) diagnostic is applied to measure the safety factor q and current density profile of a tokamak device, which are important parameters in realizing the high-performance and long-pulse steady state of a tokamak. A single-channel MSE diagnostic based on dual photoelastic modulators, whose sightline meets with the neutral beam injection at a major radius of R = 2.12 m, has been built for the D window of the Experimental Advanced Superconducting Tokamak (EAST). According to the requirements of MSE diagnostic polarimetric calibration, a high-precision four-dimensional calibration turntable, driven by four stepping motors and controlled by software running on the computer, was designed for EAST. The turntable allows us to rapidly calibrate the MSE diagnostic in a series of positions and angles during EAST maintenance. The turntable can move in four dimensions of translation, yaw, pitch, and roll of the polarizer and can create linearly polarized light at any given angle with accuracy of ∼0.05° for the MSE system offline calibration. The experimental results of the MSE diagnostic calibration in the laboratory show that the turntable has the advantages of high positioning accuracy, flexible spatial movement, and convenient control and fully meets the calibration requirements of an MSE diagnosis system.

BACKGROUND AND PURPOSE The efficacy of dual antiplatelet treatment may be modified by many factors. The aim was to assess whether the effect of clopidogrel plus aspirin versus aspirin alone on recurrent stroke would be affected by admission activated partial thromboplastin time (aPTT). METHODS Data were derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A total of 5074 patients were categorized into three groups based on the aPTT distribution according to the 15th and 85th percentile. The primary outcome was any stroke within 90 days. The interaction of aPTT with antiplatelet therapy on stroke risk was assessed with a Cox proportional hazards model with adjustment for covariates. RESULTS In the high aPTT group (defined as ≥35.9 s), stroke occurred in 6.7% of patients in the clopidogrel-aspirin arm and 11.9% in the aspirin arm [adjusted hazard ratio (HR) 0.50; 95% confidence interval (CI) 0.29-0.85]. In the medium aPTT group (24.6-35.8 s), stroke occurred in 7.7% of patients in the clopidogrel-aspirin arm and 11.8% in the aspirin arm (adjusted HR 0.62; 95% CI 0.50-0.75). Furthermore, in the low aPTT group (≤24.5 s), stroke occurred in 11.2% of patients in the clopidogrel-aspirin arm and 9.9% in the aspirin arm (adjusted HR 1.07; 95% CI 0.65-1.62). The interaction P value of antiplatelet therapy with aPTT level at the cut-point of approximately 25 s or below was significant (P

The low voltage Charge-Coupled MOSFET with deep-submicron technology is fabricated with extra thick trench oxide process. The extra process module consists of thick oxide growth in trench, resist coating, resist expose to control thick oxide height in trench which would finally affect the break down voltage of the device. The effects of trench length, thickness of the thick trench oxide layer and cell pitch size on the breakdown voltage were discussed in this work. This low voltage Charge-Coupled MOSFET with deep-submicron technology provides an approach to achieve the significantly smaller specific on-resistance at the same break down voltage that obtained on the conventional trench MOSFET by using a greater doping concentration in the drift region.

The incidence of rectal carcinoma (RC) has been increasing recently, and becomes the second most common digestive tumors besides gastric cancer, with a rise in the incidence of RC in younger populations. The early diagnosis and treatment are thus critical for the improvement of survival rate and life quality of patients. Stomatin-like protein 2 (SLP-2) is a type of membrane factor, which is generally found highly expressed in various tumors. Collagen and calcium-binding EGF domain (CCBE1) belongs to lymphatic tube genesis factor. The regulatory role of SLP-2 gene on CCBE1 expression in RC tumor and adjacent lymphatic tube tissues, however, has not been studied.52 RC patients were recruited, and tumor and adjacent lymphatic tube tissues were collected. Real-time PCR, western blotting and immunohistochemistry (IHC) staining were used to analyze SLP-2 and CCBE1 expressions. Human lymphatic endothelial cells (LECs) were cultured in vitro and were assigned to control, scramble, and SLP-2 siRNA group. MTT assay was used to detect cell proliferation, while caspase 3 activity was detected.SLP-2 and CCBE1 levels were significantly elevated in tumor lymphatic tissues, compared to that in adjacent tissues. Statistically positive correlation between SLP-1 and CCBE2 was found (p0.05). The downregulation of SLP-2 by siRNA inhibited cell proliferation, elevated caspase3 activity, and decreased CCBE1 expression (p0.05 compared to control group).SLP-2 is up-regulated in RC lymphatic tissues, and is positively correlated with the level of CCBE1, which provides the academic the basis for the development of medicine targeting SLP-2 in the anti-rectal carcinoma therapy.

