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

　　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.

The Israeli bombing campaign in Gaza has lasted for 20 days. The scale of this round of air strikes and the heavy casualties have attracted worldwide attention, and the Palestinian death toll has surpassed the fifth Middle East war.

The Israeli military has attacked more than 7,000 targets in Gaza.

The Israeli bombing campaign in Gaza lasted for 20 days, and it has become one of the most intense bombing campaigns in the 21st century, which has attracted increasing global attention to its scale, purpose and casualties. The Israeli military says it has attacked more than 7,000 targets in Gaza. This figure is higher than any previous Israeli military action in this narrow flying field.

Communication and Internet services in Gaza were completely disrupted.

On the evening of 27th, the Palestinian Telecommunications Company announced that all communication and Internet services in the Gaza were completely cut off due to intensive bombing by Israeli warplanes.

Israeli Army 27 expanded the scale of ground operations in the Gaza.

The World Health Organization (WHO) said on the 27th that it has lost contact with its staff in Gaza and other local humanitarian partners. Due to the interruption of communication, the ambulance could not reach the bombing site. At present, there are no specific statistics on casualties. On the 27th, the Israeli military expanded its ground operations in the Gaza and intensified its air strikes in the Gaza.

The Israeli army said that the main operation base in Hamas is located on the ground floor of Shifa Hospital.

According to the Israel Times reported on the 27th, Daniel Hagari, the chief spokesman of the Israel Defense Forces, said that Hamas’s main operation base is located in the underground of Shifa Hospital in Gaza. According to Hamas, according to the information available, there are several tunnels leading to underground bases outside the hospital, so Israeli officials can access them without entering the hospital.

Israeli army spokesman Hagari:

Hamas has turned hospitals into command and control centers and hiding places for terrorists and commanders in Hamas. Besides, according to the information we have, I can confirm that there is fuel in hospitals in Gaza. I repeat, there is fuel in hospitals in Gaza, and Hamas is using it to maintain its terrorist infrastructure.

An IDF spokesman warned Gaza Hospital.

Hamas later issued a statement saying that Israel’s claim that Shifa Hospital was used for military purposes or as an organizational base was false, and called on the United Nations and Arab countries to intervene immediately to stop Israeli air strikes and damage to the medical system.

According to Al Jazeera, the Israeli Air Force bombed the vicinity of Shifa Hospital and an Indonesian hospital on the evening of 27th.

Israeli army spokesman Peter Lerner:

What I want to say is that if hospitals continue to take these actions under certain circumstances, hospitals may indeed lose the protection they have obtained.

The Palestinian death toll has surpassed the fifth Middle East war.

Since the outbreak of the new round of Palestinian-Israeli conflict, Israel’s bombing of Gaza has lasted for nearly three weeks, and its scale and heavy casualties have attracted worldwide attention. According to the data of the British Conflict Monitoring Agency, this round of air strikes by the Israeli army even exceeded the one-month heavy bombing of the Iraqi city of Mosul controlled by extremist organizations by the US-led military alliance. In March 2017, the military alliance against extremist organizations fired about 5,000 artillery shells, and Israel fired at least 2,000 more in less than three weeks. Health authorities in the Palestinian Gaza said that more than 7,300 people had died in the Gaza since the current round of Palestinian-Israeli conflict broke out. This is the conflict with the largest number of Palestinian deaths since the fifth Middle East War in 1982.

The General Assembly adopted a resolution calling for a humanitarian truce between the Israeli and Palestinian parties to the conflict.

On 26th local time, in view of the tension in Gaza, the United Nations General Assembly resumed its tenth emergency special session on the Palestinian-Israeli conflict.

Mansour, Permanent Observer of Palestine to the United Nations:

In the past three weeks, 7,000 Palestinians in the Gaza were killed by Israelis, and 70% of the victims were women and children. Why can some people feel the pain of Israelis, but not the pain of Palestinians? What the hell is going on here?

On the 27th, the emergency special session of the United Nations General Assembly adopted a resolution with 120 votes in favor, 14 votes against and 45 abstentions, calling on the Israeli and Palestinian parties to the conflict to immediately implement a lasting and sustained humanitarian truce, thus contributing to the cessation of hostilities.

