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In the economic field, debt economy is a common and complicated economic model. Simply put, debt economy is to obtain funds by borrowing and issuing bonds to promote economic development. This economic model is very common in the modern economic system, and many countries, enterprises and even individuals will use this method to meet their own capital needs.

At the national level, the government may issue treasury bonds to raise funds for infrastructure construction and social welfare. For example, some countries will build highways, railways and other transportation facilities on a large scale, and these projects need a lot of capital investment. The government will attract investors to buy them by issuing government bonds, thus obtaining funds to support the development of the projects. For enterprises, in order to expand production scale and carry out technological innovation, they will also borrow money from banks or issue corporate bonds. Like some emerging science and technology enterprises, in the process of developing new products, they need a lot of money for scientific research investment and equipment purchase, so they will choose debt financing to solve the funding problem.

Triangular debt is a special and thorny phenomenon in debt economy. Triangular debt refers to the debt chain formed by mutual arrears of payment between enterprises. In this case, enterprise A owes money to enterprise B, enterprise B owes money to enterprise C, and enterprise C may owe money to enterprise A, forming a complex debt cycle.

The influence of triangular debt is various. For enterprises, it will seriously affect the capital turnover of enterprises. When an enterprise’s payment is in arrears by other enterprises, its own funds cannot be withdrawn in time, which leads to the enterprise’s failure to pay the payment of raw material suppliers and the wages of employees on time, thus affecting the normal production and operation of the enterprise. In the long run, it may also lead to the reduction of the production scale of enterprises and even face the risk of bankruptcy.

From the macro-economic perspective, triangular debt will affect the operational efficiency of the whole economy. A large number of enterprises fall into the dilemma of triangular debt, which will make the capital flow in the market not smooth and hinder the rational allocation of resources. Debt disputes between enterprises may also trigger a series of legal proceedings and increase the transaction cost of society.

In order to understand the debt economy and triangular debt more intuitively, the following table is used for comparison:

In short, debt economy and triangular debt are both important issues that need to be paid attention to in economic operation. Correctly understanding and handling them is of great significance for maintaining economic stability and healthy development.

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　　Reform and opening up is the most distinctive feature of contemporary China and the most distinctive banner of the Communist Party of China (CPC) in the new historical period. Since the 18th National Congress of the Communist Party of China, under the strong leadership of the CPC Central Committee with the Supreme Leader as the core, the overall goal of comprehensively deepening reform has been set, and the reform has changed from partial exploration and breaking through the ice to systematic integration and comprehensive deepening, thus creating a new situation for China’s reform and opening up.

　　Deepen reform in an all-round way and stimulate vitality

　　Since the 18th National Congress of the Communist Party of China, China has faced a complicated and severe situation in promoting reform and opening up, but the pace of comprehensively deepening reform is firm.

　　Internationally, the international environment facing China is generally favorable, but positive and negative factors are intertwined. Domestically, the economy is changing from medium-high-speed growth to high-quality growth, and the development faces new tasks of power transformation, mode transformation and structural adjustment. Some deep-seated institutional and institutional problems and barriers to solidification of interests are increasingly emerging, and the reform has entered a critical period and deep-water areas.

　　Hit the water in the middle stream, and those who are eager to advance; When people get halfway up the mountain, only the brave win. The reform has made full efforts and made many breakthroughs, and it has been comprehensively promoted and accumulated.

　　Focusing on further liberating and developing social productive forces, liberating and enhancing social vitality, China’s "streamline administration, delegate power, strengthen regulation and improve services" reform has been further promoted, reforms in key areas have been accelerated, an international business environment based on marketization and rule of law has been accelerated, and the endogenous power of the market has been optimized and improved.

　　— — Stimulate the vitality of market players and achieve new results in reform.

　　The potential of micro-subjects is further released. In November 2018, a private enterprise symposium was held in Beijing, and a series of policy measures were put forward to support the development and growth of the private economy, which created a better development environment for the private economy.

　　By the end of 2021, there were 154 million registered market entities in China, including 48.42 million enterprises and 103 million individual industrial and commercial households, with private enterprises and small and medium-sized enterprises accounting for over 90%. The rapid growth of newly established market players has played an important role in promoting high-quality economic development and stabilizing employment. At the same time, the burden of market players was reduced by more than 2.6 trillion yuan in the whole year, and the new tax reduction and fee reduction exceeded 1 trillion yuan. The balance of small and micro loans in the country increased by 27.3% year-on-year, which played a huge role in "staying green and winning the future".

　　— — Press the "fast forward button" in the reform of state-owned enterprises.

　　In June 2020, the 14th meeting of the Central Committee for Comprehensively Deepening Reform deliberated and adopted the Three-year Action Plan for State-owned Enterprise Reform (2020— 2022), which is a programmatic document for deepening the reform of state-owned enterprises in China in the new stage of development.

　　In 2021, with a series of major strategic reorganization and professional integration, such as China Star Network, China Logistics and China Rare Earth Group, the state-owned economy will further move towards strategic emerging industries. The reform of mixed ownership of state-owned enterprises continued to deepen. In 2021, central enterprises implemented more than 890 mixed ownership reforms and introduced more than 380 billion yuan of social capital. The three-year reform of state-owned enterprises has achieved 70% of the target tasks.

　　— — New steps have been taken in building a high-standard market system.

　　Market system is the carrier of market economy. Since the 18th National Congress of the Communist Party of China, the CPC Central Committee has attached great importance to the construction of a high-standard market system, and the decisive role of the market in resource allocation has been increasingly enhanced.

