foreword　 　

At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT). Chimeric antigen receptor (CAR) and engineered T cell receptor (TCR) are the main adoptive T cell immunotherapy in recent years. TCR engineering T cells express tumor antigen-specific receptors, and their α chains and β chains are produced by high-quality and high-affinity antigen-specific T cell clones.

TCR molecule belongs to a superfamily of immunoglobulin, which consists of two covalently bound polymorphic subunits, each of which is antigen-specific, and they are related to at least four different types of signal transduction chains. In order to activate T cells, there must be interaction between TCR and MHC.

The interaction between TCRs and pMHC(peptide-MHC) determines the fate of immature thymocytes, which is very important for the survival of naive T cells. Therefore, TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells. TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize tumor-specific antigens on the surface. This makes TCR-T cells more effective in tumor treatment.

At present, some new technologies and tools are being applied to TCR-T, which is helpful to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.

　 Comparison between CAR-T and TCR-T

In ACT therapy, TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CAR contains single chain antibody targeting tumor antigen, transmembrane domain and intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and CAR can bind untreated tumor surface antigens without MHC treatment.

The first generation of CAR-T cells showed limited expansion and relatively short persistence, and the "second generation" CAR-T added costimulatory receptors CD28, 4-1BB/CD137 and OX40. These costimulatory receptors are added to the CD3ζ domain of CAR-T cells, thus promoting a more powerful and lasting T cell response. The third generation CARs combines two co-stimulatory signals (CD28 and 4-1BB) at the same time, which has better amplification and longer persistence than the second generation CARs.

On the contrary, TCR is an α/β heterodimer that binds to MHC antigen complex. Compared with TCR, CARs has some disadvantages in identifying tumor antigens, such as extratumoral toxicity. Compared with CARs, TCRs has some structural advantages in T cell-based therapy, such as more subunits (10: 1) in its receptor structure, more tyrosine-based activation motifs (ITAMs) in immune receptors (10: 3), less dependence on antigens (1: 100), and more costimulatory receptors (CD3, CD4, CD28, etc.). TCR with a low MHC affinity range (104-106M-1) can effectively activate T cells, whereas CARs needs a higher affinity range (106-109M-1).

Therefore, CAR-mediated cytotoxicity depends on higher density of cell surface antigens. In addition, T-cell/antigen interaction IS initiated in the structure of immune synapse (IS), in which TCR presents an annular region with peripheral LFA-1 adhesion, while CAR presents a diffuse LFA-1 distribution without annular region. Therefore, TCR-IS is slower but lasts longer than CAR-IS. At the same time, CAR-T cells show faster killing function and migrate to the next tumor target (serial killing), which is in sharp contrast to TCR-T cells’ prolonged signal transduction and killing time.

Recombination TCRs 　

TCR is one of the most complex receptors in human body. It contains six different receptor subunits, which have a very wide range of functions in T cells. The change of TCR of tumor infiltrating lymphocytes (TILs) significantly affects tumor-specific T cells. Among them, the change of TCR is helpful to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.

TCR engineering of TIL is one of the best treatment methods for tumors. TCR consists of α chain and β chain bound to peptide -MHC ligand, signal subunits (,γ and δ) of CD3 complex and CD3ζ homodimer. Except CD3ζ, all subunits have extracellular immunoglobulin (Ig) domain. Based on these structures, new technologies using engineering TCR include ImmTAC, TRuCs and TAC.

Immune mobilization monoclonal t cell receptor (ImmTAC)

ImmTACs is designed using engineered, soluble and affinity-enhanced monoclonal TCRs(mTCRs). ImmTACs is basically a fusion protein, which combines the engineering TCR targeting system and single chain antibody fragment (scFv) effector function. In the construction of ImmTACs, TCR can recognize peptides from intracellular targets presented by human leukocyte antigen (HLA).

ImmTAC specifically targets HLA- peptide complexes on the surface of tumor cells, and promotes T cell-mediated effector function through the interaction between scFv antibody fragments and CD3. ImmTAC also activates CD8+T cells in a dose-dependent manner, and can effectively redirect and activate CD8+ and CD4+ cells. ImmTAC shows multifunctional reaction by secreting various cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β and IFN-γ inducible protein 10.

In addition, selecting the appropriate target antigen is the key to ImmTACs, and mass spectrometry and MHC polymer technology are helpful to identify the appropriate antigen. It is worth noting that TCR engineered T cells also show unexpected targeted toxicity. Generally speaking, ImmTACs has been proved to enhance the anti-tumor response of TCR-T cells, but its safety needs further study.

T cell receptor fusion structure

T cell receptor fusion structure (TRuCs), an antibody binding domain fused with T cell receptor subunits, is designed to effectively recognize tumor surface antigens. TRuCs is composed of specific antibodies targeting tumor-associated antigens fused to the extracellular N- terminal of five TCR subunits (TCRα, TCRβ, CD3, CD3γ and CD3δ), which provides new targeting specificity and HLA-independent target cell clearance for engineered T cells and can be activated by corresponding target cells.

Compared with the second generation of CAR-T cells, this method shows better anti-tumor effect. In addition, TRuCs dominates all the signal mechanisms of TCR complex, while CARs only uses the limited signal of the isolated intracellular segment of CD3ζ.

T cell antigen coupling agent (TAC)

T cell antigen coupling agent is another engineered TCR cell, which can induce more effective anti-tumor response and reduce toxicity in an MHC-independent way. TAC chimeric protein can form TCR/CD3 complex and get more T cell responses by binding to CD3 domain.

The activity of TAC receptor is closely related to the selection of CD3 binding domain. For example, a single chain antibody from OKT3(muromonab-CD3) has lower cytokine production and cytotoxicity compared with UCHT1, which may lead to substantially different functional results. Compared with the second generation of CARs, T cells engineered with TAC gene are not only beneficial to the greater infiltration in solid tumors after adoption, but also reduce the expansion and extratumoral toxicity of T cells in healthy tissues expressing antigens.

Workflow of TCR-T cell therapy 　

In order to isolate therapeutic TCR, antigen-specific T cells must be isolated from the blood of patients or healthy blood donors and amplified in vitro with specific peptide antigens and cytokines (such as IL-2 and IL-15). This process needs to determine the specific tumor-related peptide targets that can be safely targeted to patients in advance. After selecting the target antigen, different methods can be used to screen TCR with the required high affinity and tumor specificity. Pre-clinical safety testing is also necessary to ensure the minimum off-target effect and cross-reactivity of isolated high affinity TCR. Viral vectors are usually used to genetically modify autologous patient T cells to express the proven therapeutic TCR, and then transfuse it back into patients.