Israel refused to accept the relevant resolutions adopted by the General Assembly.

Israel said it refused to accept the relevant resolutions adopted by the UN General Assembly and would use "all means" to attack Hamas.

US media: The Israeli army is conducting simulation training in the southern "Little Gaza"

According to the Wall Street Journal, the Israeli army has been training in a simulated Palestinian town in southern Israel, which is equipped with a tunnel network and officially called an urban training center. The soldiers called it "Little Gaza".

Wall Street Journal reporter:

This simulated small town is located in the middle of the desert. It has minarets of mosques, simulated schools and hospitals, and completely reproduces the enemy towns that the IDF is about to infiltrate and fight in.

Israeli gun shops and shooting training grounds have seen a sharp increase in customers.

After the new round of conflict between Palestine and Israel broke out, the number of customers in Israeli gun shops and shooting training grounds surged to a record high. The Israeli authorities have set up hundreds of voluntary security groups composed of civilians throughout the country and equipped them with weapons such as guns. These members of the civil security group patrol the streets and cooperate with the police. The purpose is to prevent conflicts between Arabs and Jews in Israel. Ithama Ben-Gewell, Israel’s Minister of National Security, has ordered the relaxation of restrictions on Israeli citizens’ obtaining gun licenses.

Expert: The game between the international community and Israel will continue.

In March 2021, when the financing was announced, media reports showed that there were more than 1 million riders in the flash.

Just over three years later, the flash prospectus shows that there are 2.7 million registered riders, an increase of nearly 1.7 million.

However, during this period, the revenue of flash delivery only increased by about 50%, far less than the growth rate of riders.

The result can only be the compression of delivery time and the decline of revenue per order.

Just needed, small track

Express delivery, logistics, take-out and instant delivery are essentially the exchange of money and time. It takes some people’s time to help others complete time-consuming and labor-intensive things.

Express delivery and logistics are long-distance delivery, take-out is short-distance delivery, and running errands and the same city are in between. Flash is located on this track. Because Dada occupied the "first share of instant retail" and SF City became the "first share of third-party instant delivery", Flash delivery had no chance to become the "first share", so it was necessary to emphasize its uniqueness, so it became the "largest independent on-demand delivery service provider".

The so-called on-demand courier service is one-to-one express delivery, and the flasher only serves one customer at a time from picking up to delivery, and delivers it point to point. In this mode, flash has several core advantages.

First of all, one-to-one service, each important document has a direct person in charge, and there are almost no problems such as lost parts and damage. The flash prospectus shows that in 2023 and the first half of this year, its loss rate is very low, only 0.01%.

Secondly, compared with other distribution, one-to-one service naturally costs more. According to the prospectus, customers are willing to pay a high price for the service experience. According to iResearch, the average price per order in the first half of the year was 16.5 yuan, which is a significant premium compared with other major participants in the on-demand distribution industry.

Third, just need. In the case of safety requirements, one-to-one distribution is naturally more secure than centralized distribution, especially for items with strong timeliness and great importance. For first-tier cities, although such scenes do not often appear in work and life, most people will have demand more or less.

The story of "saving" the marriage between Justin and Zhang Xinyi is often mentioned. In 2016, Zhang Xinyi and Justin will hold a wedding in Germany. At the airport, because Zhang Xinyi forgot to bring his mobile phone and wedding veil, thanks to the timely delivery of the younger brother, the trip was not delayed. This aspect reflects the value of instant delivery.

According to the prospectus, on this track, flash has occupied 33.9% market share. However, this is not a big track. In 2023, the revenue of flash delivery was 4.5 billion. From this calculation, the whole market was only 13.2 billion, and it was a small track with a very obvious ceiling.

Focus is the key to the success of flash.

The flash startup team lacks "star flavor". Founder Xue Peng graduated from the School of Science of North China University of Science and Technology in 2005, majoring in information and computing science, and then went to the Royal holloway College of University of London to study for a master’s degree. He has very little information. It is reported that his family conditions are good, and his family involves many enterprises such as real estate, taxis and driving schools, but this low-key "rich second generation" finally chose to start a business. In 2007, Xue Peng returned to China to start a business and founded an integrated service platform for express logistics-Easy Post.