　　In February 2021, with the release of the Action Plan for Building a High-standard Market System, another powerful measure to speed up the improvement of the socialist market economic system began to be implemented. At the end of the same year, the Central Committee comprehensively deepened the 23rd meeting of the Reform Commission, deliberated and adopted the Opinions on Accelerating the Construction of a National Unified Market, and pointed out that to build a new development pattern, it is urgent to speed up the construction of an efficient, standardized, fair competition and fully open national unified market, establish a national unified market system and rules, and promote the smooth flow of commodity elements and resources in a wider range.

　　With the great progress in the construction of the market system, the market scale and volume are constantly increasing, the market structure is continuously optimized, and the market development environment is continuously improved, and the external attraction of the domestic market is obviously enhanced.

　　Implement a more proactive opening-up strategy

　　In September, 2021, China International Fair for Trade in Services, Beijing, in the first digital service area, virtual reality glasses, unmanned vehicles and drones showed a picture of future digital life … … In this year, China’s supply-side structural reform has achieved new results, and the trend of industrial structure upgrading is more obvious. The high-tech manufacturing industry and equipment industry have developed rapidly, and new products, new formats and new models have emerged in the fields of sharing economy and digital economy, which has become the latest footnote for building a new development pattern.

　　General Secretary of the Supreme Leader pointed out that opening to the outside world is China’s basic national policy; Taking the domestic macro-cycle as the main body is by no means a closed operation behind closed doors, but by exerting the potential of domestic demand, the domestic market and the international market can be better connected, and the international and domestic markets and resources can be better utilized to achieve stronger and sustainable development.

　　Accelerate the promotion of better connectivity between the domestic market and the international market. In 2013, China became the world’s largest commodity trading country, with the total import and export volume reaching 4.16 trillion US dollars. In 2021, China’s import and export scale reached 6.05 trillion US dollars, a record high. Meanwhile, the trade structure continued to improve. In 2021, the import and export volume of general trade accounted for 61.6% of the total import and export volume, and the export volume of mechanical and electrical products accounted for 59.0% of the total export volume. Structural optimization enhanced the stamina of foreign trade; The import and export volume of cross-border e-commerce reached 1.98 trillion yuan, an increase of 15.0% over the previous year, and the number of overseas warehouses exceeded 2,000. The new model has become an important support for foreign trade development.

　　Actively expand imports, release the potential of domestic demand, and make a strong domestic market the main engine of its own development and the accelerator of common development. In 2018, the first China International Import Expo was held in Shanghai, which was the first national-level exhibition with the theme of import in the world. In 2021, the 4th China International Import Expo(CIIE) held an unprecedented grand occasion. More than 2,900 enterprises from 127 countries and regions participated in the exhibition, and China International Import Expo(CIIE) became a "demonstration window" to build a new development pattern.

　　Promote the joint construction of the "Belt and Road" and make new progress. In recent years, more than 200 cooperation documents have been signed with 147 countries and 32 international organizations to jointly build the "Belt and Road". Over the years, China-Europe trains have broken through 50,000 trains and transported more than 4.55 million TEUs. Building the "Belt and Road" has become a popular platform for international public goods and international cooperation in the world today.

　　The construction of Pilot Free Trade Zone and Hainan Free Trade Port promotes institutional opening. On September 29, 2013, China (Shanghai) Pilot Free Trade Zone was put into operation, and a national experiment to explore new ways and accumulate new experiences for comprehensively deepening reform and opening up set sail here. At present, China has set up 21 pilot free trade zones in batches, covering the east, west, north and south, and gradually growing into an important pole to stimulate China’s economic growth.

　　… …

　　Opening up will not stop, and reform will not stop. The CPC Central Committee with the Supreme Leader as the core made a scientific judgment on the economic situation, made timely adjustments to the development concepts and ideas, and guided the steady and healthy development of China’s economy and society. The open China injected strong kinetic energy and warmth into the recovery of the world economy.

　　Focus on establishing a basic institutional framework in various fields.

　　Since the 18th National Congress of the Communist Party of China, under the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the New Era, Socialism with Chinese characteristics’s market economy system has been continuously improved. The basic institutional framework in various fields has been basically established, and many fields have achieved historic changes, systematic remodeling and overall reconstruction.

　　Through the comprehensive deepening of reform and opening up, we have formed a strong domestic economic cycle system and a solid basic disk, and continuously increased the attractiveness of global factor resources, competitiveness in fierce international competition, and driving force in global resource allocation.

　　In 2022, the General Office of the State Council issued the "Overall Plan for Comprehensive Reform of Factor Marketization Allocation" to promote the further development of factor marketization allocation reform. We will carry out pilot projects for comprehensive reform of market-oriented allocation of factors, strive to break down institutional and institutional obstacles that hinder the independent and orderly flow of factors, and comprehensively improve the efficiency of coordinated allocation of factors. According to the plan, by 2025, the pilot tasks will be basically completed, and the market-oriented allocation reform of factors will achieve landmark results, making an important demonstration for improving the national factor market system.

　　The Guiding Opinions on Accelerating the Construction of a Unified National Electricity Market System was published in February this year, which started a new round of power system reform. According to the Guiding Opinions, by 2030, the national unified power market system will be basically completed, and the sharing and mutual assistance of power resources and optimal allocation will be promoted on a larger scale throughout the country, laying the foundation for economic development.

　　The new open economic system at a higher level has reached a new level. We are accelerating the construction of new international economic and trade relations, promoting coordination and cooperation among major powers, deepening economic and trade relations with neighboring countries, strengthening solidarity and cooperation with developing countries, expanding mutual benefit and win-win results, and actively creating a good external environment.

　　The negative list of foreign investment access in the 2021 edition of the National Pilot Free Trade Zone was further reduced. After the implementation in early 2022, the manufacturing items on the negative list of the Pilot Free Trade Zone were cleared.

