Topic: 16th National Congress of China Communist Youth League.

　　On the afternoon of June 11th, a report on the heroic deeds of the 16th Communist Youth League’s earthquake relief was held in the Great Hall of the People. Six heroic models and one representative of the grassroots league cadres of the heroic deeds report group on earthquake relief organized by Publicity Department of the Communist Party of China, the Central Organization Department, the General Political Department of the People’s Liberation Army and the Sichuan Provincial Committee of the Communist Party of China reported to all the representatives of the 16th Communist Youth League.

　　The delegates said that they were deeply moved and infected after listening to the report on the advanced deeds of young heroes in earthquake relief. While being baptized by their souls and sublimated, they were determined to follow the example of young heroes, actively participate in the earthquake relief struggle and contribute their youth. The following is Li Changxiu, secretary of the directly under the authority Youth League Committee of the National Development and Reform Commission.

　　The two-hour report meeting ended in a blink of an eye, and I was deeply moved by the deeds of the disaster-resistant warriors. Their heroic earthquake relief actions have shown the world that our government, army and people are United as one, United as one, indomitable, and concentrated on the glory of the traditional virtues of the Chinese nation, which moved the whole world and made all Chinese sons and daughters proud! I will take these advanced figures and typical deeds as examples with the broad masses of young cadres of the National Development and Reform Commission, carry forward the spirit of not being afraid of fatigue and fighting continuously, do a solid job in emergency coordination and support, and further play the role of a new force and commando in earthquake relief. I feel that my post is also a battlefield for earthquake relief. Together with the youth members of the National Development and Reform Commission, I will learn and carry forward the lofty spirit of heroes who are fearless, resourceful and brave, and the people’s interests are above all else. I will dare to overcome difficulties, do my duty, be the new force and commando of development and reform, and support the reconstruction of disaster areas with practical actions to serve the motherland.

Editor: Li Erqing

Wushentan Village, bacheng town City, Kunshan City, creates a water town with "black tiles and white walls, clear and refreshing". Photo by Wu Qiong

　　Small bridges and flowing water, white walls and tiles, sitting and watching dragonflies play in the water, and listening to children frolicking … … Is this rural area homesick in your memory? With the acceleration of rural environmental improvement, the beautiful rural picture of "seeing the mountains, seeing the water, remembering to stay homesick" is spreading in Jiangsu.

　　The provincial party committee and government regard the improvement of rural human settlements as the hard task of "agriculture, rural areas and farmers" and the first battle to implement the rural revitalization strategy this year and next, and make it clear that 70% of the goal of "Three-year Action Plan for the Improvement of Rural Human Settlements in Jiangsu Province" will be completed before the end of the year, and all tasks will be successfully completed by 2020. The reporter learned from the office of the joint meeting of the provincial rural human settlements improvement that the province has achieved more than half of the tasks in the three-year plan, especially since this year, all localities and departments have comprehensively promoted the improvement of rural human settlements with high quality, and the appearance of villages has improved significantly. Recently, the reporter went to many places for on-the-spot interviews.

　　Carrying rural homesickness and embodying modern civilization.

　　Passing through the grassy central park at the entrance of Wushentan Village, bacheng town, Kunshan City, and walking on the slow walking trail built by the water, the uniform white-walled and black-tile water town architecture comes into view.

　　Xing Long, secretary of the General Party Branch of Wushentan Village, told the reporter that in order to improve the living environment, on the basis of maintaining the original natural features, history and culture of the village, the village carried out infrastructure construction and village appearance improvement according to the overall effect of "black tiles and white walls, refreshing and refreshing".

　　What is visible is beautiful scenery, but what is invisible is governance. All the 13 natural villages below Wushentan Village have been introduced into property management companies, the garbage sorting facilities have been fully covered, and all domestic sewage has been managed. Twelve automatic sewage treatment stations using biotechnology have been built. At the same time, carry out environmental improvement in front of and behind the house to further enhance the village appearance.

　　"In the process of rural environmental improvement, we insist on taking into account the protection of rural pastoral features, digging deep into the ancient rhyme of history and inheriting the local context." Yu Deshan, deputy director of the Agriculture and Rural Affairs Bureau of Kunshan City, introduced that the renovation of rural human settlements pays attention to the local flavor. In the process of inheriting homesickness and excavating characteristics, it comprehensively enhances the style of Tianshui Road forest village, protects the beautiful scenery of homesickness, promotes the harmonious coexistence between man and nature, and the village form and natural environment complement each other, and builds an "upgraded village" that carries rural homesickness and reflects modern civilization.

　　Last month, Kunshan added more weight to the renovation of rural human settlements, and formulated and issued the "Assessment Method of" Red and Black List "for the renovation of rural human settlements in Kunshan City (Trial)", focusing on the supervision and assessment of rural domestic garbage disposal, rural water environment management and protection, rural public toilets management and protection, and village appearance improvement. Every month, the inspection team will check and assess one-third of the total number of natural villages, and set up a "red and black list" for the top ten and the last ten natural villages, which will be publicized in the news media and government websites. If there are outstanding problems, a rectification supervision sheet will be issued, and the whole process will be tracked and supervised, and the rectification will be implemented within a time limit. The ranking results of assessment scores are included in the annual target assessment of districts and towns, and are directly linked to the year-end 100% assessment remuneration of village cadres.