In contrast, Kuai Jiaqi, founder of Dada Group, graduated from Massachusetts Institute of Technology. He holds a bachelor’s degree in logistics engineering from Tongji University and a master’s degree in logistics engineering from Massachusetts Institute of Technology.

However, Flash finally broke through in the fierce competition and once became the "leader" of the industry. It has successively completed 11 rounds of financing, attracting many well-known investment institutions such as Lei Junshun Capital and Jingwei Venture Capital, and Pusi Capital, a subsidiary of Wang Sicong, has also participated in the investment for two consecutive rounds.

Listing is capital.

Flash delivery has always been the main on-demand mail service, and today, it still maintains a good development situation.

According to Xue Peng’s understanding, once the city-wide real-time distribution mode from person to person forms a scale, it will form a strong competitive advantage and the entry threshold is relatively high. Flash delivery has indeed built a certain industry barrier for itself. For example, there are 2.7 million registered riders, 88.9 million users, more than 270 million orders a year, and higher customer unit prices in the industry. In terms of rider and user scale, brand awareness, customer consumption willingness, etc., flash delivery does have a good accumulation.

In terms of performance, the development of flash delivery is in good condition. The overall order volume of flash delivery keeps increasing. The orders in 2021-2023 and the first half of 2024 were 159 million, 213 million, 271 million and 138 million respectively. With the increase of orders, the revenue also keeps growing, which is 3 billion yuan, 4 billion yuan, 4.5 billion yuan and 2.3 billion yuan respectively. Under normal circumstances, it is highly probable that this year’s growth will continue to be positive, but the growth rate continues to slow down.

Flash also maintained a stable profit. In 2023, the profit was 110 million, and in the first half of this year, the profit was 120 million, which had the effect of government subsidies, but it was still profitable if this factor was excluded. In contrast, Dada Group has never made a profit, losing 600 million yuan in the first half of this year.

Cash flow has also steadily turned positive in the last year and a half. The inflow was 45.71 million yuan in 2023 and 20.67 million yuan in the first half of this year. Cash increased from 690 million in the same period last year to 710 million in the middle of this year, which has increased steadily in recent years.

As early as 2020, Flash executives said in an interview with the media that the company may go public soon. At that time, Flash was in a state of loss, and perhaps it really needed listing financing, but the financing was received in the following year, and it was profitable again in 2023. Flash has entered a relatively positive track, and the urgency of the company’s listing financing is not strong, more like listing to meet the requirements of the capital side.

In mid-2020, Dada Group became the first share of instant delivery. After more than four years, its share price has shrunk by 90%. At the end of 2021, SF Express, an independent company, went public in Hong Kong, and its share price was slightly better, shrinking by 30%.

With the previous reference, Flash was broken on the second day of listing and once fell to $11.47, which was not sought after by the market.

The problems faced by flash at this stage make the future more unknown.

Struggling 2.7 million riders

Focus is the key to the listing of Flash, but it is also the reason why Flash can’t open the situation.

There are few companies that don’t make any kind of distinction between revenues, and flash delivery is one of them. A single business is closely bound to the order volume, and the revenue will increase when the order volume is high. After 10 years of development, the on-demand courier service has entered a gentle development period, which is also the reason why there has been no financing for flash delivery in the last three years. If you want to increase orders, you need to reduce prices and expand the market.

According to the order volume and revenue, the average revenue per order in 2021-2023 and the first half of 2024 was 19.12 yuan, 18.79 yuan, 16.71 yuan and 16.55 yuan respectively. In a state of continuous decline.

In addition to price reduction, flash delivery is also increasing consumption scenarios. At first, the main scenes were urgent matters, important documents, etc. Later, Flash began to provide expedited delivery services for customers of local restaurants, flower shops and bakeries, and to distribute valuable electronic products to consumers.

The expansion of the scene will indeed increase the order volume, but as mentioned above, the space in this market is too small. Instant delivery can be divided into four categories, namely, food and beverage takeout represented by Meituan and Hungry, which is high frequency, strong demand and most valuable. Fresh home delivery and Shangchao, represented by Dada, are equally high-frequency and just needed, but to a lesser extent than takeout. The logistics in the same city, represented by SF Express, is not high-frequency, but it faces more scenes and has stronger carrying capacity. Finally, there is the running errands represented by flash, and the demand frequency is lower than other modes.

