Cctv newsAccording to "Sanya Released" WeChat WeChat official account News, at about 11: 22 on January 17th, Haitang Branch of Sanya Public Security Bureau received instructions from the command center of the Municipal Bureau, and people smashed mass vehicles at the east-west Sanya Tengqiao Interchange of G98 Expressway. After receiving the report, the police immediately intervened in the investigation, and on the morning of January 18, they arrested the illegal personnel Li (male, 40 years old) and Li Mouyuan (female, 42 years old) suspected of causing trouble.

　　After investigation, on the same day, when a car driven by the masses Zhuang was slowly passing through the Tengqiao Interchange section of the G98 Expressway in the east to the west of Sanya, Li drove a blue car without a motor vehicle number plate to the emergency lane on the right side of his vehicle, trying to overtake, which caused Li and his fellow driver Li Mouyuan to be unhappy, and took the opportunity to overtake from the emergency lane into the driveway and park the vehicle in front of the car driven by Zhuang. Subsequently, Li got off the bus and knocked on the door and window of a vehicle in Zhuang. Li Mouyuan smashed the door, window and left and right side mirrors of a vehicle in Zhuang and fled.

　　At present, Haitang Branch of Sanya Public Security Bureau has imposed administrative detention on Li and Li Mouyuan for 15 days and imposed a fine of 1,000 yuan. The traffic police detachment of Sanya Public Security Bureau punished Li for three traffic violations, namely, failing to hang the motor vehicle number plate (pro), driving in the emergency lane in non-emergency situations and illegally parking in the expressway lane.

　　Cctv newsOn the morning of February 15th, the State Council Press Office held a press conference to introduce the first national comprehensive risk survey of natural disasters and answer reporters’ questions.　　

　　Zheng Guoguang, Secretary-General of the National Disaster Reduction Committee and Director of the Office of the First National Comprehensive Risk Survey of Natural Disasters in the State Council, said that in the past three years, all the member units and regions of the first national comprehensive risk survey of natural disasters in the State Council organized nearly 5 million professional and technical personnel nationwide, and obtained billions of national disaster risk factor data, and completed the tasks of general survey, data quality inspection and submission. At present, the survey data are being used to carry out disaster risk assessment and zoning at the national, provincial, municipal and county levels.

　　The task of disaster risk survey is to comprehensively obtain the data of disaster-causing factors of 23 kinds of disasters in 6 categories, including earthquake disasters, geological disasters, meteorological disasters, floods and droughts, marine disasters and forest and grassland fires, the data of 27 kinds of disaster-bearing bodies in 6 categories, including population, housing, infrastructure, public service system, industry, resources and environment, and the data of 16 kinds of comprehensive disaster reduction capabilities in 3 categories, including government, society and grass-roots families. Since 1978,

　　In the past three years, under the unified organization and leadership of the leading group for the first national comprehensive risk survey of natural disasters in the State Council, the survey task has been fully completed through the concerted efforts of all parties. For example, the housing and urban-rural construction industry has obtained the construction data of nearly 600 million urban and rural houses and more than 800,000 municipal facilities nationwide. The transportation industry has completed the investigation of more than 5 million kilometers of road network, more than 900,000 bridges and tunnels, more than 6,000 coastal berths above 10,000 tons and inland river berths above 1,000 tons, and 15,000 kilometers of third-class and above inland river channels. The forestry and grass industry has completed more than 110 thousand forest and grassland combustible sample surveys, and nearly 800 thousand laboratory samples have been tested. The natural resources geological industry has carried out geological disaster risk surveys in 2081 counties (autonomous regions and municipalities), and has mastered more than 280,000 hidden danger data of geological disasters in China. The marine industry has completed the investigation of 13,900 (segment) marine disaster-bearing bodies and more than 6,000 key hidden dangers. The water conservancy industry has completed the investigation of reservoirs, sluices, dikes and other water conservancy facilities in China, and obtained more than 70,000 data of drought-induced disasters. The emergency management industry cooperated with education, health, cultural tourism and other industries to obtain more than 700,000 public service facilities, nearly 150,000 hazardous chemical enterprises (including gas filling stations), more than 30,000 non-coal mines (including tailings ponds) and coal mines, 4.5 million pieces of comprehensive disaster reduction capacity data, and more than 2.3 million pieces of annual historical natural disaster data. The eco-environmental industry has obtained 23,000 pieces of national survey data on civil nuclear facilities.The meteorological industry has obtained 6.64 million pieces of information on disaster-causing factors of 10 meteorological disasters. The seismic industry has obtained drilling data of seismic engineering geological conditions of more than 27,000 sites.