Determine the target antigen

Melanoma antigen 1(MART-1) recognized by T cells is the first tumor-related antigen targeted in TCR-T clinical trials. After this breakthrough, TCR-T therapies for various tumor antigens have been developed, including TCR-T therapies for MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1 and viral peptides derived from HPV and EBV. Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and it has achieved success in the treatment of synovial sarcoma, with an objective effective rate of 67%.

The ideal TCR-T target antigen shows the following characteristics: (1) the ability to induce immune response; (2) It is related to driving tumor phenotype (such as oncogene) to reduce the risk of antigen loss and tumor immune escape; And (3) expression on tumor stem cells to promote permanent tumor eradication.

Identification method of tumor-associated antigen

High-resolution mass spectrometry (MS) has been proved to be the most powerful Qualcomm method to promote the direct identification of HLA-I binding peptides from tumor cells. In this method, HLA-I/ peptide complexes are separated from tumor tissues or cell lines by immunoprecipitation (IP), and then the binding peptide antigens are separated from HLA-I molecules and antibodies for IP by fully washing and applying acidic elution buffer. This strategy allows each tumor sample to identify thousands of validated peptide targets, and has been used to identify HLA-I ligands of glioblastoma (GB), melanoma, renal cell carcinoma (RCC) and colorectal cancer (CRC).

Identification method of new tumor antigen

Although MS-based technology can be used to identify new antigens, it is more difficult to identify them, especially for tumor samples with limited size, because of their relatively low abundance and limited sensitivity of MS. However, the development of new generation sequencing technology is helpful to identify and locate such tumor targets. All-exon DNA sequencing, combined with computational prediction algorithm, allows to identify specific genetic changes in cancer cells, which can produce mutant peptides and present them on tumor HLA-I molecules.

All somatic mutant genes can be analyzed by computer to predict the potential high affinity epitopes that may bind to HLA-I molecules of patients, so as to be recognized by T cells. With the use of large MS elution peptide database, HLA-I peptide binding prediction algorithm is constantly updated and improved, and other prediction algorithms try to consider biological variables related to the complexity of intracellular processes.

Another commonly used method is tumor RNA sequencing, which allows the selection of new antigens with the highest transcriptional expression. It is worth noting that although these prediction methods usually show very good accuracy in identifying presented and highly immunogenic new antigens, the number of new antigen targets they usually predict is 1 to 2 orders of magnitude higher than the actual number of real targets.

Discovering new antigens by trogocytosis is a new method in recent years. Trogocytosis is a biological phenomenon in the process of cell combination, in which cells share and transfer membrane and membrane-related proteins. Li et al. found that T cell membrane proteins were specifically transferred to tumor target cells, which presented homologous HLA-I/ peptide complexes. Using these T cell-target cell interactions, they created a new antigen discovery system by incubating T cells expressing orphan TCR with homologous target cells. By transferring fluorescent markers from T cells to target cells, this method can isolate these target cells and sequence homologous TCR ligands, thus establishing a new antigen library.

Isolation of tumor-specific T cells and TCR

Using HLA-I polymer, single cell TCR sequencing or antigen-negative humanized mice, tumor-reactive T cells and TCR can be identified from autologous, allogeneic or xenogeneic cell banks.

Using HLA-I multimer method, antigen-specific CD8+T cells can be directly separated by multimer staining and flow cytometry. Before isolating the paired full-length TCR sequences, these polyclonal T cells were tested for homologous peptide recognition and anti-tumor function. TCR with high affinity and specificity can be obtained by using a highly sensitive PCR-based single cell TCR analysis method (TCR-SCAN).

Another method uses humanized mouse TCR gene bank, which will not cause T cell clone deletion or tolerance in humans. Therefore, Li et al. used the whole human TCRα/β gene locus and chimeric HLA-A2 transgene to construct transgenic mice to isolate human TCR against human TAA.

Single cell sequencing method represents a more promising method to isolate tumor-specific TCR coding genes by Qualcomm method. Using RNA bait libraries targeting each individual V and J element in TCRα and TCRβ loci, TCR coding genomic elements can be selectively isolated from excised genomic DNA(gDNA) fragments for subsequent paired terminal deep sequencing. This makes it possible to identify antigen-specific TCR from human materials or oligoclonal T cell populations of TCR humanized mice.

Infantile T cells can also be used as TCR sources for TCR-T therapy. TAA and new antigen-specific T cells can be derived and amplified from low-frequency precursors in peripheral blood of cancer patients, and can be reinfused or used as the source of antigen-specific TCR. Because cancer patients usually show immunosuppression or dominant T cell tolerance, the original sequence of HLA-I matched healthy donors also represents a reliable source, because it has a huge diversity of TCR sequences, and theoretically T cells have any antigen specificity, including new tumor antigens. A Qualcomm-quantity technology platform has been developed to find the original sequence, so as to quickly and effectively identify the rare but valuable TCR for personalized adoptive T cell therapy.

Cloning of TCR

Most TCR-based gene therapy methods rely on in vitro transduction of T cells with viral vectors, and adenovirus is the earliest vector used for gene therapy. However, due to their inability to integrate transgenes into the host genome, TCR expression will be lost during T cell proliferation. In addition, the immune genetic characteristics of adenovirus also limit its application as a gene therapy vector. In contrast, retroviruses show greater prospects as gene transfer vectors, because they can infect a variety of cells and have the ability to insert transgenes into the host genome, thus making the ectopic TCRα/β chain stably expressed.

Retroviral vectors derived from γ -retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This method has been used to transfer various genes, including suicide gene, TCR and CARs. The main disadvantage is that they cannot transduce non-proliferative target cells, which excludes the application of resting T cells in TCR-T therapy. In addition, retrovirus insertion mutation may cause potential side effects.

Recently, lentiviral vectors (LV) have attracted more attention as gene transfer vectors, because they can transfer genes into mitotic and non-splinter cell. Various techniques, such as Golden Gate cloning and LR cloning, are usually used to construct a vector for inserting TCRα/β gene.

Adeno-associated virus (AAV) is another widely used virus vector. Compared with adenovirus vector, AAV has lower immunogenicity and wider cell tropism, so it has been widely used in tumor gene therapy. In order to promote the integration of transgenes, people have developed self-complementary AAV vector (scAAV) to make AAV independent of the complementary strand synthesis of host cells. scAAV is more effective than traditional AAV in preclinical model.

At the same time, some non-viral gene editing methods have also been developed. MRNA electroporation has been proved to achieve transient expression of TCR and CAR, thus minimizing the risk of persistent virus components. Clinical data show that both TCR-T and CAR T cells modified by mRNA are feasible and safe, and there is no obvious evidence that they have non-targeted toxicity to normal tissues. However, the lack of continuous TCR expression may limit the curative effect and require repeated infusion. In addition, the non-viral sleeping beauty retrotransposon system is also used for the transduction of TCR and CARs.

