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Focusing on Drug Targets: "Fighting poison with poison" —— The latest research progress of oncolytic virus

Since the 19th century, virus therapy for cancer has been studied. However, due to technical barriers and safety problems in genetic engineering, great progress has not been made until the last 20 years. At present, viralvectors for gene therapy and oncolytic viruses (OVs) are the main methods used by viruses as tumor therapy. The main difference between gene therapy virus vector and OVs is that the virus used in gene therapy virus vector is a non-replicating virus, while the vector used in OVs is a virus with replication ability.

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OVs refers to a kind of viruses that can selectively infect and kill tumor cells without damaging normal cells, and they often have good tumor lysis and targeting. OVs can replicate in the host cell after infecting tumor cells, and the released progeny viruses can continue to infect surrounding tumor cells, at the same time activate local or systemic anti-tumor immune effects, change tumor microenvironment and further improve anti-tumor effects. Natural oncolytic virus has some limitations, such as inconsistent safety or weak ability to stimulate the body to produce tumor immunity. In order to overcome the above shortcomings, oncolytic virus vector came into being: it not only retains the ability of oncolytic virus to kill tumor cells, but also enhances its efficacy of activating immune response after genetic modification.

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From non-gene editing type to gene editing type, OVs contains many kinds and characteristics. According to the different nucleotide types of virus genome, OVs vectors can be divided into DNA virus vectors and RNA virus vectors. Among them, the main DNA viruses are herpes simplex virus (HSV), adenovirus (AdV), vaccinia virus (VV) and H1(parvovirus H1. RNA viruses are mainly reovirus (RV), coxsackie virus (CV), poliovirus (PV), measles virus (MV), NDV and vesicular stomatitis virus (VSV).

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The latest research progress

1. At present, five products have been approved for listing in the world, and it is predicted that they will reach the market of over 10 billion dollars in the future.

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2. According to the data of Toubao Research Institute, the market size of oncolytic drugs in China will continue to grow at a compound annual growth rate of 16.2%, and it is expected to rise to 1.43 billion yuan by 2024.

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3. According to the number of research targets, they are IL-12, GM-CSF, PD1, IL-15, PDL1, CD, CD19, CTLA4, NIS, etc.

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4. In the research enterprises, among them, there are many researches and developments on oncolytic viruses, such as Icell Kealex Therapeutics(10), Cell Genesys(7), Virogen Biotechnology (6), PsiOxusTherapeutics(5), Transgene(5) and Jennerex(4). In addition, domestic enterprises such as Innomicro, Synbiotics, Shanghai Medicine, Ruotai Medicine, Kangwanda Medicine, Saibainuo, Lepu Bio, Tasly, and Funuojian are also deployed in this field.

5. Statistics of drugs currently in clinical research stage are as follows:

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two

Introduction of key drugs

Among the five oncolytic viruses approved worldwide, including picornavirus Rigvir, which is approved for the treatment of melanoma in Latvia; Secondly, today’s reborn (recombinant human P53 adenovirus injection) and recombinant human adenovirus type 5, which were approved in 2004 and 2005 respectively, were approved for the treatment of solid tumors such as hepatocellular carcinoma, nasopharyngeal carcinoma and pancreatic cancer. In 2015, the United States and Europe approved the engineered herpes simplex virus (HSV-1) of talimogene laherparepvec(T-VEC) for the treatment of unresectable metastatic melanoma. Finally, in 2021, Japan approved the improved herpes simplex virus teserpaturev for the treatment of brain cancers such as glioblastoma. The statistic of some drugs in that lead stage of clinical development are as follows:

1、CG0070

CG0070 is a genetically modified adenovirus type 5 (Ad5), which contains cancer selective promoter E2F-1 and immune cell stimulating factor GM-CSF gene, and selectively replicates and lyses tumor cells in Rb-deficient tumor cells. The rupture of cancer cells will release tumor-derived antigen and GM-CSF expressed with the virus, thus stimulating systemic anti-tumor immune response. CG0070 was introduced by Lepu Bio from CG Oncology in the United States, and obtained its product development rights and global supply rights in China; Except China, the rights and interests in Japan, South Korea, China, Taiwan Province and other Asian countries were acquired by Kissei Pharmaceutical.