Without the high-frequency feature, flash can’t use full-time riders like Meituan and Hungry, so it can only adopt crowdsourcing mode. Therefore, there are a large number of riders, with 2.7 million riders far exceeding 1.2 million in Dada Group and 950,000 in Shunfeng City, almost reaching the scale of being hungry. But obviously, the presence of the flash rider is far lower than that of hungry.

The advantage of flash delivery is that the customer unit price is high, and there is a lot of room for operation. However, crowdsourcing riders are not loyal, and they often take orders from multiple platforms at the same time, resulting in high personnel mobility. This requires flash delivery to benefit riders as much as possible. In 2021-2022, the salary and reward paid by flash delivery will exceed 90.5% of the revenue. However, the flashing needs to be profitable, and it has to be directed at the rider. In 2023 and the first half of this year, the proportion dropped to 85.4%.

To sum up, on the one hand, it is necessary to reduce the price and increase the order, on the other hand, it is necessary to maintain a high share for the rider, and on the other hand, it is necessary to consider its own operation and reduce the cost from the rider as much as possible. According to the scale of 2.7 million riders, combined with revenue, order volume and unit price, in 2023, there will be 740,000 orders per day, generating revenue of 12.41 million yuan, and the reward allocated to riders will be 10.9 million yuan. By this year, although there are 770,000 orders every day, the reward allocated to riders is only 10.84 million, with the increase of orders and the decrease of rewards.

At the same time, the prospectus shows that in 2021-2023 and the first half of this year, the average delivery time of orders was 35 minutes, 31 minutes, 29 minutes and 27 minutes respectively, which has been compressed, and the delivery pressure of riders continues to increase.

The rider’s income drops, the pressure of order limitation continues to increase, the competition becomes cruel, and the living environment is very difficult. At the present stage, it is no problem for riders to increase their income sources, but after all, they can’t keep the platform running by squeezing riders.

Of course, rider ecology is not a serious problem, and the real challenge comes from the external environment.

Small and beautiful, false proposition

Without backing the giants, the most well-known employer is Shunwei Capital of Xiaomi, accounting for only 7.8% of the shares. Although it is known as the largest on-demand delivery service platform, the scale of flash delivery is only half that of Dada and less than 40% of that of SF. Such a "small but beautiful" platform is often difficult to maintain for a long time in China Internet market.

The so-called moat flashing is more relative to the start-up platform. At this stage, it is not a small platform that competes with flash. Meituan’s errands, hummingbirds, SF Express and Dada are all backed by super platforms, and the order volume is incomparable. These platforms are involved in the field of flash, which is just a supplement to the business. Taking SF City as an example, getting involved in the same city business is only to supplement the short-distance delivery business and improve the choice of customer unit price, which can increase the income of the courier brother, and also expand the fresh home delivery, Shangchao and even take-away business when necessary, and improve the human efficiency without harm.

Giants not only have traffic, brands, service guarantees, but also the ability to price war. Previously, SF executives in the same city mentioned that the price is expected to fall this year, and the price is its core competitiveness. There is no doubt that in the face of price war, flash has basically no ability to parry. Flash delivery has almost no counter-ability, and it can be said that it is difficult for flash delivery to enter the take-away and logistics markets.

In fact, flash delivery is in a state of being a fish. In 2021, after the D2 round of financing, the flash valuation reached 2 billion US dollars. In 2024, the Hurun Global Unicorn List, the flash valuation was 7.1 billion yuan. After listing, the market value of Flash is only $1.07 billion. The downward adjustment of the flash valuation in the capital market has already explained many problems.

Flash delivery is actually a microcosm of the economic development of the Internet platform. Small and beautiful is a false proposition. If the scale is not reached, it will be impossible to compete with the giants. We can only pray that the giants will despise the "fly legs". An action of a giant that is often completely irrelevant may directly determine the life and death of a platform.