Gene editing can insert large gene fragments into target cells specifically and efficiently through homologous directional repair (HDR). TCR-T cells developed by CRISPR/CAS9 have been proved to specifically recognize tumor antigens in vitro and induce a productive anti-tumor response in vivo.

Verification method of TCR

After TCR cloning, extensive preclinical verification is needed to prove the specificity and safety of engineered TCR-T cells. Verification includes evaluating the affinity of TCR by titration of homologous peptide antigens and measuring the killing effect of a group of HLA-I matched tumor cell lines. If there is no such tumor cell line, the target cells can transductively express related antigens and related HLA-I molecules. The new antigen can also be expressed in autologous antigen presenting cells to evaluate the antigen reactivity of TCR.

The safety test includes testing the ability of candidate TCR-T to identify HLA-I matching primary tissues, so as to ensure that there is no normal tissue as the target, which may lead to non-targeted toxicity. In at least two clinical trials of TCR-T cell therapy, there was a cross reaction between normal brain cells and heart cells, which led to the death of patients. These test results emphasize the importance of extensive safety tests before TCR enters clinical trials.

Safety of TCR-T 　

The ACT of TCR-T cells showed high tumor killing, but some serious adverse events also appeared in some clinical studies. It is very important to optimize TCR affinity in engineered T cells, and receptor affinity can determine the safety and effectiveness of T cell therapy. In terms of curative effect, affinity TCR interaction is enough to activate T cells, but strong affinity is needed to maintain the expansion of T cells.

In phase I/II ACT clinical trials, engineered T cells with low affinity show safer characteristics, but their anti-tumor response is weak. By identifying the TCR-pMHC interaction of T cells, engineered T cells can be divided into high affinity type and low affinity type. In addition, some technologies have been developed to improve the safety of TCR-T.

The safety switch mechanism based on engineered T cells is an attractive strategy. Thymidine kinase gene from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.

Although HSV-TK shows safety in cell-based immunotherapy, it is necessary to introduce phosphorylated nucleoside analogues. Another safer induced T cell safety switch is called inducible caspase-9(iC9). IC9 is a modified human FK binding protein, which can be activated by a small molecule compound AP1903, and this process depends on the mitochondrial apoptosis pathway.

The immunogenicity of iC9 suicide gene is low, and the immune response to transgenic cells is reduced. IC9-based safety switch has been proved to be more potential for cell therapy than previous suicide genes.

Clinical status of TCR-T cell therapy 　

As of August 9, 2021, there are 175 studies using TCR-T therapy in ClinicalTrials, 71 of which are specific TCR for specific TAA or new antigen, and 32 studies have been completed. NY-ESO-1 is the most common targeted antigen, which is expressed in many cancers, including myeloma and melanoma. Other tumor testis-associated antigens, such as PRAME and MAGE proteins, melanoma differentiation antigens MART-1 and gp100, and recent cancer drivers, such as WT1, KRAS and TP53, are also popular TCR-T targets.　 　 　 　 　 　 　 　 　 　 　

　　　　

A total of 83 sponsors/collaborators initiated or participated in the research of TCR-T cell therapy, including the National Institutes of Health (NIH), government organizations, industries and universities/academic institutions. At present, the National Cancer Institute (NCI) has supported 53 TCR-T projects, accounting for 20% of all ongoing projects.

Among the 29 pharmaceutical companies developing TCR-T therapy, GlaxoSmithKline and Adaptimunime initiated the most clinical trials, with 11 and 7 respectively. Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV)-16 E7 protein in the treatment of metastatic human papillomavirus-related epithelial cancer was reported. In this study, 6 of the 12 patients who received treatment showed objective clinical response and observed steady tumor regression. This is a landmark clinical trial of TCR-T cell therapy, which proves that targeted virus antigen has good clinical effect on patients with virus-related cancer. Other viral antigens explored as TCR targets include HPV-E6 protein, antigens from Epstein-Barr virus (EBV) and human endogenous retrovirus (HERV) targets, such as Herv-E.

MART-1 and NY-ESO-1 TCR-T therapy targeting TAAs also showed clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer. The total effective rate (ORR) of TCR-T clinical trial is between 0 and 60%. It is worth noting that most of these TCR-T clinical trials only enrolled a small number of patients (2 to 25), so ORR may not be statistically accurate. Therefore, larger-scale phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.

Challenges and potential solutions of TCR-T cell therapy 　

Although immunotherapy based on TCR-T cells has shown certain clinical efficacy in most patients receiving treatment, it still faces many challenges in many fields. These challenges include: (1) Immunotoxicity caused by targeting normal tissues; (2) The expression of TCR in engineered T cells is insufficient or transient; (3)T cell exhaustion and dysfunction; (4) tumor immune escape, and (5) most cancer patients lack effective tumor-specific antigens as targets. Overcoming these challenges will be the key to greater clinical success in the future.　 　 　 　 　 　　

　 　 　 　 　 　

Discovery of new targets

At present, the target of peptide antigen for effective and safe immunotherapy of TCR-T is very limited. At present, most of the targets used are TAA. Although it is up-regulated in tumor tissues, it still maintains a low level of expression in normal tissues, which may lead to autoimmune toxicity. Therefore, the new antigen seems to be the safest target for TCR-T cancer treatment. However, the main challenges of developing new antigens in TCR-T clinic include: (1) the mutation of new antigens is individualized to a great extent, and there are differences among cancer patients, so it is difficult to develop widely used immunotherapy products; (2) The expression of new antigens in tumor tissues is often heterogeneous.

Nevertheless, recent reports have highlighted the emergence of new immunogenic antigens widely shared by tumor cells, including mutated KRAS and TP53. Many other studies have also demonstrated the immunogenicity of shared new antigens that can be used to generate potential therapeutic tumor-specific TCR. With the development of next generation sequencing technology, especially single cell DNA sequencing, transcriptome sequencing and mature in vitro verification methods, TCR-T immunotherapy targeting personalized new antigens may become a popular cancer treatment method in the next few years. In addition, the emerging TAA class, such as carcinoembryonic antigen, may also constitute a feasible target for the future development of TCR-T.

Maximize therapeutic TCR expression

The correct pairing of transgenic α and β chains is one of the main challenges that hinder the development of TCR-T cells. Since each transduced T cell includes two endogenous TCR chains and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences. Another related problem is that improper α/β chain TCR pairing will compete for CD3 complex, thus reducing the surface expression and signal transduction of therapeutic TCR.

There are several methods to properly pair the transduced TCR chains, including: (1) the constant region of partially murine TCR; (2) adding cysteine residues to promote the introduction of disulfide bonds in TCR chains; (3) changing the secondary structure of the constant region of endogenous TCR; (4) adding a signal domain to the intracellular part transduced with TCR; (5) Introducing TCR-α/β chain into substitute effector cells or constructing single-stranded TCR.