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2、Pelareorep

Pelareorep(AN1004) is a non-pathogenic reovirus introduced by Oncologics Biotechnology by Arnold Pharmaceuticals. It can overcome the neutralizing antibody, selectively infect and destroy tumor cells by activating the body’s own immune system, and is used to treat various solid tumors and hematological malignancies. Pelareorep is a rapidly developed oncolytic virus product that can be administered by intravenous injection in the world. The second phase clinical trial of Pelareorep in the treatment of metastatic breast cancer found that the overall survival rate of patients with ER+PR+/HER2- breast cancer was doubled (21.8 months vs. 10.8 months). In its global phase II clinical trial (BERIL-1) for the treatment of head and neck squamous cell carcinoma (HNSCC), the median survival time of patients was as high as 10.4 months. In March, 2022, Oncologics Biotechnology announced that it had completed the safety assessment of three patients in the metastatic colorectal cancer (mCRC) cohort of the oncolytic virus Pelareorep phase 1/2 GOBLET study.

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3、pexastimogene devacirepvec

Pexastimogen devacirepvec (JX-594) is a genetically engineered vaccinia virus introduced from abroad by Lee’s Pharmaceutical Factory. Its TK gene is mutated, and human GM-CSF gene is inserted to enhance the anti-tumor immune response. The advantages of using vaccinia virus include the stability of intravenous infusion, strong cytotoxicity and the safety of classical live vaccine. Previously, the drug had poor clinical performance in phase III of hepatocellular carcinoma, and the efficacy of the drug in combination with cemiplimab in the treatment of renal cell carcinoma is currently being evaluated.

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4. Naomi Loki

Loki (GL-ONC1, Olvi-Vec) was developed by Genelux Company, and Hengyi Bio owns its development rights in Chinese mainland. It is an oncolytic vaccinia virus. Three expression cassettes encoding β-galactosidase, β-glucuronidase and renin luciferase/green fluorescence (RLuc-GFP) fusion proteins are used to replace virus TK, hemagglutinin and F145L genes respectively. A phase I clinical trial of GL-ONC1 in patients with head and neck cancer showed that intravenous injection of GL-ONC1 combined with standard chemotherapy could improve the overall survival rate. This study also proved the safety of the virus.

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5、OH2

OH2(BS001) is the first candidate drug for oncolytic virus in the world, which is independently developed by Binhui Ib/II-tech, and has chosen HSV2-2 as the carrier and entered clinical trials. Clinical data show that the objective remission rate (ORR), disease control rate (DCR) and one-year survival rate (OS) of BS001 are 30%, 50% and 50%, respectively. In addition, the latest clinical data in the treatment of colorectal cancer show that the objective remission rate of BS001 injection in the treatment of colorectal cancer patients has exceeded 10%. The objective remission rate of BS001 injection combined with PD-1 monoclonal antibody was 18.2%.

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prospect

In recent years, with the development of genetic engineering technology, people have a deeper understanding of the function and structure of virus genes. Optimizing the design and operation of virus genome to produce non-pathogenic viruses has become the research direction of oncolytic viruses, which has greatly promoted the progress of oncolytic virus therapy. Combined treatment of oncolytic virus with chemotherapy or immunotherapy drugs, or even combined application of multiple oncolytic virus drugs, may control tumor progression or cure tumor more effectively, and provide potential clinical treatment options for tumor patients. We believe that with the deepening of oncolytic virus research, oncolytic virus therapy will play a wider and deeper role in treating human diseases.

references

Yang Hao, Zhang Shaogeng, Yang Penghui. Immunological mechanism and clinical research progress of oncolytic virus [J/OL]. Progress in biochemistry and biophysics: 1-16.

[2] Liu P, Wang Y, Wang Y, et al. Effects of oncolytic viruses andviral vectors on immunity in glioblastoma[J]. Gene therapy, 2020: 1-12.

[3] Kaufman H L, Kohlhapp F J, Zloza A. Oncolytic viruses: a newclass of immunotherapy drugs[J]. Nature reviews Drug discovery, 2015, 14(9):642-662.

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Beijing urban management changes new uniforms, and each player has a number on his chest.

  Since yesterday (October 1st), the city’s urban management team members in Beijing have started to carry out law enforcement inspections with new uniforms. Recently, the Municipal Urban Management Law Enforcement Bureau has uniformly renewed the uniforms and signs of law enforcement personnel in the city’s urban management system. On the first day of the Eleventh Golden Week, the city’s environmental order was good. During the festival, all urban management and law enforcement departments will take a break and take up their posts, focusing on strengthening the prevention and control of bustling commercial districts and characteristic blocks, major transportation hubs, large-scale gatherings, activities and other crowded areas.

  After asking the way, the tourist said, Have you changed your uniforms?