　　In addition, the Ministry of Industry and Information Technology, the Ministry of Agriculture and Rural Affairs, the Bureau of Statistics, China Banking and Insurance Regulatory Commission, China State Railway Group Co.,Ltd. and other departments and units organize relevant investigations or provide relevant data according to the division of tasks, and share relevant data such as communication facilities, crop distribution, population census and economic census, insurance enterprises and railways. The Ministry of Finance arranges special funds to support the census work. The Development and Reform Commission, the Chinese Academy of Sciences, the Academy of Engineering, the Energy Bureau, and the Central Military Commission’s Joint War Insurance Bureau actively participated in the formulation of census plans and technical specifications, the coordination of investigation work, and the application of results.

　　The quality, completeness and standardization of data is the difficulty and focus of general survey, and it is also an important basis for disaster risk assessment and zoning. According to the work plan and the division of tasks, the industry departments and localities involved in the survey carried out quality inspection of survey data at different levels and by industry. The industry departments of natural resources, ecological environment, housing and urban and rural construction, transportation, water conservancy, emergency, meteorology, forestry and grass, earthquake and other industries respectively formulated quality inspection plans for survey data, developed quality inspection software, and organized a team of experts to carry out quality inspection of survey data, including spot checks. Those who failed the quality inspection were returned for rectification. The survey data submitted to the State Council Census Office should be comprehensively inspected, that is, the integrity and standardization of the data should be checked, and those that fail should be returned to the industry department for rectification, thus ensuring the quality and reliability of the survey data.

　　Through the investigation, we have basically found out the hidden dangers of natural disasters in China, identified the disaster resistance of key areas, laid a solid foundation for comprehensive disaster risk assessment and zoning, trained local disaster prevention and mitigation management and technical teams, and created a good social atmosphere in which the whole society cares, participates and supports disaster prevention and mitigation.

　　Armed police officers and soldiers left a message on the blackboard in the classroom of Shilou Central Primary School.

　　In Shilou Middle School, the workers are repaving the plastic playground.

　　The staff of Shilou Middle School decorated the classroom before the start of school.

　　People’s Liberation Army (PLA) and Armed Police (CAPF) who left their expectations and entrustment on the school blackboard after the flood fighting and disaster relief, principals who "cut the wall" to help the affected villagers out of danger in times of crisis, and construction workers who still stick to the campus to help restore and rebuild in the new semester … …

　　In the past few days, the disaster-stricken schools in Mentougou and Fangshan District have carefully planned various forms of "the first lesson of starting school" on the basis of ensuring that "no one can be less", and skillfully incorporated the touching stories and experiences in the flood into the "first lesson" so that the teachers and students of the school can always remember these "most lovely people".

　　The "first lesson" of the disaster-stricken school conveys the entrustment and expectation of the People’s Liberation Army

　　"Young strong, China is strong. I hope that you will live up to your youth, make a difference and be a pillar of the motherland. " In the classroom blackboard of Qingshui School in Mentougou District, there is still a message left by the uncle of the People’s Liberation Army of China, who used to fight floods and provide disaster relief here. In the middle of the blackboard, there is a chalk picture of the People’s Liberation Army holding the national flag, and on both sides, it says, "We are willing to guard the prosperous China with our youth". It is understood that at the beginning of August, a certain unit of the People’s Liberation Army was ordered to go to Qingshui Town to support local flood fighting and disaster relief, and help the territory to carry out emergency rescue, material transportation, road rushing, dredging and clearing obstacles. As they are temporarily stationed in Shimizu School, the officers and men of the Armed Police live in the students’ classrooms. In mid-August, when the rescue mission was evacuated, the uncle of the People’s Liberation Army left a warm message for the students on the blackboard. Wang Hui, president of Qingshui School in Mentougou District, told Beijing Youth Daily that the teachers of the school will tell the students the story of the People’s Liberation Army’s flood fighting in the "first lesson" and convey the entrustment and expectation of the uncle of the People’s Liberation Army.