　　On January 1, 2022, the Regional Comprehensive Economic Partnership Agreement (RCEP) came into effect. Building a new open economic system at a higher level ushered in a new opportunity. The RCEP origin accumulation rule will strongly promote the minimization of production costs and the optimization of trade efficiency in the region, which is conducive to strengthening the cooperation of industrial chain and supply chain in the region. At the same time, it will enhance the mutual investment growth among member States.

　　Up to now, China has signed 19 free trade agreements with 26 countries and regions, with free trade partners covering Asia, Oceania, Latin America, Europe and Africa. The trade volume between China and its free trade partners accounts for about 35% of the total foreign trade.

　　Facing the future, the closer we get to national rejuvenation, the more full of risks and challenges. However, we firmly believe that with the strong leadership of the Communist Party of China (CPC) and the United struggle of hundreds of millions of people, there will be overwhelming power. "Today, the Chinese nation is showing the world a thriving atmosphere and is moving towards a great rejuvenation at an unstoppable pace." The sonorous words of the General Secretary of the Supreme Leader show firm confidence and winning strength. (Economic Daily reporter Feng Qiyu)

　　Zhongxin. com, Guangzhou, June 6 (Fang Weibin, Jiang Xiaobo, Wang Xisong) Guangdong Marine Police Bureau reported on the 6 th that recently, it seized a batch of suspected smuggled frozen products in the waters of Zhanjiang Port, Guangdong Province, seized an iron-clad transport ship on the spot, and arrested three suspects. The frozen products were about 485 tons, and the case value was about 40 million yuan.

　　According to the report, at 0: 20 on May 30, the Guangdong Marine Police received a report from the masses that there were smuggling activities in the waters near Zhanjiang Port in Zhanjiang City. The bureau immediately assigned the law enforcement boat of Zhanjiang Marine Police Bureau of Guangdong Province to the target sea area for investigation.

　　At about 1 o’clock, the law enforcement boat arrived at the target sea area. After searching the sea, it was found that a ship was very suspicious. Law enforcement officers quickly locked the suspected ship, shouted a warning to it and stopped the ship for inspection. However, the suspected ship refused to cooperate with the inspection in an attempt to speed up the escape. Law enforcement officers immediately pursued it and intercepted the suspected ship in the waters off Zhanjiang Seaside Shipyard, and controlled three suspects on the spot.

　　After investigation, it was found that the suspected ship was an iron transport ship, with a cargo hold behind the bridge. The cargo hold was filled with white and black plastic woven bags, which contained about 485 tons of frozen products such as beef, brisket, tripe, beef tendon and donkey offal of unknown origin, with a case value of about 40 million yuan. The crew on board failed to provide proof of the relevant legal origin of the goods loaded on board, and law enforcement officers detained the ship and frozen products according to law.

　　At present, the case is under further investigation.

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.

　　synopsis

　　Socialist core values are the concentrated expression of contemporary China spirit, which embodies the common value pursuit of all China people and is a powerful force to unite people’s hearts and gather people’s strength. In the new era, the construction of socialist core values has been further promoted and achieved remarkable results. We should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the New Era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, and better inspire China’s strength with the spirit of China.

　　Core values are an important stabilizer of a country. Whether we can build core values with strong appeal is related to social harmony and stability and the long-term stability of the country. General Secretary of the Supreme Leader made important instructions on propaganda and ideological and cultural work, emphasizing "focusing on cultivating and practicing socialist core values". Cultivating and practicing the socialist core values is the basic project to gather the spirit and strengthen the foundation. Since the 18th National Congress of the Communist Party of China, the CPC Central Committee with the Supreme Leader as the core has attached great importance to ideological work and incorporated upholding the socialist core value system into the basic strategy of upholding and developing Socialism with Chinese characteristics in the new era. In the new era and new journey, propaganda and ideological and cultural work is facing new situations and new tasks. We should adhere to the guidance of the Supreme Leader’s Socialism with Chinese characteristics Thought in the new era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, further promote the construction of socialist spiritual civilization, and gather the majestic strength of unity and struggle for the great rejuvenation of the Chinese nation.

　　Cultivating and practicing the socialist core values is the basic project to gather the spirit and strengthen the foundation.

　　The socialist core values are the concentrated expression of contemporary China spirit, which embodies the common value pursuit of all China people. Cultivating and practicing the socialist core values is an important task to uphold and develop Socialism with Chinese characteristics in the new era, and it is also an inevitable requirement to unite social consensus and enhance people’s spiritual strength. It is necessary to cultivate and practice the socialist core values, so that all the people can closely unite in ideals, beliefs, values and moral concepts, and constantly consolidate and develop the common ideological foundation for the United struggle of all the people.

　　An important way to unite social consensus. General Secretary of the Supreme Leader pointed out: "There are various values and orientations in any society. To unite the will and strength of the whole society, we must have a set of core values that are compatible with the economic foundation and political system and can form a broad social consensus." People’s heart is the biggest politics, and consensus is the driving force for forging ahead. Human society is in a period of great development, great change and great adjustment. All kinds of ideas and cultures around the world are stirring with each other, and our social ideas and concepts have undergone profound changes. Cultivating and practicing socialist core values and adhering to the guidance of socialist core values are conducive to correctly handling the relationship between main melody melody and diversity, consistency and diversity, effectively integrating social consciousness, striving for the greatest common denominator, drawing the greatest concentric circle, mobilizing all positive factors to the maximum extent, uniting all those who can unite, and maximizing the consensus and joint efforts of the whole society.