　　Preserve the texture of the village and build it without planning.

　　The clear water winds, and every family sleeps on the river. Panlou Village, Sanbao Town, tongshan district, Xuzhou used to be one of the most remote and poor villages in the southeast of Tongshan, but now it is known as "Little Jiangnan in Northern Jiangsu".

　　More than 20 years ago, when Zhang Yangang, the general secretary of the village party branch, first took office, the sanitary environment in the village was very poor. Through years of investment promotion, the enterprises in the village have continued to grow and develop. With money in his hand, Zhang Yangang began to think about how to make the living environment of the villagers beautiful. According to the development concept of "people change the environment, and the environment shapes people", Panlou Village has implemented the village environment upgrading project drastically. "Since last year, we have combined public space management to further improve the appearance of villages, implement road hardening, put all weak network cables into the ground, dredge the river ponds, and turn stagnant water into living water. Now there are fish in the river." As Zhang Yangang said, he led the reporter to the Little Square in the village. As the sun set, the villagers who were preparing to dance in the square dance gathered one after another. "This used to be an idle wasteland. We made it into a square and installed an electronic screen for the villagers to entertain and exercise." Under the premise of not changing the texture of the village, Panlou Village has greatly changed its appearance. Now walking in the village, the houses are neat and beautiful, the squares are scattered, the streets are spacious and clean, and the water is clear and the shore is green.

　　According to Wu Yun, deputy director of the Agriculture and Rural Affairs Bureau of tongshan district, the improvement of rural human settlements is the highlight of Tongshan’s rural revitalization strategy. "Last year, the district carried out the demonstration of rural human settlements, the improvement of thousands of villages, and the centralized residence of thousands of households ‘ 100 million projects ’ Through the landscape renovation of villages, beautiful villages are gathered into pieces and connected into lines, and bonsai becomes scenery. "

　　In the process of environmental improvement, Tongshan insists on no planning and no construction, paying special attention to highlighting the distinctive village features and making the countryside more like the countryside. "A planning and design team has been set up in the district to create different types of villages with different characteristics according to resource endowment, human characteristics, historical inheritance, industrial form and natural texture." Wu Yun said.

　　Attract social capital and implement market operation.

　　The abandoned cowshed has been transformed into an exquisite guest room with a price of more than 1,000 yuan a night, and a cafe with full atmosphere has been built on the former site of the pigsty. The small bungalow where farm tools were once piled up is now a popular pub … … In Sujia Village, Moling Street, Jiangning District, Nanjing, the "Hometown with Sujia" cultural tourism project, which was transformed from more than 60 farmhouses, is hard to find a room every weekend.

　　"Our company invested 150 million yuan to carry out the overall transformation of the village environment. It officially opened on April 20 this year and has now received 150,000 tourists." Wen Ying, the person in charge of the township companion travel, told the reporter that Langshi property was introduced in the village and a professional cleaning and security team was formed. In Sujia Village, all domestic sewage will be filtered and purified by sewage treatment facilities before being discharged. Walking on rural roads, there will be garbage sorting facilities at intervals, and villagers will consciously sort domestic garbage.

　　Rural environmental improvement needs the participation of the whole society, and the addition of social capital is conducive to reducing the burden on the government and forming a joint effort of co-construction and governance. Yang Ming, Social Undertaking Promotion Section of Agriculture and Rural Affairs Bureau of Jiangning District, introduced that the renovation of rural human settlements in the whole area actively attracts social capital and state-owned enterprise groups to participate. In addition to projects involving social capital such as "Hometown with Sujia", state-owned enterprises such as District Urban Construction Group and Jiaojian Group are also paired with five streets for construction, and the group organizes the implementation of environmental renovation projects and the streets cooperate.

　　It is understood that this year, our province has budgeted over 10 billion yuan for the improvement of rural human settlements, a substantial increase compared with last year, and actively guided all localities to broaden channels and increase investment. Our province will also select 1000 villages as comprehensive demonstrations, set up a number of demonstration models of rural human settlements improvement that are easy to copy and popularize, and guide and promote the high-quality improvement work on the surface. (Xinhua Daily reporter Wu Qiong)

Into thin air concept poster


Ada is under the cherry tree.

　　　 The mystery of the mystery thriller films directed by the famous Hong Kong director Chen Desen and starring Chinese and foreign stars such as Ada, Christy Chung, Li Cansen and Jun Kunimura is being unveiled one after another. This domestic film was shot abroad with a record investment scale. Jun Kunimura, an old Japanese actor who starred in "Kill Bill" and other films, played the villain in the play. This is also his first time to work for a China film. Recently, the film exposed a group of Ada’s stills. In the vast sea of cherry blossoms, Liu Yan is a virgin and beautiful. With the falling of cherry blossoms, the picture is extremely beautiful, as if it also indicates the ultimate fate of the film starring.

Ada stills

Into thin air stopped work for half a month waiting for cherry blossoms to fall.