Methods to enhance the expression of therapeutic TCR include: (1) codon optimization of TCR-α and TCR-β chain transgene, and (2) changing the configuration of TCR-α/TCR-β vector to optimize expression.

Reduce adverse events

Usually, targeting non-tumor toxicity is the main key obstacle of TAA, and this risk urges researchers to study common new antigens more carefully. At present, several oncogene hot spot mutations are being studied as potential TCR targets, such as phosphoinositide -3- kinase (PI3K), KRAS and TP53. In addition, genetically engineered TCR-T cells with suicide genes are an important safety measure. Obviously, it is very important to develop reliable, identifiable, personalized, highly specific and immunogenic tumor antigen targets to reduce adverse events related to TCR-T cell therapy.

Graft-versus-host disease of allogeneic T cells

Using allogeneic T cells is a very promising scheme, which can overcome manufacturing problems, patient-related immune cell defects and treatment delays. In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced allogeneic reactive lymphocytes and rejection of engineered lymphocytes by host immune system.

The deletion of endogenous TCR gene, HLA-I locus or CD52 molecule is one of the strategies to avoid the failure of TCR-T transplantation, which can be achieved by many methods, such as gene editing or using siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.

　 summarize

In recent years, engineered T cells have shown excellent curative effect in the treatment of hematological tumors. TCR regulation is very important for T cell reactivation, immune response and its clinical effect on foreign antigens. TCR-T cells have incomparable advantages over CAR-T cells, and show great potential in preclinical and clinical research.

However, there are still several key challenges to improve the anti-tumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCR, how to identify the common tumor-specific antigen and TCR in the patient population, and how to regulate the expression of TCR and achieve the best function. The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.

References:

1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol.　2021; 12: 658753.

2. Evolution of CD8+　T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells.　2021 Sep; 10(9): 2379.

　　
The People’s Liberation Army (PLA) has accumulated rich operational experience after a year and a half of fighting, especially since it turned to a strategic offensive. Mao Zedong made a systematic and scientific summary of these experiences. From December 25th to 28th, 1947, the Central Committee of the Communist Party of China held an enlarged meeting in Yangjiagou, Mizhi County, northern Shaanxi, at which Mao Zedong made a report on "Current Situation and Our Tasks". In this report, the famous "Ten Military Principles" were put forward. The main contents are: fight scattered and isolated enemies first, and then fight concentrated and powerful enemies; Take small cities, medium-sized cities and vast villages first, and then take big cities; The main goal is to annihilate the enemy’s effective forces, not to preserve or seize cities and places; Concentrate absolute superior forces in each battle, surround the enemy on all sides, and strive to wipe out the enemy, so as not to escape the net; Don’t fight unprepared battles, don’t fight uncertain battles; Carry forward the style of fighting bravely, not afraid of sacrifice, not afraid of fatigue and continuous fighting; Strive to annihilate the enemy in the movement, while paying attention to position attack tactics; On the issue of siege, all enemy strongholds and cities with weak defenses are firmly seized, all enemy strongholds and city cameras with medium defenses are seized, and all enemy strongholds and cities with strong defenses are seized when conditions are ripe; Replenish ourselves by capturing all the enemy’s weapons and most of their personnel. The source of our army’s manpower and material resources is mainly at the front. Be good at using the gap between the two campaigns to rest and train troops.
The full text of the top ten military principles is 593 words. In incisive language, Mao Zedong made the strategic and tactical principles of the People’s Liberation Army clear, which is both easy to understand and easy to remember. It is completely different from his opponent Chiang Kai-shek’s long speech. In the later stage of strategic decisive battle and strategic pursuit, the People’s Liberation Army flexibly applied ten military principles, further enriched and developed this theoretical treasure, and finally relied on this treasure to completely defeat eight million Kuomintang troops.
From the sixteen-character formula to the ten military principles, it marks the improvement of the strategic and tactical theory of the people’s army, and marks that Mao Zedong’s military thought reached an unprecedented height during the War of Liberation. Therefore, it is not difficult for people to understand why Chiang Kai-shek, who was an excellent cadet studying in the Japanese military academy and the president of the Whampoa Military Academy, was finally defeated by Mao Zedong, who had never been to a military academy for a day. Batman, a British military expert, commented: "Mao Zedong is an era figure who holds all the keys to unlock the military mysteries of this era." (Xinhua News Agency)

Editor: Cao Jin

Since the Eighth Five-Year Plan, the Tobacco Monopoly Bureau of Hanshou County, Changde has actively explored and innovated the ways, contents and forms of popularizing the law, carried out in-depth publicity for consumers, retailers and minors, and promoted the effectiveness of tobacco publicity and education under the rule of law.

Explain the law to consumers and improve the awareness of consumer rights protection.

(The staff of Hanshou County Bureau introduces the identification skills of true and false cigarettes to consumers)

"This is a fake cigarette? What do you think is no different from real cigarettes? How can you tell? "

As soon as the publicity booth of Hanshou Tobacco Monopoly Bureau was set up, enthusiastic people gathered around to ask questions. The staff of the county bureau gave patient answers to the preaching, while making detailed comparisons with the real and fake cigarette exhibits, and carefully answered the knowledge points of identification of real and fake cigarettes for the onlookers by means of "you ask me and answer me".

Over the years, Hanshou County Bureau has taken various effective forms to carry out regular publicity on legal popularization. In 2024 alone, it has held similar legal popularization activities for more than 10 times, distributed more than 300 tobacco monopoly legal popularization brochures printed by the county bureau, such as "Quick Identification of True and False Cigarettes", "How much do you know about the harm of fake cigarettes? Stay away from new disguised drugs-"E-cigarettes on the top ",and printed QR codes on brochures and exhibition boards to realize the popularization and dissemination of legal popularization audiences.

Send it to French retailers to improve the standard operation level.

(The staff of Hanshou County Bureau gives publicity to retailers)

"Grandma Liu, you are going to be demolished here. I have prepared some materials to facilitate your application!" Xiao Xie, a monopoly worker of the county bureau, walked into Grandma Liu’s shop and said enthusiastically.