References:

1. A single income in 16 yuan, 2.7 million riders sent to the market, source: fixed focus.

2. Before going to the US IPO, flash to deal with the "same paragraph" problem of SF. Source: Wall Street.

3. Flash IPO to the United States: the price of a single customer has been declining year after year, and the unicorn valuation is "big waist" | BUG, source: Sina Technology

　　Reference message networkReported on September 4On August 23rd, the website of Jane’s Defense Weekly published a report entitled "Army -2018" Weapons Exhibition: Russia Releases the Production Version of "Pine Tree" Short-range Air Defense System, saying that at the "Army -2018" Weapons Exhibition held in Kubinka near Moscow from August 21st to 26th, Russia publicly released the "Pine Tree" short-range mounted on MTLB multi-purpose tracked armored vehicles for the first time.

　　According to the report, "Pine Tree" is a key defense system developed by Nudelman Design Bureau, and it was also loaded on BMD-4 infantry fighting vehicle for display. The system loaded by MTLB is called "Pine Tree", but the system loaded by BMD-4 is called "Puji Tselov". The manufacturer said that the turret and the complete system were called "Pine Tree", but also said that "Pine Tree" was an export version, and the version in the Russian army was called "Duxiang".

　　This system can be loaded on other platforms according to customer requirements. The system has two crew members: the driver and the gunner. It is equipped with a set of optical sensors, including a remote thermal imager for target capture and fire control.

　　Profile picture: The "Pine Tree" short-range air defense system at the "Army -2018" defense exhibition. (Image from the Internet)

　　Profile picture: Russian 2K22 "Tunguska" self-propelled air defense system uses rapid-fire guns to fire. (Image from the Internet)

　　According to the report, the system is equipped with 12 9M340 missiles, which are installed in storage and transportation launch boxes, and there is a launch unit on each side of the turret (each unit contains 6 missiles). This layout is similar to the 9M331 missile used in the 2K22 Tunguska system, but it uses laser beam guidance instead of radio frequency control. This 38kg missile contains a large high-explosive warhead with a trigger fuse and a proximity fuse (non-trigger fuse). Each missile unit can be raised independently. These missiles have a maximum linear range of 10 kilometers and a shooting height of 5 kilometers. All missile units can be reloaded within 8 to 10 minutes, and the response time of the system from detecting the target to attacking the target is 5 to 8 seconds. The system can be launched on the move, and can attack ground targets, with limited (light) armor penetration.

　　In 2016, the Russian Army decided to purchase the "Pine Tree" system, although the purchase quantity has not been confirmed. In 2017, the missile of "Duxiang" air defense missile system passed the national test, and will replace the 9K35M3 "Arrow -10M3" system currently serving in the Russian Army (which uses 9M37M infrared guided missile).

　　"Pine Tree" system only relies on the passive infrared radiation of the target to acquire the target and carry out fire control, which, together with its hard-to-fight laser beam guidance system, makes it particularly suitable for fighting in controversial electromagnetic environment.In view of the fact that Russia has recently purchased a variety of electronic warfare equipment for ground troops, it seems to meet the requirements of Russian operational theory.

　　According to the report, although laser beam steering guidance has its advantages, it needs a launch vehicle to track and control the missile until it hits or approaches the target. This may cause the launch vehicle to be countered by enemy fire, in addition, the missile tracking system (rather than the laser beam guidance system itself) will be subject to electronic interference, and the missile will be subject to some active interference. The launch of missiles and their propulsion to cruising speed will also generate considerable electromagnetic (visible, infrared and ultraviolet) signals, which can be used by sensors on the target aircraft or vehicles to detect missile launch and prepare for defense or counterattack. (Compile/Feng Xue)

　　The rainstorm is spreading and the flood is severe! In the past two days, many places in the north have suffered the largest range of heavy rainfall this year. Six provinces and cities, including Beijing, have experienced heavy rain or rainstorm.

　　In such extreme weather, many units and companies have chosen to leave work early, but some people have always stuck to their posts, braved the wind and rain, and never left.

　　Three unsung heroes who have passed through the house but not entered.

　　On the afternoon of July 20th, a Beijing girl posted this status in the WeChat circle of friends. The CCTV reporter conducted a telephone interview for the first time, which revealed a warm and touching story in the rainstorm in Beijing. The girl’s father is a worker in Beijing’s drainage emergency line. Whenever there is a rainstorm, it is also the busiest time for him. As a rescuer in charge of more than a dozen bridge areas, he ran out of the house from the beginning of the rainstorm and has been fighting in the front line, never leaving.