　　During the post-disaster restoration of Shilou Central Primary School in Fangshan District, the mud on the playground was dirty, thick and heavy. The officers and men of the Armed Police stepped forward and took the initiative to send a dredging team of more than 200 people. It took only one afternoon to completely clean up the mud and provide a clean and tidy sports ground for teachers and students. Before leaving school, they gave the school an unexpected surprise and left a precious gift: in every classroom, the soldiers drew a beautiful blackboard newspaper for the teachers and students, which read, "Move at the news of the flood, be fearless and retrograde", "The flood is merciless, there is love on earth", "The people are supreme, and the military and civilians are deeply in love" … …

　　At the same time, in order to let the children feel the military life personally, they left the children with compressed biscuits, instant meals in the field and other foods. In their letters to the children, they wrote: "Thanks to the rising sun of the motherland. During our mission, you gave us a warm home. Whether we are practicing martial arts and strengthening the army or studying and making progress, our tasks are different, but we all have the goal of devoting all our strength to the future socialist construction. You study with peace of mind, and we hold steel guns to protect you. "

　　The officers and men of the armed police also left a letter to the teacher in the office where they lived. The letter wrote: "Soldiers, guarding their homeland, are lovely; Teachers, cultivate the pillars of the country, respectable; Different positions and equal responsibilities. " Jiang Fuying, president of Shilou Central School, said, "These exquisite blackboard newspapers and letters will become children ‘ The first lesson ’ The best educational material. "

　　The "hero" of flood fighting and disaster relief went to school to tell personal stories.

　　At the beginning of the new semester this year, schools in Fangshan District have carefully designed the opening ceremony with the theme of "forge ahead with one heart and one mind", combined with the characteristics of the school period and the actual situation of the school, with "inspiration, gratitude and feeling" as the emotional main line. Through the opening speech of the party secretary and principal, the Blue Sky Rescue Team, armed police officers and soldiers, fire fighters, community cadres, parents’ representatives and other groups involved in the rescue are invited to tell advanced stories and touching stories. In addition to inviting officers and men of the armed police, Shilou Central Primary School also invited firefighters and staff of China Railway Jingxiong Project Department who had helped the school with dredging work to return to the school and tell their stories to the students. At the same time, the principal of the school will restore the school’s restoration work around the theme of "gratitude" in his speech, so that students can appreciate China’s great love spirit of "one party is in trouble and all parties support him" and pass it on.

　　The "First Class" of Xiayunling Central Primary School in Fangshan District issued a "Praise Sign-in Form" for each student, so that the students could go to the campus to find more than 150 staff and teachers of Beijing Construction Engineering Machinery Group who were helping the school to rebuild, and listen to their stories about what they saw and heard about the flood and the post-disaster reconstruction. "We want to invite every child to participate in the opening ceremony instead of attending it, so that the children can guess what we have experienced during the campus restoration, and let the children know the story behind every ordinary hero through interviews." The headmaster of Xiayunling Central Primary School said that the form of "Praise Sign-in Form" contains questions such as "expressing your feelings in six words" and "praising words you want to say", and at the same time, students will be asked to find the corresponding person according to the tips in the form, communicate with them and ask them to sign their names. The reporter of Beiqing Daily saw that there were "those who wore black leather shoes", "those who were 20 years older than me", "those with single eyelids", "those I admired" and "the most serious" in the sign-in form. "This is also for children to communicate socially in an open space.Stimulate children’s initiative and accumulate successful experience of individual socialization. "The headmaster of the school said.