　　　 It is reported that into thin air was filmed in the spring of 2012, and most of the scenes in the film were taken in downtown Tokyo and Wenquan Villa in Mount Fuji. The film tells the story of a China girl who mysteriously disappeared while traveling to Japan, and her good sister went to Japan alone to rescue her friends. It can be said that it is a China version. The director of this film is Tak-Sam Leong, a Hong Kong director who has been studying in Japan for many years. Director Tak-Sam Leong once studied under Shohei Imamura, movie master, and was a proud disciple of Shohei Imamura. He once directed the very commercial films "Forbidden Room for Sexual Desire" and "Old Corpse in Mountain Village", and there have been such films with both commercial selling points and artistic pursuits. The director has very high requirements for shooting, which is also the reason why this film invested in creating a domestic reasoning thriller record. It is reported that in order to shoot the film’s finale, the crew stopped working in Japan for half a month, waiting for the sad feeling created by the falling cherry blossoms. During the shutdown, the actors and creators were very happy and enjoyed the world-famous beauty one after another, but they were bitter for the producer of this film and had a cold war with the director every day. But in the end, the director waited for the magnificent scenery of cherry blossoms falling and achieved his artistic pursuit.

The flowers in Ada are as beautiful as a fairy.

　　　 This is also the first time that Ada came to work in Tokyo during the cherry blossom season. In addition to physical suffering during filming, Ada was in high spirits. She said that living and working in the sea of flowers will not get bored even if she is tired. After filming, she will pick up the camera and assistant to record the moving moments every day. When shooting the most important ending scene, the blue long skirt provided by the crew was very beautiful, and it was accompanied by an overwhelming sea of pink cherry blossoms. Charming Ada feels like a fairy. But it is not difficult to see from the stills that with the falling of cherry blossoms, this beauty is a kind of sadness. The final shot of this group of dramas also seems to indicate that the ending of the whole film is not sunny and family reunion. What is the specific outcome? Ada also refused to disclose it to reporters, only stressing that everyone should wait patiently. No one can guess the result.

　　CCTV News:according toChina Federation of Logistics and Purchasing website news,The China warehousing index jointly investigated by China Federation of Logistics and Purchasing and China Storage Development Co., Ltd. was 53.5% in September, 2023, up 1.5 percentage points from last month, and remained in the expansion range for eight consecutive months. The increase this month was obvious and reached the high point in the last five months, indicating that the warehousing industry maintained a relatively rapid development level. New orders, business volume, facility utilization rate, business profit, ending inventory, business activity expectation and other indexes have all rebounded, indicating that the demand for warehousing business has increased well, the profitability of enterprises has improved, the enthusiasm for replenishing warehouses has increased, and the expectations for the future are more optimistic. Specifically, this month’s index has the following characteristics:

　　Business demand grew well and the utilization rate of facilities improved significantly.In September, the business volume index was 56.2%, up 3.7 percentage points from the previous month, reaching a high point in the past five months; The new order index was 55.2%, up 1.5 percentage points from last month; The facility utilization index was 56.2%, up 5.3 percentage points from last month, reaching a high point in the past seven months. The three indexes reflecting the business demand are all at a high level in the expansion range, indicating that the warehousing market is running well and the business demand is showing an obvious growth trend. In terms of varieties, affected by the approaching Mid-Autumn Festival and National Day holiday, residents’ willingness to shop has increased, and the business volume of consumer goods and the utilization rate of facilities have greatly improved, especially food, clothing, textiles and daily necessities. Due to the arrival of the peak construction season for bulk commodities, the business volume of steel, building materials, machinery and equipment has also picked up significantly compared with the previous period.

　　Business profits rebounded and business conditions improved.In September, the charge price index was 50.6%, although it dropped by 0.6 percentage point from last month, but it was still in the expansion range, indicating that the charge price of warehousing business continued to increase slightly; The business profit index was 51.9%, up 2.2 percentage points from last month, and returned to the expansion range, indicating that the growth of business demand and charging price has strengthened the supporting role of profits, and the business situation of enterprises has improved to some extent.

　　Turnover remained efficient and inventory levels rebounded.In September, the average inventory turnover index was 53.8%, which was 0.5 percentage points lower than that of last month, but it still maintained a high level of prosperity in the expansion zone, indicating that the commodity turnover efficiency continued to improve and the upstream and downstream of the supply chain were smoothly connected. The ending inventory index was 54.2%, up 3.9 percentage points from the previous month, indicating that the commodity inventory level increased significantly. The holiday season is approaching, which stimulates the rapid growth of consumer demand, and the commodity market is also picking up during the peak season. The enthusiasm of enterprises for stocking has been greatly improved, and the overall inventory has been significantly improved compared with the previous low level.

　　Judging from the quarterly average value of the warehousing index, the overall trend in the first three quarters was on the rise, with the average value reaching 52.6% in the third quarter, and the recovery rate at the end of the quarter was accelerated, and the industry continued to develop well. In the fourth quarter, as the economy maintained a stable recovery trend, both supply and demand rebounded, and the effects of various policies were further manifested. In addition, the warehousing industry is expected to continue to maintain a good development trend.

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