　　He can be seen everywhere where there is stagnant water in more than a dozen bridge areas. It happened that he couldn’t go home when he got to his home and got into the water. He passed by the house three times during the rescue, but he never left the front line and didn’t go back to take a look. In his mind, the things of his own small family are small things. The drainage site needs him more, and it is the most important thing to protect the safety of every people in the segment.

　　Eat in the rain when you are hungry, and take turns to have a rest in the emergency car when there is no danger. It is his duty to stand by at any time in the face of heavy rain, and it is also the deep love of all rescuers like him for the people. This positive energy eliminates the rain and floods, so that everyone can be safe in the face of heavy rain, and the people-oriented interpretation is more dazzling and brighter.

　　A bright light standing in danger

　　In Beijing, a sanitation worker found that a manhole cover had been washed away on the flooded road section at work. In order to prevent pedestrians from falling into the water, he stood in the water and guided everyone around him for more than an hour.

　　Such sanitation workers are not a case. In Beijing, Tianjin, Hebei, Henan, Shandong and Shanxi, in such a rainstorm, countless sanitation workers are sticking to their jobs, cleaning up the dirt and hidden dangers under everyone’s feet in the rain. Their fluorescent clothes, like sunshine, become a warm energy in the rainstorm.

　　Of course, our people’s police are indispensable to the same struggle in the front line. Heavy rain caused many ground collapses in many cities, and many pedestrians and vehicles were trapped on the road. The police and traffic policemen took to the streets in the rain, pushed away the cars soaked in the water, checked the road sections with problems, and surrounded the places where the manhole cover was lost or collapsed. If there was no sign to fence, they stood there, one stop and one walk, which was a few hours.

　　Ordinary work also has great love.

　　Every time we encounter extreme weather, it is the time when online orders for meals surge. In the heavy rain, the takeaway buddy is still busy rain or shine. Minions, Little Blue Man and Little Red People riding on the road are particularly eye-catching. A delivery clerk said that orders will skyrocket in this weather, but the food must be delivered, but the time may be delayed. Please forgive me.

　　The rainstorm did not dilute human feelings and people’s hearts, but stimulated the responsibility and morality of people in the city and stimulated the positive energy of the city. Here, I would like to say, "You have worked hard, and you must pay attention to safety!" Thank you! "

　　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.

Related reading:

　　[car home Information] Kailing, Fengzhe and Kubo are the three power forwards of Dodge’s China strategy. Kailing was listed at last year’s Guangzhou Auto Show, and Fengzhe was officially listed on January 22nd this year. Although Kubo is still on the list to be imported, it is only a matter of time. However, there are still many consumers who have only heard of the Dodge brand as an old American manufacturer and have no detailed understanding, so here I will introduce the Dodge brand and these three new cars to you.

　　DODGE: English Dodge is a famous old American automobile manufacturer, and now it belongs to Chrysler. Dodge was founded in 1914 by John Dodge, born in 1864, and Horade Dodge, born in 1868. Because Dodge had been manufacturing engines, chassis and all transmission parts for Ford before that, it already had certain automobile production technology until it produced its first car in 1914. However, in 1915, Dodge was affirmed by both sides in the border war between the United States and Mexico with its own brand of trucks. Even during World War I, Dodge trucks were equipped with the United States Army.

　　In 1915, the sales of Dodge cars ranked fourth in the United States. In 1917, Dodge Brothers reached the record of selling 100,000 cars a year. Just two years later, it made a profit of $24 million on the sale of 121,000 cars. By 1919, Dodge had sold 400,000 cars and employed 17,000 people.

　　In 1920, Dodge’s commercial vehicle production accounted for 10% of the company’s total production. The Dodge brothers died of pneumonia in the same year. Since 1921, Dodge has started its own bumpy route, and the company’s profits began to decline. In 1928, Chrysler acquired Dodge Brothers. Dodge brothers Co became a division of Chrysler.