　　The inherent requirement of strengthening people’s spiritual strength. General Secretary of the Supreme Leader pointed out: "Socialist core values and Chinese excellent traditional culture are powerful forces to unite people’s hearts and gather people’s strength." To realize the great rejuvenation of the Chinese nation requires not only strong material strength, but also strong spiritual strength. Socialist core values are formed in the great practice of leading hundreds of millions of people to struggle for a long time. They have profound historical background and solid realistic foundation, profound nationality, distinctive times, inherent advancement and extensive inclusiveness. Cultivating and practicing the socialist core values will help us hold high the banner of ideals and beliefs, carry forward the national spirit and the spirit of the times, improve the ideological realm of the people, enrich the spiritual world of the people, unite the national will with common ideals and beliefs, and inspire China’s strength with the spirit of China.

　　An important support for maintaining the independence of national spirit. General Secretary of the Supreme Leader pointed out: "Cultivating and carrying forward the socialist core values and enhancing Socialism with Chinese characteristics’s road confidence, theoretical confidence, institutional confidence and cultural confidence are important supports for maintaining the independence of the national spirit." Core values are the spiritual ties that a nation depends on and carry the spiritual pursuit of a country and a nation. Only by standing up and standing firmly in spirit can a nation stand firm in the tide of history. In today’s world, exchanges and exchanges between different civilizations are more frequent. We must speed up the construction of a value system that fully reflects China’s characteristics, national characteristics and characteristics of the times, and strive to seize the commanding heights of the value system. Cultivating and practicing the socialist core values is conducive to strengthening our faith and confidence in our own value pursuit, consolidating cultural subjectivity, constantly strengthening the "four self-confidences" and standing among the nations of the world with a high degree of national pride and self-confidence.

　　Significant achievements have been made in cultivating and practicing socialist core values in the new era.

　　Thought is the forerunner of action, and theory is the guide of practice. General Secretary of the Supreme Leader pointed out: "It is necessary to strengthen the construction of the socialist core value system, actively cultivate and practice the socialist core values, comprehensively improve the moral quality of citizens, and cultivate a good fashion of knowing honor and disgrace, stressing righteousness, making contributions and promoting harmony." A series of important expositions by the Supreme Leader General Secretary provide a scientific action guide for cultivating and practicing socialist core values. Under the scientific guidance of the Supreme Leader’s Socialism with Chinese characteristics Thought in the new era, the construction of China’s socialist core values has been further promoted and achieved remarkable results.

　　The CPC Central Committee with the Supreme Leader as the core has taken a series of major measures to cultivate and practice the socialist core values. Give full play to the policy-oriented role, and successively formulate and issue a series of guiding policy documents such as Opinions on Cultivating and Practicing Socialist Core Values and Guiding Opinions on Further Integrating Socialist Core Values into the Construction of the Rule of Law. The socialist core values run through the daily situation propaganda, achievement propaganda, theme propaganda, typical propaganda, hot spot guidance and public opinion supervision, and run through the cultural activities and literary works that the people love, and actively promote the online promotion of socialist core values. Insist on cultivating people with socialist core values, promote socialist core values into textbooks, classrooms and minds, and strive to cultivate new people of the times who are responsible for national rejuvenation. Promote the integration of socialist core values into various spiritual civilization creation activities, and strive to draw rich nutrition from Chinese excellent traditional culture, so as to better cultivate the spiritual world of contemporary Chinese. Closely link the promotion of socialist core values with people’s daily lives, make efforts to implement them in detail, and strive to transform socialist core values into people’s emotional identity and behavior habits. We will continue to strengthen institutional guarantees, improve the codes of conduct such as citizens’ conventions, village rules and regulations, and student codes, integrate socialist core values into the rule of law, and promote the normalization and long-term promotion of cultivating and practicing socialist core values.

　　From advocacy to practice, from concept to action, the core values of socialism have been widely promoted, and the people’s ideological consciousness, moral standards and civilized accomplishment have been significantly improved. In the process of cultivating and practicing socialist core values, the exemplary role of advanced models has been fully exerted, the activities of mass spiritual civilization have been deepened, the construction of social morality, professional ethics, family virtues and personal morality has achieved fruitful results, the soft power of national culture and the influence of Chinese culture have been significantly improved, and the socialist core values have been internalized, externalized and educated to the public, giving full play to the important role of rallying social consensus and enhancing people’s spiritual strength. By cultivating and practicing the socialist core values, and constantly strengthening the spiritual calcium of the Chinese nation and the soul of rejuvenating the country in contemporary China, the "four self-confidences" of the whole party and people of all ethnic groups have been significantly enhanced and their mental outlook has become more energetic.

　　Give further play to the leading role of socialist core values

　　In the new era and new journey, there must be new weather and new actions. To build a socialist modern country in an all-round way and promote the great rejuvenation of the Chinese nation in an all-round way, we need to further play the leading role of socialist core values and let the people of all ethnic groups in the country think in one place and work hard in one place. We should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the new era, thoroughly study and implement the cultural thought of the Supreme Leader, focus on cultivating and practicing socialist core values, and gather stronger spiritual strength for the great rejuvenation of the Chinese nation.

　　Promote the normalization and institutionalization of ideal and belief education and build a common ideological foundation for the United struggle of people of all ethnic groups throughout the country. Vigorously carry forward the spiritual pedigree of the Communist Party of China (CPC) people with the great spirit of party building as the source, carry out publicity and education on the history of the Party, the history of New China, the history of reform and opening up, the history of socialist development and the history of the development of the Chinese nation, deepen the education of patriotism, collectivism and socialism, guide people to strengthen the "four self-confidences", and enhance their confidence and determination to stick to their common ideals and realize their common dreams. Strengthen the protection and utilization of red sites, revolutionary cultural relics and memorial facilities, make good use of communist party Historical Exhibition Hall and patriotism education base, and play the role of red tourism education. Make good use of the "fresh values" of advanced models, persistently publicize the revolutionary heroes, the model of the times, the moral model, the most beautiful figures, etc., and publicize the typical figures from all walks of life who study hard and dedicate themselves, and carry forward the power of example.