  "Have you changed your uniforms?" Yesterday morning, outside the East Palace of the Summer Palace, Mr. Li, who was traveling from Hebei to Beijing, was surprised after asking the urban management team for directions. He said: "I mainly asked the city management for directions in the Bird’s Nest two days ago, and the answer was very detailed. I still have an impression of the previous uniforms."

  Beijing Youth Daily reporters saw in Qianmen and the Summer Palace and other popular National Day attractions that all urban management team members have put on new uniforms and started to perform their duties. The clothing color is navy blue, with a golden logo, and each team member’s number is on the chest.

  According to reports, the new uniforms mainly consider adapting to the fact that urban management law enforcement workplaces are mostly outdoors and on the streets, which is convenient for duty activities. This is also the requirement of the Municipal Urban Management Law Enforcement Bureau to implement the "Administrative Measures for the Supply of Clothing and Signs for Urban Management Law Enforcement" by the Ministry of Housing and Urban-Rural Development, strengthen the construction of urban management law enforcement teams, and further promote standardized and civilized law enforcement.

  Solve the problem of people who are not empty in the three-meal car

  After the flag-raising ceremony yesterday morning, crowds poured into Qianmen area, and the law enforcement team members of Dongcheng Urban Management began to guide the crowd. According to reports, in view of the relatively dense number of tourists watching the flag-raising during the holiday season, Dongcheng City Management has sent six law enforcement teams to strengthen the deployment in Qianmen Arrow Tower, Qianmen East Street and Chang’ an Avenue from 5: 00 every day, and sell tourist goods to the following tourists. Personnel engaged in unlicensed catering will be disposed of promptly and quickly.

  在东城,每天将有300余名队员巡查在全区各个街道和社区,发现各类问题及时解决。在簋街、南锣鼓巷及北京站等重点地区,更是每天32个车组全天连续14小时定人定岗盯守,队员一日三餐均在执法车内解决,确保每个时段岗位不空人。

  节日期间 北京城管全员停休

  为确保今年国庆期间环境秩序良好,节日期间城管执法部门全员停休,全员上岗,实名管控,重点对无照经营、非法运营、非法小广告、占道经营、店外经营、非法停车场等环境秩序问题进行查处,全面遏制重点地区环境秩序类问题。

  黄金周期间,城管执法部门重点加大对天安门及周边地区、长安街沿线,故宫、奥林匹克公园、什刹海、恭王府、八达岭、十三陵及市属11大公园,繁华商业区和特色街区,主要交通枢纽,大型集会、活动等人流密集地区的防控力度。同时对违规户外广告、牌匾标识、夜景照明、山寨指路牌、临窗广告以及车身广告等,及时督促责任人进行拆除、清理、维修或更换,对附带电话号码的,及时进行警示提醒。

  According to the person in charge of the Municipal Urban Management Law Enforcement Bureau, the management of construction sites will continue to be strengthened during the festival, and the construction enclosures in key areas will be checked according to the specifications, and the construction dust will be strictly controlled, and the management of construction waste transportation will continue to be strengthened to prevent road spillage; Increase the control of illegal activities such as open-air barbecue, burning garbage and white pollution. Visit and investigate the gas supply, users, kitchen waste generation and collection and transportation units around the key security areas one by one, and rectify the problems.

  Urban management volunteers help serve tourists.

  In addition, the urban management law enforcement departments, in conjunction with the Beijing Urban Management Volunteers Association, set up publicity service stations for urban management law enforcement in tourist attractions and window areas during the National Day to monitor the environmental order and provide tourists with services such as inquiries, directions and simple medical care.

  Yesterday, in Qianmen Street, Nanluoguxiang Pedestrian Street, Summer Palace and other areas, volunteers organized by urban management departments participated in the publicity of laws and regulations, stopped uncivilized behavior, and provided some services urgently needed by tourists, such as directions.

  The person in charge of the Municipal Urban Management and Law Enforcement Bureau said that mobilizing members of the association, volunteer groups and the general public to actively participate in the maintenance of holiday environmental order, especially guiding social units in key areas to actively participate in environmental governance and rectification, can jointly create a beautiful and clean urban environment.

  Text/Reporter Li Tao

  Photography/Reporter Wang Zhenlong Cui Jun

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Attention! This virus has entered a period of high incidence!

recent days

# Guangdong Norovirus enters a high incidence period #

Rushed to the top of the hot search list in Weibo

Many netizens commented.

"vomiting and diarrhea" and "very uncomfortable"

Even "the whole family turns to recruit"

Multi-site disease control department reminded

Acute infectious diarrhea caused by norovirus

Has entered the peak of the disease

Previously, Guangdong CDC had issued prevention guidelines.