　　Chang Zhangchang, the principal of Datai Central Primary School, served as a guide for the armed police during the flood season, just to see the children safe; Gao Lianchao, the headmaster of Wang Ping Middle School, "cut the wall" to save people, making the school a "safe island" in times of crisis; Ma Huan, the headmaster of Miaofengshan National School who just finished the operation, is on duty 24 hours a day, and has resettled more than 270 villagers affected by the disaster nearby … … During the flood fighting and disaster relief, many touching stories have emerged among the educators in Mentougou District, which will become an important resource for the "first lesson" and even the future teaching. "Disaster suddenly came, I didn’t consider anything! The safety of people’s lives and property is the first. This is my responsibility and mission. " Gao Lianchao, president of Wang Ping Middle School, told the reporter of Beiqing Daily that on the morning of July 31, the flood did not reach the school gate, and the water depth was waist-deep. The affected villagers across the road could not enter the school to take refuge. Gao Lianchao took the initiative to borrow a machine, cut a big hole in the west wall of the school, cut off the protective barbed wire, led the teachers and village cadres, took the villagers to the west wall with less water potential, and transported 87 villagers to the school through the cut hole for more than 20 trips, and temporarily arranged them in the student dormitory. Now, the cut wall has been restored, but the disaster relief story of President Gao Lianchao will remain in the hearts of every student and faculty of the school in the "first lesson" this year.

　　"At that time, there was only one thought in my heart, that is, I had to see with my own eyes 80 families in the Qianjuntai community farthest from Datai Street, as well as the students and staff there, and know that they were safe." Chang Zhangzhang, the 60-year-old principal of Datai Central Primary School, walked for more than five hours with 20 kilograms of materials on his back on August 6, and led a team of officers and men of the armed police to deliver materials to Qianjuntai Community, while looking for the lost students and faculty of Qianjuntai Primary School under his jurisdiction. After the disaster was stable, he quickly devoted himself to the post-disaster reconstruction of the school. In the new semester, Datai Central Primary School will be relocated to Wang Ping Central Primary School. The story of President Chang Zhangzhang will also serve as the "first lesson" for students at the new school site, inspiring the teachers and students of the two schools.

　　Touching stories in flood fighting and disaster relief have become unique educational and teaching resources.

　　The reporter of Beiqing Daily learned from the Mentougou District Education Committee that this year’s "First Class" is very special and will be presented in the form of situational psychological class meeting. The head teachers of each school will combine the psychological characteristics of students in different classes and the actual situation of the school, and under the guidance of psychological researchers and psychological teachers in Mentougou District, make good use of the special educational and teaching resources of floods and flood fighting stories to carefully design a unique, intelligent class meeting activity that reflects psychological health counseling.

　　Schools in Mentougou District will also enable teachers and students to turn floods and disasters into special educational and teaching resources through interdisciplinary project-based learning. Teachers of mathematics, Chinese, physics, chemistry, biology, geography, politics, fine arts and other disciplines are eager to try, and decided to combine the flood with the knowledge in books to educate and guide students to feel, understand and interpret the disaster from a scientific perspective. The teaching department of Dayu No.2 Primary School, combined with the actual situation, guides teachers to carry out "colorful promenade — — Warm heart, accompany happy growth, improve campus protection, build campus safety island, and how to make rainwater safe to drink. After the start of school, the teachers of the three research groups will lead students out of the classroom to participate in the reconstruction of their homes, and guide students to improve their comprehensive quality and social responsibility in project-based practical learning.

　　Around the theme of "Rebuilding a Beautiful Home", the kindergarten affiliated to Sanjiadian Primary School organizes all classes to study and design the "First Class" with the characteristics of children’s age as the core, focusing on flood fighting and disaster relief, psychological counseling and post-disaster reconstruction, focusing on the education of emotional communication and love, managing emotions, sharing people who helped us in disasters, and building a beautiful home together, so as to make the grades focused and the classes themed. The "Praise Sign-in Form" at the opening ceremony of Xiayunling Central Primary School in Fangshan District will also be combined with the school’s teaching curriculum after the school starts, and the relevant contents of floods will be integrated into daily teaching.