　　Grasp the key groups of young people and cultivate new people of the times who can shoulder the heavy responsibility of national rejuvenation. Guided by socialist core values, we should cultivate talents who can shoulder the heavy responsibility of the times, run socialist core values through basic education, higher education, vocational education and continuing education, innovate working methods, promote the integration of ideological and political education in universities, primary and secondary schools, and guide young people to buckle their first buttons and take the first step in life. Adhere to moral education and moral education as the first priority, cultivate innovative consciousness, encourage young people to be brave in hardships and dangers, unite and struggle, shoulder the heavy responsibility of the times to realize the great rejuvenation of the Chinese nation, and ensure that the party’s cause and the construction of a socialist modernization power will be followed by others.

　　Adhere to the rule of virtue and law, and integrate socialist core values into the whole process of rule of law construction and social governance. Constantly improve the legal and policy system to carry forward the socialist core values, improve the people’s awareness of the rule of law and moral consciousness, integrate the mandatory provisions of laws and regulations with the internal spirit of the socialist core values, and cultivate people’s legal beliefs and concepts of the rule of law. Strengthen the supporting role of morality in the rule of law, implement the civic morality construction project, lead the construction of social morality, professional ethics, family virtues and personal morality with socialist core values, improve the long-term mechanism of honesty construction, and create a social trend of advocating morality and doing good.

　　Promote the construction of socialist spiritual civilization and make socialist core values become people’s emotional identity and behavior habits. Insist on breaking and breaking at the same time, be guided by trees and establish rules, and resolutely resist, confuse and clarify the words and deeds of advocating money worship, hedonism and extreme individualism, and the phenomena of breaking through the bottom line of value, subverting moral cognition and violating public order and good customs. Adhere to the people as the center, optimize the selection and commendation activities of civilized cities, civilized villages and towns, civilized units, civilized families and civilized campuses, and improve the effectiveness of work. Innovate ways and means of spiritual civilization construction, enrich people’s spiritual and cultural life, and constantly satisfy people’s yearning for a better life. Integrating the socialist core values into all aspects of social development and social life has become people’s emotional identity and behavior habits. Let the socialist core values be as ubiquitous and ubiquitous as the air, become the common value pursuit of all the people, and become the code of conduct that the people use every day without knowing it.

　　(Written by: Xu Zhong Wang Qingjie)

　　
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

[Original of Truck House] Because pulling agricultural and sideline products can enjoy high-speed and free policy treatment, many card friends are also more willing to pull green links, but we should keep our eyes open about pulling green links.

Since it is a "green channel", there must be many restrictions. It is impossible for all agricultural products to take the green channel. Recently, card friends in Shaanxi have suffered in this respect.

Recently, when a netizen dragged Apple through Shaanxi Ankang Expressway toll station, the toll collector said that the card friend’s vehicle could not enjoy the green channel treatment. Although the load of the vehicle met the requirements of Lutong, the toll must be paid in full.

Here, many card friends are puzzled. Ran He is listed in the catalogue of fresh agricultural products. Why does Ankang toll collector decide that the car apple does not belong to Lutong? Is this apple kicked out of the catalogue of agricultural products by Ankang?

The toll collector said that it is true that apples are green products, but the apples on the car have rotted in a large area and do not meet the definition of "fresh".freshIs the first condition to take the green link.Since you don’t meet the requirements, why can you enjoy green treatment?

The staff of Shaanxi Traffic and Transportation Service Hotline responded to the incident, saying that there is no dispute that apples belong to Lutong products. According to the on-site toll collector’s inspection, the apples loaded on the vehicle are all rotten apples, commonly known as "falling fruit". Therefore, even if the load of the whole vehicle is within the standard range, the cargo occupies more than 80% of the car volume, but because the fruits on the vehicle are rotting in a large area and are very stale, it is compliant not to let Lutong go.

The staff of Shaanxi Expressway Baihe Management Office introduced that enjoying the green channel policy refers to fresh vegetables and fruits, and the staff checked the vehicles, and the loaded goods (apples) had obvious rot.It does not meet the requirements of "liveliness" stipulated in the document, so it is feasible not to give green channel treatment.

According to the spirit of the document "Notice on Further Optimizing the Green Passage Policy of Fresh Agricultural Products Transportation" issued by the three ministries and commissions, fresh agricultural products enjoying the "green passage" policy refer to fresh vegetables, fruits, fresh aquatic products, live livestock and poultry, fresh meat, eggs and milk. If it is found that it is mixed or counterfeit and does not meet the policy requirements, it needs to be handled according to the regulations.

That is to say, the toll collectors have the right to inspect the vehicles carrying Lutong. As long as the loaded goods do not meet the requirements and specifications in the Catalogue of Fresh Agricultural Products, or the bearing quality does not meet the minimum load requirements of the documents, they are not allowed to take the green channel and must pay the toll.

● 　Postscript

Not all green products are green links. There used to be pineapple, pineapple and cherry cherries, but now there are fresh and rotten ones. I wonder what card friends think about the fact that rotten fruits are not green links. You can make your voice heard in the comments section. (Text/Wei Qingbo Source/Shaanxi Expressway Baihe Management Office)

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Intel’s ninth-generation Core has now begun to spread out gradually, and it has launched a comprehensive fight with AMD’s Ruilong.

The performance is quite powerful, but the corresponding power consumption and price are also amazing, soRelatively speaking, many students will pay more attention to the i7-9700K. After all, it is more balanced in terms of specifications, performance and price.

Today, I will bring the test report of the first i7 processor without hyper-threading technology.

Description of product specifications: The appearance of i7-9700K is exactly the same as that of i9-9900K, so I won’t repeat it here. Here is a brief look at the product specifications.

