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SummaryT-cell receptor (TCR)-engineered T cells can precisely recognize a broad repertoire of targets derived from both intracellular and surface proteins of tumor cells. TCR-T adoptive cell therapy has shown safety and promising efficacy in solid tumor immunotherapy. However, antigen-specific functional TCR screening is time-consuming and expensive, which limits its application clinically. Here, we developed a novel integrated antigen-TCR screening platform based on droplet microfluidics technology, enabling high-throughput peptide-major histocompatibility complex (pMHC) library-to-TCR library screening with high sensitivity and low background signal. We introduced DNA barcoding technology to label peptide antigen candidate-loaded antigen-presenting cells (APCs) and Jurkat reporter cells to check the specificity of pMHC-TCR candidates. Coupled with the next-generation sequencing pipeline, interpretation of the DNA barcodes and the gene expression level of the Jurkat T-cell activation pathway provided a clear peptide-MHC-TCR recognition relationship. Our proof-of-principle study demonstrates that the platform could achieve unbiased pMHC-TCR library-on-library screening, which is expected to be used in the cross-reactivity and off-target testing of candidate pMHC-TCR libraries in clinical applications.

New pH-sensitive polysaccharide supramolecular hydrogel microparticles (HMPs) were constructed based on carboxymethyl β-cyclodextrin/chitosan inclusion complex (CM-β-CD/CS) and EDTA-chitosan (EDCS) in aqueous solution. The incorporation of components in HMPs was characterized by ultraviolet, fluorescence and FTIR spectroscopy. The morphology measurements of HMPs were investigated by particle size analyzer and fluorescence microscope. These results showed that CM-β-CD was integrated on the CS by electrostatic interactions, while the hydrogen bonding between CM-β-CD/CS complex and EDCS resulted in the formation of self-assembled HMPs. The swelling and shear rheological behaviors of the HMPs were also investigated, confirming the pH sensitive of the HMPs. In vitro drug release behaviors of the HMPs conducted in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4) were studied by using bovine serum albumin (BSA) as model protein drug. Results indicated that the BSA-loaded HMPs exhibit highlighted pH-dependent release characteristics and the release of BSA from the HMPs could be described by the Ritger–Peppas model equation, suggesting that the HMPs might be formulated to be a promising candidate for the release of protein drugs.

Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APPNL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APPNL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APPNL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APPNL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD

In this paper, a phytoplankton and zooplankton relationship system with two delays is investigated whose coefficients are related to one of the two delays. Firstly, the dynamic behaviors of the system with one delay are given and the stability of positive equilibrium and the existence of periodic solutions are obtained. Using the fact that the system may occur, the stable switching phenomenon is verified. Under certain conditions, the periodic solutions will exist in a wide range as the delay gets away from critical values. Fixing the delay [Formula: see text] in the stable interval, it is revealed that the effect of [Formula: see text] can also cause the vibration of system. This explains that two delays play an important role in the oscillation behavior of the system. Furthermore, using the crossing curve methods, the stable changes of the positive equilibrium in two-delays plane are given, which generalizes the results of systems for which the coefficients do not depend on delay. Some numerical simulations are provided to verify the theoretical results.

Cognitive decline is a major symptom in Alzheimer's disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in

Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory autoimmune disease associated with the disorder of intestinal microbiota. Unfortunately, effective therapies for AS are lacking. Recent evidence has indicated that indole-3-acetic acid (IAA), an important microbial tryptophan metabolite, can modulate intestinal homeostasis and suppress inflammatory responses. However, reports have not examined the in vivo protective effects of IAA against AS. In this study, we investigated the protective effects and underlying mechanisms through which IAA acts against AS. We constructed a proteoglycan (PG)-induced AS mouse model and administered IAA (50 mg/kg body weight) by intraperitoneal injection daily for 4 weeks. The effects of IAA on AS mice were evaluated by examining disease severity, intestinal barrier function, aryl hydrocarbon receptor (AhR) pathway, T-helper 17 (Th17)/T regulatory (Treg) balance, and inflammatory cytokine levels. The intestinal microbiota compositions were profiled through whole-genome sequencing. We observed that IAA decreased the incidence and severity of AS in mice, inhibited the production of pro-inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin [IL]-6, IL-17A, and IL-23), promoted the production of the anti-inflammatory cytokine IL-10, and reduced the ratios of pro-/anti- inflammatory cytokines. IAA ameliorated pathological changes in the ileum and improved intestinal mucosal barrier function. IAA also activated the AhR pathway, upregulated the transcription factor forehead box protein P3 (FoxP3) and increased Treg cells, and downregulated the transcription factors retinoic acid receptor–related orphan receptor gamma t (RORγt) and signal transducer and activator of transcription 3 (STAT3) and decreased Th17 cells. Furthermore, IAA altered the composition of the intestinal microbiota composition by increasing Bacteroides and decreasing Proteobacteria and Firmicutes, in addition to increasing the abundances of Bifidobacterium pseudolongum and Mucispirillum schaedleri. In conclusion, IAA exerted several protective effects against PG-induced AS in mice, which was mediated by the restoration of balance among the intestinal microbial community, activating the AhR pathway, and inhibiting inflammation. IAA might represent a novel therapeutic approach for AS.

In this paper, the kinetics of a class of delayed reaction-diffusion musselalgae system under Neumann boundary conditions with the half- saturation constant is studied. The global existence and priori bounds as well as the existence conditions of positive equilibrium are obtained. The half-saturation constant affect the stability of the system and may result in Turing instability. When the half-saturation constant exceeds a certain critical value, the boundary equilibrium is globally asymptotically stable which means that the larger half-saturation constant forces the mussel population toward extinction. By analyzing the distribution of the roots of the characteristic equation with two delays, the stability conditions of the positive equilibrium in the parameter space are obtained. The stability of the positive equilibrium can be changed by steady-state bifurcation, Hopf bifurcation, Hopf-Hopf bifurcation or Hopf-steady state bifurcation, which can be verified by some numerical simulations. Among parameters, the half-saturation constant and two delays drive the complexity of the system dynamics.

The International Maritime Organization (IMO) enforced stricter sulphur abatement regulations since shipping emission has become one of the most major cause of the atmospheric pollution. Experts from the industry and academicians try to find the balanced solution among low-sulphur fuel, clean energy, and purposely fit scrubber by conventional statistical methods however failed to reach a satisfying conclusion. In addition, maritime datasets are usually massive, multi-source, and heterogeneous, it seems imperative for the maritime industry to adapt to the worldwide trend of intellectualisation and promote sustainable development.This work delineates and compares three main sulphur abatement solutions for ships through a thorough investigation of the current research state, and proposes a new framework based on a fusion model using modern big data and data mining algorithms. This work identifies and summarises major factors (with high impacts) in sulphur abatement solutions in the ocean shipping industry and integrate those high-level impacting factors to the proposed fusion model. The proposed framework can be optimised and utilised in determining suitable solutions for different ships, as well as shipping routes.

Distributed denial of service (DDoS) attacks pose a huge threat to the Internet. Follow the rapid usage of the Internet of things (IoT), the DDoS attack is no longer a mere traffic attack, the original attack on the application layer surpasses the attack on the network layer. Furthermore, DDoS attacks using Bonnets result more destructive effects. This research aims to propose a new collaborated active defense framework between Honeypot and cloud platform to detect and defend future DDoS attacks in the context of the IoT with the instantaneous malicious traffic measured in Terabytes.

Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy.

In recent years, with the development of network technology and the development of real estate industry, intelligent apartments are becoming more and more popular. The intelligent door lock equipment is becoming more and more popular. Compared with the traditional door lock, the intelligent door lock has higher security and convenience. The user controls the door lock through the mobile device, and the apartment controls the door lock through the computer. Compared with the traditional apartment door lock or electronic access card, it is more convenient. Therefore, a management system that can manage the door locks intelligently through the Internet is of great significance to the real estate industry and social development. In this paper, using the existing knowledge of electronic door lock in the industry, combined with the author's professional ability, an intelligent door lock management system based on raspberry pie, Java EE and Android is designed. The door lock end is controlled by raspberry pie, which scans fingerprint data and enters fingerprint data by as608 fingerprint module. Rpi-lcd35b display screen is used as password input interface, RPI camera is used as monitoring equipment of door lock. Raspberry pie controls electronic door lock and sends door opening record to server. Users can get the information of the door lock through the mobile app, modify the door lock password, save the household information and perform other operations, which can be monitored by the camera on the door lock.