　　In addition, Mentougou District will also implement the "Safe Island" plan to upgrade and transform the school into an emergency shelter center in its community, which has the functions of refuge for victims, airdrop of materials, medical rescue, disaster relief command, and the stationing of rescue troops. Mentougou District Education Committee said that at present, the plan is being applied for expert demonstration, and plans to declare the experimental area for the construction of emergency shelters in schools.

　　Text/reporter Pu Changting Ye Wei Photography/reporter Cui Jun

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　　The teachers and students of the two schools will jointly perform the school drama of fighting floods.

　　School starts on September 1st, and Xiacun Middle School in Fangshan District, which was severely damaged and could not start at the original site, will be merged with Shilou Middle School. What is the preparation for the merger? What "cooperation" will the two schools have in the new semester? Recently, a reporter from Beijing Youth Daily visited Shilou Middle School.

　　In front of the teaching building, several workers are repairing the floor tiles. Into the teaching building, from time to time there are workers carrying decoration tools to walk back and forth. In the classroom, desks and chairs have been placed, and staff are cleaning the floor and pasting tips; The teacher drew a welcome print on the blackboard … … In order to welcome 87 students from Xiacun Middle School, Shilou Middle School rearranged 16 classrooms. The original wall was painted white, and the slightly damaged prompt board was replaced with a new one.

　　"We hope that the school will also have a new atmosphere. There are many new prompts in the classroom, which represent our expectations for students." Guo Hongsheng, the principal of Shilou Middle School, told the reporter of Beiqing Daily that in the face of the upcoming new semester, the school has carefully prepared the "first lesson of school" with the theme of "empathy and common growth". According to Guo Hongsheng, "empathy" means that students can experience the love and support of the people from all walks of life through flood fighting and disaster relief, so that students can understand the emotion of "one side is in trouble and all sides support". "Common sense" means that without the leadership of the Communist Party of China (CPC) and the strong support of local governments, the disaster would be hard to pass. "We told the students about the support of the government and all sectors of society for the disaster relief people and let them feel how good our society is now." Guo Hongsheng said. "Growing together" means that the teachers and students of the two schools will grow together and develop together through merger.

　　It is reported that in order to boost students’ morale, Shilou Middle School will perform a traditional school project — — Play "Man Jiang Hong" with drums. "We also arranged a campus drama, which was jointly performed by students from Shilou Middle School and the former Xiacun Middle School, showing three parts: flood control, resettlement sites and future life." Guo Hongsheng said that the school drama will also be performed at the opening ceremony.

　　It is worth mentioning that, because Xiacun Middle School is about 10 kilometers away from Shilou Middle School, in order to facilitate students from the former Xiacun Middle School to go to and from school, the school has rebuilt 22 6-person dormitories to meet the accommodation problems of students from Xiacun and surrounding villages in the next few years. At the same time, the school also plans to equip four boarding teachers, two men and two women, to ensure the safety of students’ evening self-study and accommodation. "Our canteen has been renovated and will provide a better environment for more students to eat. The floor, wall and roof of the dormitory are being renovated, and air conditioners will be installed and new beds and bedding will be purchased, including washbasins, toothbrushes and towels. We will provide them for the children. " Guo Hongsheng said that after the renovation of the dormitory, it is necessary to wait for the environmental inspection to pass before moving in. Therefore, the school also communicated with the District Transportation Committee and the bus group to arrange a special shuttle bus before moving in the dormitory to ensure the commuting safety of students.

　　Cai Yali, the former director of moral education in Xiacun Middle School, told the reporter of Beiqing Daily that after the merger of the two schools was confirmed, the teacher had explained the relevant situation to the students and parents in advance by telephone and home visits, and asked for your opinions. "Some students are brought by the elderly on weekdays. When the elderly hear that students can stay in the future, they all say ‘ That’s great ’ 。” Cai Yali told the reporter of Beiqing Daily that if students choose accommodation, the school will take care of meals, self-study at night and accommodation, and life and rest will be regular. "Many students and parents are still looking forward to it." Text/reporter Pu Changting Ye Wei

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)

　　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)

[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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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.