Compared with i9-9900K, the obvious difference is that the core scale has changed from 8 cores and 16 threads to 8 cores and 8 threads, and the hyper-threading technology has been cancelled. In fact, except i9-9900K, all the nine generations of Core have no hyper-threading.

The core frequency drops slightly,The dual-core turbo frequency is 4.9GHz and the full-core turbo frequency is 4.6GHz.

Introduction of test platform:

This time, the motherboard is Huaqing Z390-TAICHI, which is also a product with high attention at present. After careful disassembly, it is found that this product is quite different from Gigabyte Asustek’s design idea, which is very interesting.

The CPU base is still LGA1151, Intel’s ancestral base, which will be used in 2020.

A set of filter capacitors can be seen on the back of the CPU base, and Huaqing also added two additional polymer capacitors to improve the stability of the motherboard current.

The power supply socket of CPU is 8+4PIN, mainly to cope with i9-9900K.

The power supply of CPU is 10+2+2 phases, and heat pipe fins are used to assist heat dissipation, that is to say, the CPU core supplies 10 phases, the centralized display supplies 2 phases and the bus supplies 2 phases.

There is also a R67161PY chip next to the CPU base, which is used to unlock the CPU external frequency adjustment limit from the wiring point of view.

There are still four memory slots, which support dual-channel DDR4.

There are five expansion slots on the motherboard, which are arranged as X1X16NAX1X8NAX4 according to the PCI location, among which the slots of PCI-EX1 are all designed with notches, which can be compatible with high-bandwidth PCI-E expansion cards, such as SATA cards of PCI-E X4.

There are three M.2 SSD expansion slots on the motherboard, all of which can support PCI-E X4 and SATA channels. However, the slots on the left (M2_1) and the right (M2_3) in the figure occupy two SATA interfaces, which are mutually exclusive. The slot in the middle (M2_2) will eat a SATA interface when using the SSD of SATA channel. The M2_3 slot of the motherboard is covered with a metal heat sink.

There is a 24PIN power supply interface and two USB 3.0 front sockets on the side of the motherboard near the memory slot, one of which is horizontal.

The front USB 3.1 Type-C socket can be seen between the memory slot and the SATA interface. The ASM1074 chip next to it is the channel for two USB 3.0 sockets on the motherboard.

The chip of USB Type-C is on the back of the motherboard, and it is an ASM1543. It seems that the mode of chipset direct connection USB 3.1 Type-C used by Huaqing in the past is not very effective, and this time an extra bridge chip is added.

There are 8 SATA interfaces on the motherboard, of which 6 are provided by the chipset natively, 2 are extra bridges, and the bridge chip is ASM1061.

At the bottom of the motherboard is a row of expansion slots. From the chipset side, from right to left, they are SYS FAN, chassis front control pin, BIOS test pin, BIOS cleaning pin, 80 debug lamp, front USB 2.0 and front USB 2.0 (single interface 4PIN). The single-port USB 2.0 pin is a bit strange. This interface is because a USB 2.0 was eaten by wireless Bluetooth, so the general motherboard will not let go directly, because the wires of the chassis are now in groups of two. It’s ok to control the cold headlight group inside the chassis.

Close to the audio system, from right to left in the figure are TPM, SYS FAN, lightning extension pin, RGB 4PIN lamp strip pin *2, digital LED strip pin and front audio pin.

In addition to the two SYS FAN pins at the bottom of the motherboard, the motherboard has three pins between CPU power supply and memory slot, two pins next to PCI-E X1, and one pin between memory slot and M.2 SSD slot. The number of fan pins is still sufficient.

The rear window interfaces of the motherboard are, from the left in the figure, clear COMS button, Wi-Fi antenna interface, USB 3.0*2+PS2, HDMI+DP, USB 3.0*2, USB 3.1*2+LAN, USB 3.1 A+C +LAN, and 3.5 audio *5+ digital fiber.

The main chip of the audio part is ALC1220 of Little Crab, and the power amplification effect of the audio interface in the rear window of the main board is provided by ALC1220 chip. The front audio provides power amplification effect through N5532 chip.

The motherboard adopts dual Gigabit network cards and the mainstream Intel i211+i219 scheme.

The motherboard is integrated with a wireless network card, and the model is Intel’s 3168N.

You can see an ASM1562 chip next to the motherboard chipset, which is two USB 3.1 TYPE-A interfaces corresponding to the motherboard rear window. The three bridge chips behind the SATA interface at the top of the picture are used to switch with the M.2 SSD slot.

The two P13EQX chips in the rear window of the motherboard are used for signal relay of ASM1562 chip and two USB 3.1 TYPE-A interfaces in the rear window of the motherboard.

The ASM1543 on the back of the motherboard provides a bridge for USB 3.1 A+C on the rear window of the motherboard.

There are two L04083B chips at the end of PCI-E X16 slot on the motherboard, which are used to bridge the bandwidth of the graphics card slot to support the 8+8 dual card mode of the graphics card.

Next, the motherboard was disassembled, and the number of armor of Huaqing motherboard was not particularly exaggerated.

The power supply of the motherboard is 10+2+2 phases, the CPU core part is 10 phases, and the centralized display part is 2 phases, both of which share the same scheme. The PWM chip is IR 3520, which is a 6+2-phase control chip, and the DRIVER is extended to 10+2-phase power supply through IR 3598; The input capacitance is 8 solid-state capacitors of Nijikang FP12K, 16V 172 microfarads; MOS adopts one TI 87350D drMOS for each phase, and one MOS can achieve the function of bridge. The inductance is a closed inductor with one inductance R47 per phase; The output capacitors are 10 in the CPU core part and 3 in the display part. The capacitors are all Nijikang FP12K solid-state capacitors with 6.3V 561 microfarads.