Objective This study evaluated the relationship between follow-up temporomandibular joint positional change and mandibular stability among patients who had orthognathic and orthodontic treatment for a skeletal Class II malocclusion. Methods Thirty-seven patients who underwent 2-jaw surgery (Le Fort I osteotomy, bilateral sagittal split ramus osteotomy and genioplasty with rigid internal fixation) were included with an average follow-up length of 8.10 ± 2.06 years. They were categorized into a stable and unstable group according to follow-up mandibular change in the sagittal direction. Temporomandibular joint spaces were measured on serial magnetic resonance images, prior to orthodontic treatment (T0), upon completion of orthodontic treatment following surgery (T1), and at least 5 years post-completion of the treatment (T2). Results While the maxillary position was stable during the follow-up period, the mandibular positional change was statistically significant (the relapse amount was -0.81 ± 1.52 mm at B point). An increase in the anterior joint space and superior joint space was found to correlate with the follow-up mandibular backward movement. Conclusions Patients who underwent orthognathic and orthodontic treatment to correct mandibular retrognathism displayed follow-up mandibular relapse in the sagittal direction. The relapse is accompanied by condylar positional change.

Objective To explore the alteration of T and B lymphocyte subsets proportions in myelin oligodendrocyte glycoprotein (MOG)-antibody-associated demyelination. Methods 19 MOG-antibody-positive, 25 AQP4-antibody-positive and 25 double-negative NMOSD patients in the acute phase of the diseases were included in the study, as well as 29 healthy controls. The frequencies of different lymphocyte subsets, including CD19+CD27+ memory B cells, CD19+CD24hiCD38hi, and CD19+CD5+CD1dhi regulatory B cells, IFN-γexpressing B cells, IL-10 expressing B cells and CD4+CXCR5+ICOS+ T-follicular helper cells (TFH) were measured via flow cytometry and compared among the four groups. Results The frequencies of CD19+CD24hiCD38hi, CD19+CD5+CD1dhi regulatory B cells as well as the IL-10 expressing B cells were significantly lower in the MOG-antibody-associated demyelination compared to the healthy controls, whereas the frequencies of CD19+CD27+ memory B cells were significantly higher in the MOG-antibody-positive group. The frequencies of TFH were significantly higher in the MOG-antibody-positive group as compared to the healthy controls. No significant difference was detected in the above mentioned lymphocytic profile between the MOG-antibody-positive and the AQP4-antibody-positive groups. Conclusions The immuno-regulatory functions of B cells were significantly impaired whereas TFH cells were markedly increased in the acute phase of MOG-antibody-associated demyelination. Despite having distinct clinical features, MOG-antibody-associated demyelination shared a similar lymphocytic profile with AQP4-antibody-positive NMOSD in the acute relapse phase.

DBSCAN is a classic and commonly applied density-based clustering algorithm, but its clustering accuracy depends on the choice of two input parameters. This paper presents a new algorithm for adaptative parameter determination in DBSCAN. The assumption of this new algorithm is that regions with larger sample density gradient usually corresponds to the edge areas of clusters. The main idea is to generate some pre-clusters and determine the values of parameters by their statistics information. We first randomly pick pairs of points in the sample space to form circles, which are called "disks". Then we estimate the density information of a disk by random sampling, and define the criteria of disk quality to select disks with larger sample density gradient. Finally, we obtain the suitable parameters of DBSCAN in terms of the distributions of radius and points number of these extracted disks by Gaussian kernel density estimation. Experimental results show that the new algorithm improves the accuracy of DBSCAN and performs better than classic algorithms like k-means and Birch in some cases.

This study aimed to investigate the effects of Wuzhi capsule on blood concentration of tacrolimus after renal transplantation. Sixty patients after allogenic renal transplantation were enrolled in this study and randomly divided into an experimental group and a control group. One oral Wuzhi capsule was taken in the morning and evening for patients in the experimental group, while none was given to the control group, maintaining the trough blood concentration of tacrolimus in the normal range. After 3 weeks, the changes of tacrolimus dosage and hepatorenal function in the two groups were compared. Comparisons of drug dosage and blood concentration C0 value of tacrolimus before initiating the experiment showed that there was no statistically ignificant difference (P0.05) between the two groups. The differences of blood concentration of tacrolimus and hepatorenal function for patients in both two groups after 3 weeks’ treatment also showed no statistical significance (P0.05), whereas a statistically significant decrease was demonstrated in the tacrolimus dosage of the Wuzhi capsule group compared with that of the control group (P=0.0083). After renal transplantation, Wuzhi capsules were added so as to enable tacrolimus to reach a suitable blood concentration, which can prevent the occurrence of renal transplantation rejection, thus alleviating the economic burden of patients and producing larger social benefits.