Hanshou County Bureau earnestly implements the responsibility system of "whoever enforces the law will popularize it", integrates the popularization of law into market inspection and daily visits, turns static popularization of law into dynamic popularization of law, and turns the law on paper into a sensible law. The county bureau integrates law enforcement with service, and inspectors and city managers walk into cigarette retailers’ shops to carry out face-to-face publicity and one-on-one explanation on the legal issues involved in the standardized operation of retailers, so as to popularize the law in real time and accurately. To explain the case, publicize the tobacco monopoly law and its implementation regulations, help retailers to calculate the "legal account" and "economic account", warn retailers with real cases in their jurisdictions, and advise retailers to operate in good faith and abide by the law, and not to sell cigarettes and e-cigarettes to minors. Using online forms such as WeChat group and Tencent conference live class, the common illegal acts of tobacco monopoly law are interpreted for retailers in easy-to-understand language, so that retailers can understand the law and know awe, keep the "high-voltage line" of standardized cigarette operation, enhance the pertinence and effectiveness of law popularization, and maintain the market order of standardized cigarette operation.

Popularize law into campus and care for students’ healthy growth

(Hanshou County Bureau staff carry out activities of popularizing law into campus)

Hanshou Tobacco Monopoly Bureau strengthens the propaganda of tobacco hazards, makes great efforts to build a smoke-free campus environment, and forms the joint efforts of the whole society to protect the healthy growth of minors. Union County Education Bureau and Market Supervision Administration went into primary and secondary schools to carry out legal publicity activities with the theme of "protecting the future with children". By playing warning videos and explaining in kind, the staff preached to primary and secondary school students the dangers of traditional tobacco products, e-cigarettes and new illegal e-cigarettes such as "milk tea cups" and "coke cans", and resolutely resisted the temptation of tobacco. Combined with the recent popular "cigarette card" game among primary school students, the potential harm of "cigarette card" is emphasized, and students are warned not to be curious, not to follow the trend, not to be contaminated with tobacco, to stay away from Internet cafes, bars, KTV and other entertainment places that are not suitable for minors to enter, and to resolutely say "no" to cigarettes, e-cigarettes, etc. Widely publicize and publish the telephone number of complaints about selling cigarettes to minors, encourage teachers and students to actively report relevant information clues, and guide all sectors of society to protect the physical and mental health of minors.

In the next step, Hanshou County Bureau will normalize, institutionalize and carry out long-term publicity of law popularization, promote the effectiveness of the eighth five-year plan, and hand over socially satisfactory answers.

(Image courtesy of Cao Libin Guan)

The above contents are promotional information, and the contents involved do not represent the views of this website, and do not constitute investment suggestions or consumption suggestions.

　　Cctv newsOn the evening of 25th local time, a snowstorm started from southern Wyoming and headed for central Colorado. At present, the snowfall has exceeded 30cm, and the gust speed has reached 72km/h.. Up to now, this winter storm has caused hundreds of flights to be cancelled at Denver International Airport in Colorado, and more than 1,000 passengers stayed overnight at the airport. Another interstate highway was closed due to snowstorm.

　　According to the National Weather Service, the storm will then cross Nebraska and Kansas eastward, bringing 15.2~30.5 cm of snowfall to the areas along the way. At the same time, the National Weather Service also said that another snowstorm, which started on the night of 26th local time, is expected to bring heavy snow to parts of the northwest Pacific coast and reach the snowstorm level in Oregon and northern California. As two snowstorms occurred during Thanksgiving, it is expected to disrupt the plans of tens of millions of Americans to travel during the Thanksgiving holiday. (CCTV reporter Xu Wei)

　　According to reports, on 26th, US President Trump said in an interview that the US and China have exchanged views on economic and trade issues in the past few days, and the two sides may reach an agreement during the G20 summit. If no agreement can be reached, he will impose additional tariffs on China. At today’s (27th) regular press conference of China’s Foreign Ministry, Geng Shuang, a spokesman, said that the US threat could not scare the people of China, and a trade war would harm others and harm themselves, which could not solve the problem at all.

　　Foreign Ministry Spokesperson Geng Shuang:China has always advocated resolving Sino-US economic and trade frictions through dialogue and consultation, but at the same time it will firmly defend its legitimate rights and interests. The US threatened to impose additional tariffs on China, which did not scare the people of China. Chinese believes in no evil and is not afraid of pressure. He never buys it. I would like to advise the US side once again that a trade war and tariff increase will not solve the problem at all. I hope that the US side will listen carefully to the opposition of different groups and the general public in the United States to trade wars and tariff increases in recent days, and also listen carefully to the resistance of the international community to unilateralism, protectionism and bullying during the G20 summit.

　　Geng Shuang expressed the hope that the US and China will move in the same direction, take care of each other’s reasonable concerns on the basis of mutual respect, equality and mutual benefit, and strive for mutual benefit and win-win. This is not only in the interests of China and the United States and the two peoples, but also the general expectation of the international community.

Nowadays, the first thing for consumers to buy a car is to see whether this car is rich in configuration, and it is no exception to nature. Let’s look down with Xiaobian.

Let’s take a look at Komik’s appearance first. Komuk’s front face looks very clean and refreshing as a whole, and the air intake grille uses a straight waterfall shape, which is very recognizable. Coupled with fashionable headlights, it has a great visual impact. The car is equipped with LED daytime running lights, automatic opening and closing, delayed closing and so on. Coming to the side of the car body, the size of the car body is 4409 mm * 1781 mm * 1606 mm. The car adopts fashionable and dynamic lines, and the side circumference looks very sharp. With large-sized thick-walled tires, the shape is quite simple. In the design of the rear end, the rear end looks very comfortable, the taillights look very simple, and with the unique exhaust pipe, it is very simple and fashionable.

Coming to Komuk, Komuk’s interior looks solid and the visual effect is very good. The car looks very good outside the steering wheel, made of plastic, and looks a little more unique. Let’s take a look at the central control. The design of the center console is reasonable, which makes the interior design quite layered and conforms to the mainstream aesthetics. The dashboard and seats are equally eye-catching, and the car is equipped with a stylish dashboard with excellent display effect. The car adopts imitation leather seats, which are wrapped in place, with exquisite materials and comfortable ride.

Komik is matched with an automatic manual transmission (AT) gearbox, with a maximum power of 80KW and a maximum torque of 141N.m, with good power performance.

The car is equipped with driving mode selection, remote control key, rear wiper, engine start and stop, traction control (ASR/TCS, etc.) and other configurations, which greatly improves the convenience of using the car.

The car introduced today is remarkable in terms of space, configuration and power, and home travel is also a good helper. If you are interested, you might as well experience it.

　　Recently, the General Office of the Guangdong Provincial Committee of the Communist Party of China and the General Office of the Guangdong Provincial People’s Government issued the Notice on Doing a Good Job during the Spring Festival of New Year’s Day in 2024, requiring all localities and departments to conscientiously implement it. The full text is as follows.