The other two items on the motherboard are for the power supply of VCCSA and VCCIO, and the materials used in this part have been reduced. The input capacitance is shared by one Nijikang FP12K solid-state capacitor, with 16V 101 microfarads; MOS is 1 7341EH； per phase; The output capacitor is 1 Nijikang FP12K solid capacitor per phase, 2.5V 821 microfarads.

Memory power supply is a luxury, using 2-phase power supply directly. The PWM chip is UP1674P；; The input capacitance is 2 solid-state capacitors of Nijikang FP12K, 6.3V 561 microfarads; MOS is 87350D drMOS with one TI per phase, which is the same as CPU power supply; The inductance is a closed inductor with one inductance R30 per phase; The output capacitor is 4 solid-state capacitors of Nijikang FP12K, 6.3V 561 microfarads.

There is also a hardware monitoring chip of nuvoTon NCT6791D and a super IO chip of Nuvoton NCT 5567d on the motherboard. The integration level is still a little low.

There is also an ASM1184 chip on the motherboard, which is used to switch PCI-E channels and bridge one PCI-E 3.0 into four PCI-E2.0. Generally speaking, the design ideas of Huaqing and Gigabyte Asustek are quite different. Asustek Gigabyte prefers to use a lot of SWITCH switching and speed reduction to solve the problem of insufficient chipset channels. Huaqing, on the other hand, prefers to use more HUB chips for switching, so as to minimize the loss of PCI-E bandwidth. However, the cost is also obvious. More chips reduce the integration of the motherboard.

Introduction of test platform:

First, introduce the test platform.

The memory is DDR4 8G*4 of the pirate ship. The actual operating frequency is 2666C15.

There will be a test with a unique display in the middle, and the graphics card is the water-cooled version of VEGA 64 by Dylan Hengjin.

SSD is three pieces of Intel, and the system disk uses the mainstream 535 to ensure that the test is closer to the average user. 240G is used as the system disk, and 480G*2 is mainly used to play test games.

　　 The NVMe SSD test used Intel 750 400G.

The radiator is the cool ice god G360RGB.

The power supply is an Antaike HCG-X1000.

The test platform is BC1 of Streacom.

Introduction of performance test items:

For children’s shoes interested in further understanding the comparative performance, detailed test data will be provided here. If you don’t want to see it, you can skip to the last summary.

The test will be roughly divided into the following parts:

-CPU performance test: including system bandwidth, CPU theoretical performance, CPU benchmark test software, CPU rendering test software and 3DMARK physical score.

-Integrated graphics card test: including theoretical performance test, benchmark test software and professional software benchmark of integrated display.

-Matching stand-alone test: including stand-alone benchmark test software, stand-alone game test and stand-alone professional software benchmark.

-Power consumption test: Power consumption is measured under the platform of centralized display and single display.

－ Since this test, WBE3.0 and Android game simulator have been added, and the test items will be more and more abundant.

Performance test and analysis of CPU;

The system bandwidth test shows that the system bandwidth i9-9700K has been further improved, slightly lower than i9-9900K. Compared with i7-8700K, the improvement is mainly concentrated on L1 and L2, especially the bandwidth of L1 is increased by 40%. There is also a 10% improvement in the delay of L1L2.

The theoretical performance test of CPU is carried out with the built-in tools of AIDA64. Excluding memory bandwidth, other computing power is improved by about 40% compared with i7-8700K.

CPU performance test mainly tests some commonly used CPU benchmark software, and also includes some application software and CPU test items in the game. In this part, i7-9700K mainly has advantages in single-threaded testing, and can be close to i9-9900K. However, multithreading performance is relatively general, and some tests are not even as good as i7-8700K.

CPU rendering test, which tests the rendering ability of CPU.

The 3D physical performance test measures the physical scores in the 3DMARK test, which are mainly related to the CPU.

CPU performance test section comparison section:

According to the comprehensive statistics of CPU, i7-9700K and R7 2700X are basically on the same level, but there will be obvious gap with i9-9900K.

In fact, there is still a more tangled problem, that is, single thread and multi-thread, which has also been decomposed here.

-Single thread:Single thread is quite close to i9-9900K, about 5% behind and 5% stronger than i7-8700k.

-multithreading:Multithreading is a relatively weak part, which is about 35% behind I9-9900k, 8% behind R7 2700×8, and stronger than i7-8700K 4%.

Set display performance test:

The theoretical performance test of centralized display is carried out with the built-in tools of AIDA64. Due to the compatibility problem between Intel’s integrated display driver and WIN10 of 1709, i7-9700K did not collect data for integrated display 3D benchmark test, and mainly ran some benchmark test software.

Set display OpenGL benchmark test, and the professional software part is based on SPEC viewperf 12.1.

Set display performance test section:

Since the centralized display of i7-9700K is the same as that of i7-8700K, there is no substantial difference.

With a stand-alone test:

The graphics card is VEGA 64. Simply running i7-9700K is the highest, but the advantage is weak.

Unique 3D game test, i7-9700K will be slightly weaker than i9-9900K in the game test.

In terms of each generation, i7-9700K has a slight advantage over i9-9900K in DX9 & DX11, slightly weaker than i9-9900K in DX11, and has a great advantage in DX12, with the greatest advantage over i9-9900K.

There has always been a big controversy about the resolution in game testing, so I’ll break it down directly here. Because DX11 games account for more than half of my testing, it seems that i7-9700K will be slightly weaker than i9-9900K at both resolutions, but it will be significantly stronger than R7 2700X at 1080P.

OpenGL benchmark test alone. The OpenGL part is based on SPEC viewperf 12.1. This test is a professional operation test for graphics cards, and the gap is more related to CPU single thread.