Perceiving user emotions and generating responses with specific emotions are of great significance to a social dialogue system. Much previous work still utilizes seq2seq models as the backbone to generate emotional responses. With the popularity of the generative pre-training models, we propose an emotional response generation model EmoDialoGPT based on DialoGPT by introducing emotion embedding and emotion prediction loss. In order to obtain a large-scale dialogue dataset with emotion labels, we train an emotion classifier and automatically annotate the emotion labels for the dialogue data. We evaluate our models from three aspects, including emotion expression, response quality and human evaluation. The experimental results show that, the proposed models outperform seq2seq models and baseline DialoGPT models on most metrics.

Drug information includes indications, contraindications, adverse reactions and other specific descriptions, which can provide a basis and support for rational clinical rational drug use and clinical decision-making. A Chinese medicine knowledge base with interrelated disease and drug information interrelated can effectively monitor the therapeutic effects of drugs on diseases and provide knowledge resources for drug research. In this paper, the multi-source Chinese Medicine Knowledge Base (CMKB) is constructed in view of the important role of drug information in clinical medication, auxiliary diagnosis, disease risk prediction and other practical applications. CMKB takes the mainstream medical resources such as the China Disease Knowledge Total Database and Dingxiangyuan as data sources. On the basis of the knowledge description system and classification system of the medicine database, CMKB standardizes the classification of drugs from multiple sources and forms corresponding detailed knowledge descriptions. CMKB constructed contains 14,141 drugs, which are described in detail from 7 aspects such as indications, contraindications and classification. Knowledge association between drug entities and disease entities is established through named entity recognition. The accuracy of named entity recognition reaches 90.6% and 91.4% as assessed by different models. CMKB constructed in this paper can be a useful supplement for the Chinese Medical Knowledge Graph (CMeKG) and will provide support for intelligent diagnosis and clinical decision-making.

With the development of society, more and more goods are sold intelligently and without people. The purpose of supermarket shopping robots is to help shop assistants replenish goods and free shop assistants from tedious mechanical work. Based on the “Innovation Robot Design and Production Competition–Supermarket Robot Challenge Competition”, the competition rules are taken as the design criteria. On the basis of CNN (convolution neural network), we design a CNN image recognition algorithm used in supermarket shopping robot. This algorithm overcomes the problems of low recognition accuracy and slow recognition speed in image recognition, and enables the robot to complete the competition more efficiently and quickly in the process of operation. The experimental results also verify that the image recognition algorithm can be applied to supermarket shopping robots and meet the needs of the competition.

In recent years, with the rapid development of electronic technology and the improvement of people's quality of life, smart home system gradually comes into being. People often waste the use of lighting system in places with long lighting time and more lighting equipment (such as school classrooms, shopping malls, etc.). Due to the lack of scientific management and the weak sense of responsibility of management personnel, it is necessary to implement lighting energy-saving measures on the premise of ensuring lighting quality. In order to realize the intelligent lighting control system for places with long lighting, the system mainly uses the intelligent lighting control hardware, as well as the python terminal to obtain local time. In this way, the change of lighting can be controlled according to the local time, so as to reduce the artificial management time and the waste of electric energy. This can not only save energy, but also produce obvious economic benefits.