　　The year 2024 is the 75th anniversary of the founding of People’s Republic of China (PRC), so it is very important to do all the work well during New Year’s Day and Spring Festival. All localities and departments in the province should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the New Era, fully implement the spirit of the 20th National Congress of the Communist Party of China and the Second Plenary Session of the 20th Central Committee, conscientiously implement the requirements of the Notice of the General Office of the General Office of the Central Committee of the CPC and the State Council on Doing a Good Job during the Spring Festival of New Year’s Day in 2024, implement the "1310" specific deployment of the provincial party committee, and earnestly do a good job in the work during the festival from the political height of adhering to the "two establishment" and "two maintenance" to ensure that the people spend a happy and peaceful time.

　　First, increase assistance and care for people in need.Hold fast to the bottom line of basic livelihood security, and pay basic pension, unemployment insurance, subsistence allowance, destitute support and basic living allowance for orphans (in fact, there is no one to raise children) on time and in full. Where conditions permit, the relief funds during the "two festivals" can be paid in advance or a one-time living allowance can be added. We will do a good job in helping the needy people in send warm, increase visits, condolences and assistance to the homeless and beggars, the disabled, all kinds of children in distress and other special hardship groups, strive to solve the production and life problems of the urban and rural needy people, and send the care and warmth of the party and the government to the hearts of the needy people. In-depth visits to party member, old party member, veteran cadres and retired military cadres, Red Army veterans, old demobilized soldiers, disabled soldiers, families of martyrs, etc. Solidly carry out the special campaign to eradicate wage arrears in winter, strengthen the classification, verification and disposal of clues reflecting the platform problems of the national wage arrears, and quickly check and settle the discovered wage arrears clues to protect the legitimate rights and interests of migrant workers. All localities should strictly implement the assistance system for families living on the edge of subsistence allowances and families with expenditure difficulties, strengthen active discovery, monitoring and early warning, promptly accept and respond to people in need for help, and do urgent things for the newly verified minimum living allowances, increase the intensity of temporary assistance, and timely solve the sudden and urgent basic living difficulties encountered by urban and rural people.

　　Second, strengthen market price stability and supply to meet holiday consumption demand.Strengthen the protection of important living materials, strengthen the dynamic monitoring of the supply and demand of coal, electricity, oil and gas transportation, scientifically dispatch resources, enhance the peak power generation capacity, and compact the main responsibility and territorial responsibility of the enterprise to ensure the stability of power supply and gas supply. We will implement the responsibility of the party and government for food security and the mayor’s responsibility system of "vegetable basket", do a good job in ensuring the supply and price stability of important livelihood commodities such as grain, oil, meat, eggs, milk, fruits and vegetables, strengthen the connection between production and marketing, inventory scheduling and logistics distribution, and ensure that the supply of daily necessities is not out of stock. Formulate emergency supply plans for daily necessities, closely track daily supply and prices, strengthen market price inspections on holidays, and increase reserves in a timely manner. Standardize the market order of cultural tourism holidays, strengthen price supervision in key areas of people’s livelihood such as catering accommodation, scenic spot tickets and parking fees, and promptly investigate and deal with illegal acts such as price gouging, price collusion and price fraud. Standardize promotional activities, urge online trading platforms to implement the main responsibility, strengthen online trading and service supervision, and safeguard the legitimate rights and interests of consumers. Strictly implement the "four strictest" requirements of food safety, continue to promote the work of fasting wild animals, and ensure "safety on the tip of the tongue".

　　Third, enrich the spiritual and cultural life of the masses and actively create a festive atmosphere.Focusing on the full implementation of the spirit of the 20th National Congress of the Communist Party of China and the Second Plenary Session of the 20th Central Committee, we will strengthen publicity and guidance with strong confidence as the focus, organize various cultural and artistic activities with rich connotations, arouse the enthusiasm of the broad masses for loving the Party, the motherland and socialism, consolidate and expand the mainstream ideological public opinion in the new era, carry forward the main theme, and gather the powerful forces of unity and forge ahead of the whole society. Do a good job in the free opening and service of public cultural places such as libraries, cultural centers, museums and art galleries. Vigorously carry forward the socialist core values and Chinese excellent traditional culture, eulogize the new era, and constantly meet the spiritual and cultural needs of the people.

　　Four, do a good job in Spring Festival travel rush security, to ensure the safe and orderly travel of the masses.Make a service guarantee work plan for Spring Festival travel rush as soon as possible, and do a good job in Spring Festival travel rush. Analyze and judge the changing trend of passenger and freight flow, strengthen the propaganda and guidance of off-peak travel, and optimize the transportation capacity for key periods such as college students’ school holidays and migrant workers’ return to their hometowns, as well as key areas such as passenger hubs, railway stations, port passenger stations, airports and tourist attractions, so as to improve the passenger collection and distribution capacity. Cooperate to promote cross-transport mode cohesion organizations, strengthen the overall arrangement of different modes of transport such as roads, railways, civil aviation and waterways, strengthen coordination and cooperation between intercity transport and urban public transport, improve coordination and liaison mechanisms, broaden information exchange channels, and promote open sharing of resources. Strengthen the operation and management of expressway service areas, improve the quality of services such as charging, dining and going to the toilet, strictly implement the policy of free passage of minibuses during the Spring Festival holiday, further sort out easy-to-block sections and expressway toll stations, and implement anti-blocking measures in advance. Strengthen road network operation monitoring, optimize dispatching management, strengthen on-site duty, and strengthen on-site guidance and special handling. Strengthen the smooth transportation and logistics, and ensure that the transportation services of important materials such as energy, food and medical care are not interrupted. Carefully formulate emergency plans to deal with emergencies, actively guard against the surge in passenger flow, freezing rain and snow, etc., strengthen inspection and control of key sections in mountainous areas of northern Guangdong, Qiongzhou Strait, inland river routes, etc., and do a good job in emergency rescue preparations and emergency material support. Strengthen departmental cooperation and regional joint law enforcement, severely crack down on acts such as overloading and speeding, illegal operation, illegal manned vehicles and trucks, and prevent serious traffic accidents.Ensure the safety of people’s travel.

　　Fifth, strengthen the investigation and rectification of potential risks and resolutely hold the safety bottom line.Adhere to the people first, life first, strictly implement the safety production responsibility and management system, pay close attention to various control measures, strengthen the investigation and rectification of key safety hazards, compact the main responsibility of enterprises, and resolutely curb the occurrence of serious accidents. Pay close attention to safety precautions in key industries, strengthen safety supervision of special equipment, construction, dangerous chemicals, non-coal mines, metal smelting, town gas, fireworks and firecrackers, fishing vessels, offshore wind power, religious places, and solidly carry out special actions on fire prevention in winter and spring for large-scale complexes, high-rise buildings, restaurants, "three small" places, and self-built commercial houses. Strengthen the deployment of low-temperature freezing safety precautions, encrypt meteorological monitoring and forecasting, and release early warning and forecasting information such as extreme weather, freezing frost and road icing. Strengthen the safety improvement of all dangerous operation links of dangerous projects, as well as limited space, temporary electricity consumption, cross-fire and other operations. Strictly prevent and strictly control forest fire risks, fully implement the work measures of "covering the mountain, guarding the intersection, focusing on key points, signing responsibilities, and fighting early and small", strictly control the fire sources such as returning home people entering the mountains to sacrifice graves, setting off fireworks and firecrackers, and burning in the wild to warm up, strengthen mountain patrol and forest protection, and improve the ability of monitoring and extinguishing. Closely combined with the characteristics of social security at the end of the year and the beginning of the year, we will severely crack down on "pornography, gambling and drugs", "robbery and fraud" and prominent illegal crimes in the fields of telecommunication network fraud, black and evil, food and drug environment, and strictly examine and approve large-scale activities such as New Year’s Eve, fireworks parties and temple fairs, and monitor the flow of people, so as to prevent major public safety incidents and earnestly safeguard the overall harmony and stability of society.