With a separate test section:

According to the test results, the i7-9700K is quite close to the i9-9900K, which directly throws off other CPUs.

Disk performance test:

The disk test part uses CrystalDiskMark 5,1g data file to run 9 times, which can basically eliminate the test error. The tested SSDs are 535 480G and 750 400G, both of which are hung from the disk. Simply explain the concept in this test, SATA interface and PCI-E channel can be drawn from CPU or chipset (see how CPU manufacturers design). Here, for the sake of unification, all the tests are SATA from chipset and PCI-E from CPU.

Judging from the test results, i7-9700K is roughly equivalent to i9-9900K, and R5 2600X is relatively high in NVMe test mainly because some specific vulnerabilities are not fixed. Please refer to R7 2700X.

Platform power consumption test:

In terms of power consumption, the power consumption control of i7-9700K will be better. In the most extreme case, it is 40W more than i7-87000K, which is within the controllable range.

With the unique display, the overall power consumption of i7-9700K will be between i7-8700K and R5 2600X, which is well controlled.

Detailed statistics:

Summary of test results:

The comparison groups in this test are i9-9900X, R7 2700X, i7-8700K and R5 2600X. All products are close to the current positioning or price of i7-9700K.

Because the performance test environment of CPU has been changing dynamically (system, BIOS, driver), i9-9900K, i7-8700K and R7 2700X have been tested completely. The testing time of R5 2600X is in April 2018.

AMD RYZEN has undergone some changes after updating the BIOS and drivers. The problem of memory copy performance degradation found in the initial test of B450 has been fixed, but at the cost of CPU power consumption increase and NVME disk performance decline. Therefore, it can be confirmed that AMD’s microcode in 1.0.0.4 recently corrected some Spectre vulnerabilities. Overall, the CPU performance is basically unchanged (increased by 0.5%), and the NVMe performance is reduced by 5%. In the release test, the problem of current limiting of R7 2700X baking machine has also been solved, so the power consumption of R7 2700X will be revised and increased by about 15%.

As far as the performance of CPU is concerned, it is quite interesting.After synthesizing various usage scenarios, the i7-9700K and R7 2700X are on a par. Relatively speaking, the single-threaded performance of i7-9700K is more advantageous, while the multi-threaded performance of R7 2700X is more advantageous.

As far as the performance of Jixian is concerned, there is nothing to say because Jixian has not been updated.

With the unique part, the i7-9700K has become the strongest one without any accident, but it has not opened the decisive gap.

In terms of power consumption,I7-9700K is more balanced, a little higher than i7-8700K, and there will be no out-of-control situation like i9-9900K.

Here is a screenshot of the baking machine. i7-9700K can stably bake the FPU project of AIDA 64 in 4.6G.

Finally, the last horizontal comparison table is for your reference.

The performance part only compares the test items related to CPU, and does not include the results of the game performance test. Because the graphics card has been changed in the middle and the memory frequency has changed to some extent, this table can only be used for general reference for the time being. In the table, the results of previous tests (different graphics cards) are not included, and only the test results that are not affected by the graphics card are extracted. In the horizontal test, it is found that R7 2700X is slightly higher than i7-9700K. This is because the benchmark in the previous test is i7-8700K, and the reference benchmark in the horizontal test is i7-7700K all the time, so the CPU with a particularly close performance gap will be affected by the benchmark change, and its ranking will change.

Simple summary:

About CPU performance:

As far as CPU performance is concerned, i7-9700K is quite good by itself. Single-thread performance ensures the fluency of daily software use, and multi-thread performance reaches the level of i7-8700K.

On the performance of centralized display:

The display of i7-9700K has not been updated, so there is no change. With regard to the unique display: In the case of unique display, i7-9700K and i9-9900K are quite close, and they sit firmly in the first group, but relatively speaking, the influence of CPU on game performance is really not great, and there is no substantial difference above six cores.

About power consumption:

The power consumption control of i7-9700K is quite reasonable, even if the FPU is baked alone, it will not roll over. It seems that high frequency+hyper-threading is a poison to AVX instruction set. Accordingly, the B360 motherboard with solid power supply can be considered in the matching of i7-9700K, which can greatly reduce the budget of the whole machine. The motherboard suggests that the power supply of the CPU core should be greater than or equal to 6 phases.

About overclocking:

Because the power consumption control of i7-9700K is much better than that of i9-9900K, it should be easier to achieve super 5G.

Generally speaking, the performance of i7-9700K is relatively excellent, both single-threaded and multi-threaded. However, compared with other products in the market, the biggest embarrassment is that it can’t open the gap with R7 2700X, but there is a big gap in price. The boxed price difference in JD.COM exceeds that in 1000 yuan.

I7-9700K and R7 2700X are just two CPU optimization directions, i7-9700K has advantages in single thread, R7 2700X has advantages in multi-thread, and the two on the other end are also completely qualified, so in the use scenarios of these two CPUs, single-thread performance will be more important. If the price difference between i7-9700K and R7 2700X is below 15%, then i7-9700K will have obvious purchase value.

CCTV News:Yesterday (October 4th), the reporter learned from China Railway Kunming Bureau Group Co., Ltd. that China-Laos Railway has sent 7.39 million passengers and transported 8.51 million tons of goods, including 1.54 million tons of cross-border goods. In September, 1.25 million tons of goods were transported, breaking the monthly record, and the number of goods increased from more than 100 in the early days to more than 1,200.

On October 3rd, China-Laos Railway "Lanmei Express" international freight train broke through 200 trains. The "Lan-Mei Express Line" has been favored by many cross-border enterprises since it was launched. It has expanded from an initial on-demand operation to a fixed operation at least three times a week, and the cargo transportation has covered Laos, Thailand, Myanmar, Malaysia, Cambodia and Singapore.

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)

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