Ankylosing spondylitis is a chronic, progressive disease, and its treatment is relevant to the gut microbiota. Anti‐tumor necrosis factor‐alpha (anti‐TNF‐α) therapy alters the gut microbiota in many diseases, including inflammatory bowel disease. However, little is known about the effect of TNF‐α blocker treatment on the gut microbiota in ankylosing spondylitis. Herein, the effect of a TNF‐α blocker on the gut microbiota in proteoglycan‐induced arthritis was investigated. Proteoglycan‐induced mice were treated with an rhTNFR:Fc solution of etanercept (5 µg/g) for 4 weeks. rhTNFR:Fc treatment attenuated the arthritis incidence and severity of arthritis in the proteoglycan‐induced mice and decreased inflammation in the ankle joints and ameliorated ileal tissue destruction. Moreover, high gut permeability occurred, and zonula occludens‐1 and occludin protein levels were reduced in proteoglycan‐induced mice. These levels were significantly restored by the administration of rhTNFR:Fc. The serum TNF‐α and IL‐17 levels were also decreased. In addition, flora analysis via 16S rDNA high‐throughput sequencing revealed that rhTNFR:Fc treatment restored the gut microbiota composition to a composition similar to that in control mice. In conclusion, anti‐TNF‐α therapy attenuated proteoglycan‐induced arthritis progression and modulated the gut microbiota and intestinal barrier function. These results provide new insights for anti‐TNF‐α therapy strategies via regulating the gut microbiota in ankylosing spondylitis., Anti‐TNF alpha therapy attenuated the incidence and severity of ankylosing spondylitis in mice. Anti‐TNF alpha therapy modulated gut microbiota of ankylosing spondylitis in mice. Anti‐TNF alpha therapy repaired the gut barrier function of ankylosing spondylitis in mice.

Background: The detailed structure of the lumbar intervertebral foramina has been wellstudied. Nevertheless, detailed descriptions of branches of the intervertebral vein (IV) through the lumbar intervertebral foramina are lacking. Objectives: This study aimed to provide an anatomical basis for invasive treatment targeting the branches of the IV using an approach through the lumbar intervertebral foramina, particularly for the purposes of transforaminal epidural steroid injection. Study Design: This research involved a dissection-based study of 10 embalmed human cadavers. Setting: The research took place at The Third Affiliated Hospital of Southern Medical University. Methods: One hundred lumbar intervertebral foramina from 10 embalmed cadavers were studied. Branches of the IV in the intervertebral foramina were observed. The length and diameter of the veins were measured using a Vernier caliper. Results: At a rate of 100%, branches of the IV were observed in the 100 lumbar foramina examined in our study. The following 4 types of branches of the IV were routinely found: Type I in 27 (27%) of the IV foramina, in which a superior branch of the IV ran along the inferior margin of the vertebral pedicle; Type II in 18 (18%) of the intervertebral foramina, in which an inferior branch of the IV ran along the superior margin of the inferior vertebral pedicle; Type III in 41 (41%) of the intervertebral foramina, in which the IV was divided into a superior and inferior branch; and Type IV in 14 (14%) of the intervertebral foramina, in which the IV was divided into 2 superior branches and an inferior branch. Limitations: The greatest weakness of this study is that it lacks actual clinical verification. Future clinical trials are expected to contribute more objective data concerning the IV branches. Due to the relative changes in vascular position during dissection, the relevant data warrant improvement. Conclusions: The lumbar IVs are an important part of the anatomical structure of the intervertebral foramina. Adequate knowledge of the IV may be of clinical importance to physicians performing transforaminal epidural steroid injection. Key words: Clinical anatomy, intervertebral veins, lumbar vertebra, Kambin’s triangle, safe triangle, intervertebral foramina, vertebral venous system, inadvertent injection, transforaminal epidural steroid injection

Homozygous familial hypercholesterolemia developed into severe cardiovascular consequences early. Untreated HoFH usually cannot survive over 30 years old. Acute coronary syndrome(ACS) caused by plaque rupture is one of the main causes of death in HoFH. As the highest resolution intravascular imaging technique, optical coherence tomography(OCT) can clearly show the thickness and structural characteristics of atherosclerotic plaque caps. In this study, a Chinese male HoFH received percutaneous coronary intervention for unstable angina. After analyzed his genetic and follow-up data, OCT was performed during interventional therapy. Multiple lipid rich plaques accompanied with inflammatory cell infiltration and a thin-cap fibroatheroma(TCFA) were noted, which reflected the vulnerability of plaques. The utility of OCT had certain guiding significance for strategy of interventional therapy and the long-term drug management. And this case suggested that it was important to undergo OCT examination for patients with HoFH who required percutaneous coronary intervention.

Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased Bacteroidetes/Firmicutes phylum ratio, as well as selectively promoting some probiotic populations, including Lactobacillales. Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.