　　Six, strengthen the prevention and control measures of infectious diseases, and effectively protect the health of the people.Coordinate the prevention and control of respiratory infectious diseases such as COVID-19 and influenza, increase the overall planning of medical resources, enrich the medical strength of key departments such as outpatient, emergency, pediatric, respiratory and severe diseases in medical institutions, strengthen the preparations for commonly used drugs, testing reagents, medical equipment and beds in medical institutions, optimize the diagnosis and treatment process, shorten the waiting time and reduce cross-infection. Continue to strengthen the monitoring of the diagnosis and treatment of respiratory diseases and the judgment of the situation, do a good job in epidemic monitoring, early warning and risk assessment, strengthen epidemic reporting, and release information in a timely manner. Scientifically publicize the knowledge of prevention and treatment of acute respiratory infectious diseases, continue to strengthen vaccination work, and advocate people to wear masks, do personal protection and maintain good hygiene habits.

　　Seven, advocate thrift and civilized holidays, adhere to the rectification of the "four winds".Persevere in implementing the spirit of the eight central regulations and their implementation rules, grasp the changes and trends of the "four winds" during the holiday season, strictly investigate the problems of illegal eating and drinking, illegal receiving and delivering gifts and gifts, illegal use of buses, public travel, etc., vigorously rectify the phenomena of high-end tobacco, alcohol, tea, "luxury New Year’s Eve", excessive packaging of festivals and gifts, and invisible variation behaviors such as express gift giving, receiving and delivering electronic red-envelope, "not eating public money to eat the boss" and using private cars for public support, and severely punish outstanding subsidies and subsidies. Keep a close eye on the formalism and bureaucracy that increase the burden on the grassroots, resolutely correct and punish the random assignment of tasks to the grassroots in the name of summing up and promoting the work, and set up video conferences with the same theme at different levels. Many people repeatedly ask for materials and fill out forms, supervise and check too much, leave too many marks, and engage in "formalism at the fingertips". Vigorously correct the problems of inaction and chaos in people’s livelihood security, assistance and relief, and safety in production, and promote the solution of the people’s urgent problems. Adhere to and carry forward the fine traditional style of the Chinese nation, solidly promote the change of customs and traditions, strictly educate family members, oppose bad habits such as ostentation and extravagance, showing off wealth by comparison, extravagance and waste, and advocate good social customs. Strengthen pre-warning, in-process supervision, and after-the-fact investigation, increase the investigation and exposure of violations against the wind, and create a festive atmosphere.

　　Eight, do a solid job on duty, to ensure the orderly operation of all work.Strictly implement the system of 24-hour special personnel on duty and leading cadres taking classes on the job and going out to report. Strictly implement the system of asking for instructions and reporting, and in case of sensitive incidents, serious emergencies or other important emergencies, ask for instructions and report at the first time and properly dispose of them in time. Emergency rescue teams should always be in an emergency state and preset rescue forces in advance to ensure timely and effective handling of emergencies. Units that directly serve the masses should reasonably arrange duty during the festival to ensure the quality of service. Strengthen the judgment of government affairs in public opinion monitoring, be good at capturing "weak signals" and strengthen information submission.

　　All localities and departments should improve their political positions, strengthen their organization and leadership, carefully and orderly do all the work during the Spring Festival on New Year’s Day, and ensure that the central decision-making arrangements and the implementation of the spirit of this notice are in place.

1905 movie network news Directed by Jin Zhencheng and starring Haoran Liu and Chen Douling, the youth suspense film released the finalized poster of "Falling in Love with Another Me" today, officially announcing the finalization on April 19th. At the same time, the role stills of Haoran Liu and Chen Douling also met the audience, and this much-anticipated film finally unveiled its mystery.

"Returning to the age of eighteen", Haoran Liu ushered in the biggest challenge of his film career.

Judging from the posters and role stills released this time, Haoran Liu’s role image is quite different from other works, which is mature, restrained and exudes artistic flavor. In Twins, he is no longer the talented boy who stands behind his brother and sister and is bent on solving the case, but has to face everything that happens around him alone. This was a big challenge for Haoran Liu, who was only eighteen at that time. In order to perform this role well, Haoran Liu devoted himself to the filming process. According to Haoran Liu, he was still immersed in the role for a long time after the filming, so he specially chose to go on vacation to release himself after the filming, which made people wonder what role Haoran Liu would present to everyone.

Since the film, every film that Haoran Liu starred in has had a very good box office performance. With his sunny image and excellent acting skills that are rare among his peers, he has been recognized and loved by the audience step by step. Now, after four years, Twins has finally been released, and the audience can see the 18-year-old Haoran Liu brother again, which is undoubtedly a belated surprise for the domestic youth film market and the audience who love Haoran Liu.

The first screen cooperation, the first encounter between the national school flower and the popular niche

The film Twins tells the story of Li Pin (played by Haoran Liu), an art school student, who got a one-month part-time job by chance. His job was to paint portraits of Tao (Chen Douling), a girl whose birthday is coming soon, so he came to a remote mansion. As a result, two young people who had never met each other became attached, and a youthful encounter began. However, in the process of getting along with each other, Li Pin gradually discovered that there seemed to be some unknown secrets hidden in this house, and the relationship between him and Tao gradually became subtle.

As the outstanding actors of the new generation, the first screen cooperation between Haoran Liu and Chen Douling can be described as very topical. One is a popular young actor who starred in the box office of nearly 5 billion, and his acting skills are first-class; One is a national school flower that stands out from countless competitors. The first film starring in it has achieved good box office results, and their youthful attributes perfectly match the temperament of the film. For the two leading actors, this cooperation is their "first encounter with youth" both inside and outside the play, which is of very special significance. Therefore, when the film has not yet been finalized, countless audiences have expressed their expectations for "Twins". The official announcement of the schedule this time is undoubtedly a reassurance to the audience.