We investigated the effect of pregnane X receptor (PXR) polymorphisms on tacrolimus (FK506) blood trough concentrations and the associated adverse reactions in kidney transplantation recipients (KTRs). Polymerase chain reaction (PCR)-restriction fragment length polymorphism was used to detect the genotypes of single nucleotide polymorphism loci in 336 KTRs. The PXR six-base deletion mutation was classified using specific allele PCR, and the FK506 blood trough concentration in the KTRs was measured by chemiluminescent microparticle immunoassay. There were significant differences in adverse reactions resulting from FK506 in age, weight, body mass index (BMI) and treatment course (P0.05). Logistical regression revealed that the FK506 treatment course and BMI were risk factors for hyperlipidemia, and the risk of hyperlipidemia increased 27.534 times when the BMI was less than 18.5. Moreover, age was also a risk factor leading to hyperglycemia. FK506 blood trough concentration and C

Summary. Background: Heterologous expression of factor VIII (FVIII) is about two to three orders of magnitude lower than similarly sized proteins. Bioengineering strategies aimed at different structural and biochemical attributes of FVIII have been successful in enhancing its expression levels. Objective: Disulfide bonds are vital to the proper folding, secretion and stability of most secretory proteins. In an effort to explore additional targeted bioengineering approaches, the role of disulfide bonds in FVIII secretion and function was probed in this study. Methods and Results: Single and paired cysteine mutants were generated by substituting with serine or glycine residues and analyzed by transient transfection into COS-1 and CHO cells. Seven of the eight disulfide bonds in FVIII were found to be indispensable for proper secretion and function. However, elimination of the disulfide bond formed by C1899 and C1903 within the conserved A3 domain improved the secretion of FVIII. The addition of the C1899G/C1903G mutations to a previously described FVIII variant, 226/N6, with high secretion efficiency increased its secretion by 2.2-fold. Finally, the addition of the A1-domain mutation, F309S, in conjunction with the disulfide mutation had an additive effect, resulting in a net improvement in secretion of between 35 and 45-fold higher than wild-type FVIII in CHO cells. Conclusion: Such combined targeted bioengineering strategies may facilitate more efficient production of recombinant FVIII and contribute toward low-cost factor replacement therapy for hemophilia A.

UNLABELLED Fresh air ventilation is central to indoor environmental control. Total heat exchangers can be key equipment for energy conservation in ventilation. Membranes have been used for total heat exchangers for more than a decade. Much effort has been spent to achieve water vapor permeability of various membranes; however, relatively little attention has been paid to the selectivity of moisture compared with volatile organic compounds (VOCs) through such membranes. In this investigation, the most commonly used membranes, both hydrophilic and hydrophobic ones, are tested for their permeability for moisture and five VOCs (acetic acid, formaldehyde, acetaldehyde, toluene, and ethane). The selectivity of moisture vs. VOCs in these membranes is then evaluated. With a solution-diffusion model, the solubility and diffusivity of moisture and VOCs in these membranes are calculated. The resulting data could provide some reference for future material selection. PRACTICAL IMPLICATIONS Total heat exchangers are important equipment for fresh air ventilation with energy conservation. However, their implications for indoor air quality in terms of volatile organic compound permeation have not been known. The data in this article help us to clarify the impacts on indoor VOC levels of membrane-based heat exchangers. Guidelines for material selection can be obtained for future use total heat exchangers for building ventilation.

The present study was aimed to investigate the developmental patterns of FASN (fatty acid synthase) and LIPE (lipase, hormone-sensitive) mRNA in adipose tissue in pigs of different breeds and the relation with carcass fat content. Subcutaneous adipose tissue was sampled and total RNA was extracted to determine FASN and LIPE mRNA levels by semi-quantitative RT-PCR. The results showed that the FASN mRNA level increased with age ( P < 0.05) and Jinhua gilts expressed higher FASN mRNA compared with Landrace gilts at 80 and 125 days of age ( P < 0.05). In addition, Jinhua gilts expressed lower LIPE mRNA compared with Landrace gilts at 80 days of age ( P < 0.01). Furthermore, the ratio of FASN/LIPE mRNA had a similar model in the two breeds, and was higher in Jinhua gilts than that in Landrace gilts at 80 and 125 days of age ( P < 0.05). The FASN mRNA level was positively related to carcass fat content in Jinhua and Landrace gilts (r = 0.802, P = 0.01; r = 0.734, P = 0.02; respectively), and the ratio of FASN/LIPE expression exhibited significantly positively related carcass fat content ( r = 0.804, P = 0.01; r = 0.749, P = 0.02; respectively).