A dissection-based study of 10 embalmed human cadavers.The purpose of this study was to describe the extraforaminal ligaments in the exit regions of the T1-T12 intervertebral foramina and to discuss their possible clinical significance.The ligaments at the lumbar intervertebral foramina have been well studied. However, detailed descriptions of the extraforaminal ligaments at the T1-T12 levels are lacking.Two hundred forty T1-T12 intervertebral foramina from 10 embalmed cadavers were studied. The presence of the ligament was noted. The quantity, morphology, distributions, proximal attachments, distal attachments, and spatial orientations of the extraforaminal ligaments in the exit regions of the T1-T12 intervertebral foramina were examined. The length, width, diameter, and thickness of the ligaments were measured with digital calipers by three independent investigators.A total of 564 extraforaminal ligaments were identified in the 229 intervertebral foramina; no ligaments were found in the other 11 intervertebral foramina, resulting in an occurrence rate of extraforaminal ligaments of 95.42%. One hundred thirty-six (24.11%) of the extraforaminal ligaments were radiating ligaments, and 428 (75.89%) were transforaminal ligaments. Radiating ligaments had a tendency to be abundant at T1 and T9-T12 and sparse at T2-T8. There were 245 (43.44%) ligaments at the anterior aspect of the exit regions of the intervertebral foramina, 225 (39.89%) ligaments at the posterior aspect, 64 (11.35%) ligaments at the inferior aspect, and 30 (5.32%) ligaments at the superior aspect.In the exit region of thoracic intervertebral foramina, there are two types of extraforaminal ligaments. They may serve as a protective mechanism against traction and play a role in the positioning of the nerves in the intervertebral foramen. Transforaminal ligaments may be an underlying cause of rib or chest pain after thoracic fracture and may be of clinical importance to surgeons.N/A.

Background: Sarcomas (SARCs) are rare malignant tumors with poor prognosis. Increasing evidence has suggested that aberrant alternative splicing (AS) is strongly associated with tumor initiation and progression. We considered whether survival-related AS events might serve as prognosis predictors and underlying targeted molecules in SARC treatment. Methods: RNA-Seq data of the SARC cohort were downloaded from The Cancer Genome Atlas (TCGA) database. Survival-related AS events were selected by univariate and multivariate Cox regression analyses. Metascape was used for constructing a gene interaction network and performing functional enrichment analysis. Then, prognosis predictors were established based on statistically significant survival-related AS events and evaluated by receiver operator characteristic (ROC) curve analysis. Finally, the potential regulatory network was analyzed via Pearson's correlation between survival-related AS events and splicing factors (SFs). Results: A total of 3,610 AS events and 2,291 genes were found to be prognosis-related in 261 SARC samples. The focal adhesion pathway was identified as the most critical molecular mechanism corresponding to poor prognosis. Notably, several prognosis predictors based on survival-related AS events showed excellent performance in prognosis prediction. The area under the curve of the ROC of the risk score was 0.85 in the integrated predictor. The splicing network proved complicated regulation between prognosis-related SFs and AS events. Also, driver gene mutations were significantly associated with AS in SARC patients. Conclusions: Survival-related AS events may become ideal indictors for the prognosis prediction of SARCs. Corresponding splicing regulatory mechanisms are worth further exploration.

In order to improve the safety and reliability of capacitive equipment developed online monitoring system of capacitive equipment dielectric loss. Introduce the structure and function of the software, based on the B/S skeleton, uses the modular design, improve the readability and scalability. Detail the design of communication module, parameter setting module, data acquisition and processing module, the user management module, database systems, etc. The entire process is given. By testing the monitoring software work is stable, reliable, long-term continuous and effective monitoring capacitive equipment various insulation data, can satisfy the requirements on site application.

In order to complete various treatment and control besides the real-time data acquisition, design an integrated digital monitoring unit based on DSP + CPLD and high-precision integration of AID, which gathered signal conditioning, data collecting, CPU controlling, algorithm processing, data storage and CAN bus communication in one. Simple introduce the overall structure of the system, use “zero magnetic flow and micro-current sensor” to gather signal, exposit the concrete realization method of high-speed AID converter and DSP interface circuit, phase-locked double frequency circuit and others communication interface circuit. Adopt good FFT to get dielectric loss's tgδ based on DSP, at same time software implementation process is described. After testing and field using, the monitoring unit perform reliably, stable, the monitor effect is good.