　　On November 2, 1983, the first van was born in Winsor Assembly Plant, Ontario, Canada. The original models include Plymouth Jetron, Dodge Caravan and Dodge Caravan NC/V. After this car landed in Europe in 1987, it was named "Multi-Purpose Vehicle" (MPV) by Europeans. The concept of MPV came into being and spread. Dodge has also become the backbone enterprise of Chrysler Automobile Company. And that’s how the first generation of Dodge Carroll was born.

　　Dodge Kay collar:

　　Kailing, the main model of Dodge, is made in China. The domestic Kailing maintains the original design of American MPV and incorporates some elements of fashion technology.

　　Dodge Kailing and Chrysler Grand Jetron are both brothers, and the two cars are very similar in appearance. Dodge Kailing adopts the design of electric sliding doors and electric tailgate on both sides, which is convenient for getting on and off, retracting seats and loading goods.

　　In terms of power, Dodge Kailing adopts a 3.0L V6 naturally aspirated engine with a maximum power of 165 HP and a four-speed automatic transmission. The suspension adopts front McPherson independent suspension and rear leaf spring suspension.

　　In the interior, the Dodge Collar is business-like, with a seven-seat design, and the Dodge Collar is equipped with a seat loading system pioneered by Chrysler. This system can make the second and third rows of seats in the car fold into the floor, so that the floor of the car forms a complete plane. When that seat is open, the space for store the seat can also provide a loading space of about 340L.

　　The price of Dodge Kailing is around 240,000, and it is now on the market.

　　Dodge Feng Zhe:

　　Feng Zhe is one of the main models of Dodge. On the same platform as Chrysler Platinum Rui, Feng Zhe came to China and positioned himself as a sports car.

　　Avenger, the original meaning of Dodge Vanguard, is a model with a long historical background. As early as 1963, it was conceived and developed by the British Rootes Group. After several twists and turns, the British Rootes Group was finally acquired by Chrysler, and Avenger plans to become an American car plan.

　　The first Fengzhe was born in 1970, and has undergone several years of evolution. The Fengzhe is Plymouth Cricket, Dodge 1500, Dodge 1800 and Dodge Polara. Fengzhe was once a global model sold in different regions under different names.

　　Fengzhe has a history of more than 30 years now. The appearance of the new Dodge Fengzhe adopts American-style pure muscle design, and the large cross engine intake grille has become its obvious symbol.

　　Fengzhe has been listed. There are two models with 2.4L displacement, and their prices are 278,000 yuan and 308,000 yuan respectively.

　　Dodge Cooper:

　　Cool Bo is also the main model of Dodge. It is the same platform as the familiar Jeep Guide, and it is a Cross-style crossover sedan with a certain SUV pedigree.

　　Its positioning is very strange. Nowadays, many manufacturers put their cars on SUVs, but Kubo has positioned their cars on sports compact cars, but this is also reasonable because sports is also a popular theme in recent years, but the excessive chassis and generous body still make Kubo more inclined to SUV style.

　　In terms of power, it is possible to use a 1.8L inline four-cylinder engine with a maximum power of 150 HP, a 2.0L inline four-cylinder engine with a maximum power of 172 HP and a 2.4L V6 engine with a turbocharged system with a maximum power of 300 HP.

　　Kubo is expected to be listed in March this year, and the minimum allocation may be around 180,000.

　　When the Dodge brand first entered China, it launched three models that were not very "Volkswagen". As an MPV model, Kailing is OK, but in terms of luxury, there are mercedes benz r, Buick Lu Zun at the same level and mazda 5 at home. Although Kailing is a good car in general, the brand and untimely birth will be the biggest problem for Feng Zhe. Fengzhe model is too small, its muscle shape is not necessarily accepted by many people, and the price is expensive, so it seems that the only cool blog worth looking forward to will also be troubled by the price.

　　This time, Dodge entered China too hastily. It may be that Chrysler’s successive losses forced Dodge to open up new markets as soon as possible. However, this may not necessarily achieve the expected results, not to mention that the Dodge brand is actually a popular brand in the United States, but the price of two of the three cars that entered China this time is not popular, and Dodge is indeed not kind enough in this respect.