　　

　　　 On the morning of January 31, 2008, the retired Navy 105 was towed into naval museum, Qingdao by tugboat and officially opened to tourists.

　

　　　　On the morning of January 31, 2008, the retired Navy 105 was towed into naval museum, Qingdao by tugboat and officially opened to tourists.

　　　　On the morning of January 31, 2008, the retired Navy 105 was towed into naval museum, Qingdao by tugboat and officially opened to tourists.

　　

　　　 On the morning of January 31, 2008, the retired Navy 105 was towed into naval museum, Qingdao by tugboat and officially opened to tourists, bringing the number of warships in naval museum, Qingdao to five. 105 "Jinan Ship" is the first naval ship developed by China itself and a star ship in China.

　　　

Editor: Fan Jing

　　Step 2. Check whether the network cable and telephone cable on the modem and the router are plugged in firmly, and whether they are loose. Unplug all the cables and plug them in again, just like the first step. If there is any problem with the cables, replace them.

　　Step 3. Check the status indicator of the cat (modem) or router. The one above is the cat (modem). We see that three indicators are on normally. The first one is the Power indicator, the second one is the output network cable, and the fourth one is the connected telephone line. Check which one is not on. By the way, if the cat is directly connected to the computer, the internet light is on, and mine is connected to the router, so the DSL light is on.

　　Step 4. If there is a router connected, then check the indicator light of the router, as shown in the figure (whichever is specific). The first light is the system light. If this light flashes normally, the middle ones (cg animation) are the indicator lights of the network cable interface. It is normal to see that the port you are connected to is lit, and the one behind the earth is the Internet access state. This light indicates that it is ok to access the Internet.

　　Step 5. If you check that all the above are normal, that is to say, there is no problem with the cable and the indicator light, then according to my experience, it is necessary to unplug the cat or router, and plug it in again after unplugging it, which is equivalent to restarting.

　　Step 6. If you can’t do the above methods, you should check the problem of the computer and see if the ip of the computer has changed. We usually use automatic access to the IP address.
WIN7 IP viewing method: Control Panel-Network and Sharing Center-Change adapter settings-Right-click "Local Area Connection" to select properties-Double-click "Internet Protocol Version 4 (TCP/IP)"-all of which are selected as "Automatic Acquisition".

　　Step 7. If you still can’t get on, then check whether there is a telecom fault. One way is to try whether your home phone works normally. If there is no phone installed, call your network provider and ask if there is a line fault.

　　Method 2:

　　First, restart the switch and computer, and let them automatically assign IP again.

　　Second, adjust the working mode of the network card to 10M(100M) half-duplex working mode.

　　Open a restricted Local Area Connection

　　A: Click the "Local Area Connection" attribute.

　　B: Click "Internet Protocol (TCP/IP)", and then click "Properties".

　　C: Click "Use the following IP address" in "General" and fill in the data of "IP address" and "subnet mask", and fill in the address data of "preferred dns server".

　　D: click "advanced"

　　E: Add an address in the "DNS" item and an address in the "WINS" item.

　　F: OK-OK-Close-OK.

　　If you want to repair Winsock without installing Windows XP SP2, please delete the damaged registry key and then reinstall the TCP/IP protocol.

　　Step 1: Delete the corrupted registry key.

　　Warning: If you use Registry Editor or other methods to modify the registry incorrectly, it may cause serious problems. These problems may require reinstalling the operating system to solve. Microsoft cannot guarantee that these problems can be solved. Modifying the registry is at your own risk.

　　1. Click Start, and then click Run.

　　2. In the Open box, type "regedit", and then click OK.

　　3. In the Registry Editor, locate the following registry keys, right-click each key, and then click Delete:

　　HKEY_LOCAL_MACHINESystemCurrentControlSetServicesWinsock

　　HKEY_LOCAL_MACHINESystemCurrentControlSetServicesWinsock2

　　4. When prompted to confirm the deletion, click Yes.

　　Note: Please restart the computer after deleting the Winsock registry key. Doing so allows the Windows XP operating system to create new shell entries for these two registry keys. If you do not restart your computer after deleting the Winsock registry key, the next step will not work properly.

　　Step 2: install TCP/IP

　　1. Right-click the network connection, and then click Properties.

　　2. Click "Install".

　　3. Click Agreement, and then click Add.

　　4. Click Have Disk.

　　5. Type C:Windowsinf, and then click OK.

　　6. In the list of available protocols, click Internet Protocol (TCP/IP), and then click OK.

　　7. Restart the computer.

　　If it is WINXP SP2, the solution is as follows: Please type netsh winsock reset at the command prompt, and then press Enter. Please restart the computer after running this command. (winxp sp2)

　　Method 3:

　　Sometimes "local connection" is restricted, which is manifested by a yellow exclamation mark on the network connection icon in the system tray.

　　And will prompt the company to accept the restrictions. When such problems occur, there are many methods, and one or several different methods are adopted to solve them according to the causes:

　　1. Manually set IP: The method is to open the "Control Panel" — — Network connection, find the current local connection, right-click it, select Properties, double-click Internet Protocol (TCP/IP) in the General tab, select Use the following IP address, fill in "192.168.0.1" in the IP address and "subnet mask". (If the current computer joins a workgroup or domain, it should be set according to the situation).

　　Use the method of specifying IP to solve the problem, but sometimes this method can’t solve the problem (the prompt of "connection restriction" will disappear, the local connection is normal, but the internet can’t be accessed).

　　Second, set the network card:

　　1. Disable the network card and then enable it.

　　2. Unplug the power supply of the chassis, and there is also the power supply of the kitten or rover at the other end of the chassis. Turn off the power supply and unplug the power cord, then open the chassis, unplug the network card, and then plug it in according to the original position! Install the chassis, install the power supply and connect the network cable! All the other wires are connected, start the computer! Enter XP troubleshooting!

　　Third, close the firewall.

　　4. In the local connection attribute, there is an option of "Don’t notify me when the connection is restricted or disconnected", and put a tick in front of it.

　　5. Type netsh winsock reset at the command prompt (run cmd), and then press Enter. Restart the computer after running this command.

　　6. In Network Connection, right-click Local Connection, select Properties in the pop-up menu, and then view the list of "This connection uses the following items" in the General tab in the pop-up dialog box, removing the check mark in the default Internet Protocol dialog box. After confirming the operation, the prompt of limited network connection will disappear, so see if you can surf the Internet. If you still can’t access the Internet, bring up the Local Connection Properties dialog box again, click the button in the General tab to pop up the Select Network Component Type dialog box, select Protocol from the list, and then click the Add button to pop up the Select Network Protocol dialog box, and select Microsoft as the vendor and Network Protocol.

　　Seven, a new connection, IP automatically.

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