　　The safety of Dodge cars is well-known in the United States, but this is not a reason to increase the price. Now the automobile market in China is becoming more and more mature, and consumers know more about cars, which has gradually bid farewell to the situation that foreign monks can recite scriptures. So what we want to say here is that if foreign manufacturers want to enter China now, they should start with kindness, and it is best to establish good customer awareness first. Only in this way can we gain a foothold in a growing market. (Text/car home He Kuan)

　　On the morning of February 1st, official website of Wuhan Municipal Bureau of Statistics announced the news, and Wuhan Municipal Bureau of Statistics and Wuhan Investigation Team of National Bureau of Statistics released the economic operation of Wuhan in 2022. According to the unified accounting results of the city and state GDP in Hubei Province, the regional GDP of Wuhan in 2022 is 1,886.643 billion yuan, calculated at comparable prices, up by 4.0% over the previous year. By industry, the added value of the primary industry was 47.579 billion yuan, an increase of 3.2%; The added value of the secondary industry was 671.665 billion yuan, an increase of 7.3%; The added value of the tertiary industry was 1,167.399 billion yuan, an increase of 2.3%.

　　So far, the top ten cities in China’s GDP have published their 2022 economic transcripts. The above data shows that in 2022, Wuhan’s GDP surpassed that of Hangzhou.

　　On January 20 this year, Hangzhou Municipal Bureau of Statistics released data: According to the unified accounting results of regional GDP, the city’s GDP in 2022 was 1,875.3 billion yuan, calculated at comparable prices, an increase of 1.5% over the previous year. Among them, the added value of the primary industry was 34.6 billion yuan, up by 1.8%; The added value of the secondary industry was 562 billion yuan, an increase of 0.4%; The added value of tertiary industry was 1,278.7 billion yuan, up by 2.0%; The added value structure of the three industries is 1.8:30.0:68.2.

　　According to official data, in 2022, the top ten cities in China will be Shanghai, Beijing, Shenzhen, Chongqing, Guangzhou, Suzhou, Chengdu, Wuhan, Hangzhou and Nanjing.

　　According to the data released by local statistical bureaus, in 2022, the top five cities in China are: Shanghai (4,465.28 billion yuan), Beijing (4,161.09 billion yuan), Shenzhen (3,238.768 billion yuan), Chongqing (2,912.903 billion yuan) and Guangzhou (2,883.9 billion yuan).

　　Compared with the data in 2021, the pattern of China’s top five GDP cities has changed in 2022, and Chongqing has surpassed Guangzhou to become the "fourth city" of China’s economy.

　　Judging from the GDP data in 2021, the cities ranked sixth to tenth are Suzhou, Chengdu, Hangzhou, Wuhan and Nanjing.

　　Suzhou Municipal Bureau of Statistics released data: According to the unified accounting of the Provincial Bureau of Statistics, in 2022, the city achieved a regional GDP of 2,395.83 billion yuan, an increase of 2.0% over the previous year at comparable prices. By industry, the added value of the primary industry was 19.30 billion yuan, an increase of 3.0% over the previous year; The added value of the secondary industry was 1,152.14 billion yuan, an increase of 1.8%; The added value of the tertiary industry was 1,224.40 billion yuan, an increase of 2.1%.

　　Statistics released by Chengdu Municipal Bureau of Statistics: According to the unified accounting results of regional GDP of Sichuan (prefecture), in 2022, the city’s regional GDP reached 2,081.75 billion yuan, an increase of 2.8% over the previous year at comparable prices. In terms of industries, the added value of the primary industry was 58.84 billion yuan, an increase of 3.8%; The added value of the secondary industry reached 640.41 billion yuan, an increase of 5.5%; The added value of the tertiary industry reached 1,382.50 billion yuan, an increase of 1.5%.

　　Statistics released by Nanjing Municipal Bureau of Statistics: According to the unified accounting results of regional GDP, the regional GDP of the city in 2022 was 1,690.785 billion yuan, an increase of 2.1% over the previous year at constant prices. By industry, the added value of the primary industry was 31.556 billion yuan, an increase of 3.4%; The added value of the secondary industry was 606.964 billion yuan, an increase of 1.7%; The added value of the tertiary industry was 1,052.265 billion yuan, an increase of 2.2%. The added value structure of the three industries is 1.9:35.9:62.2.