Guangdong every October to March of the following year.

It is the peak of norovirus infection outbreak.

Contact transmission and food-borne transmission are the main methods.

Key prevention and control sites

For schools and kindergartens and other collective units.

What are the characteristics of Norovirus?

What are the symptoms after the move?

Come and have a look!

"Cunning" Norovirus

First, strong pathogenic ability

Norovirus is highly infectious, and it can infect many people with only a small amount of virus particles. Therefore, in schools, kindergartens and other places where people gather, it is easy to have a cluster epidemic of norovirus infection.

Second, there are many infection tricks.

Eating can infect: eating food contaminated with norovirus.

Drinking water can infect: drinking water contaminated with norovirus.

Contact/aerosol can infect: contact with the aerosol generated by the patient’s excrement or vomit, or indirectly contact with articles or environment contaminated by vomit or excrement, etc., you may be infected by norovirus.

Third, don’t pick people.

Norovirus is generally susceptible to the whole population, and people of all ages may be infected.

Fourth, the resistance is extremely strong

It can survive in the temperature range of 0~60℃, and ordinary hot water can’t burn Norovirus.

75% alcohol and antibacterial hand gel can’t inactivate norovirus.

It can survive on the surface of objects for 2 weeks and in water for more than 2 months.

Common symptoms after infection

The incubation period of norovirus infection is 12 to 72 hours, usually 24 to 48 hours. Norovirus infection is generally mild, the most common symptoms are vomiting and diarrhea, followed by nausea, abdominal pain, headache, fever, chills and muscle aches. Children are mainly vomiting, while adults are mostly diarrhea.

How to treat norovirus gastroenteritis?

Norovirus is a self-limiting disease, and there is no effective antiviral drug at present. Most patients can recover in 2~3 days after onset, and they can take oral sugar saline or oral rehydration salt to supplement the water consumed by vomiting and diarrhea. A small number of infants and the elderly, especially those with basic diseases, may cause more serious symptoms such as dehydration and slow recovery, so they should be treated in time.

Tips for family prevention

Read a picture

besides

Nursery institutions and schools

Attention should also be paid to preventing norovirus infection.

Nursery institutions and schools

How to prevent norovirus infection?

First, timely detection and standardized management of cases

Nursery institutions and schools should do a good job in student health management, and strictly implement morning (noon) check-ups and registration of absenteeism due to illness. Once patients with vomiting, diarrhea and other symptoms are found, they should seek medical treatment in time and be isolated and managed. Report to the disease control institutions and relevant administrative departments immediately when the abnormal increase of cases is found.

Second, strengthen the management of drinking water and food hygiene

Provide safe drinking water, do a good job in drinking water management, investigate the damage and leakage of drinking water supply network, regularly clean and disinfect secondary water supply facilities, and do a good job in drinking water quality testing to ensure water supply safety. Do a good job in the supervision of food raw materials and processing links, pay attention to the separation of raw and cooked, and thoroughly cook and cook.

Three, strengthen the health management of kitchen workers, nurses and other employees.

Nursery institutions and schools monitor the health status of kitchen workers and nurses, and when there are symptoms related to intestinal infectious diseases such as diarrhea, vomiting and nausea, they should immediately suspend their work, seek medical treatment in time, and prevent them from going to work despite illness. Wear a mask and do good hand hygiene during food preparation and catering.

Fourth, do a good job in environmental cleaning and disinfection

Regularly clean and ventilate public places in campus/park (such as classrooms, dormitories, canteens, libraries, bathrooms, etc.), and regularly clean and disinfect key parts (such as door handles, stair handrails, faucets, toilet buttons, elevator buttons, handrails for getting on and off the bed, etc.).

Five, scientific and standardized treatment of vomit

The vomitus and feces found in the case should be handled by the trained personnel in accordance with the relevant operating guidelines. Focus on the disinfection of the surface of environmental objects, daily necessities, food processing tools, drinking water, etc. polluted by vomit and feces.

Original title: "Attention! This virus has entered a period of high incidence! 》

Read the original text

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Price reduction information of BMW i4 in Xuzhou area! The latest offer is 401,000 yuan. If you miss it, you won’t have it.

[car home Xuzhou Promotion Channel] Good news! At present, a large discount is being made in Xuzhou, with a maximum discount of 148,900. Now, the minimum starting price of this model has dropped to 401,000. If you are interested in BMW i4, you may wish to click "Check the car price" in the quotation form to get a higher discount.

徐州地区宝马i4降价信息!最新报价40.1万,错过就没有

The front face design of BMW i4 adopts a closed kidney grille, which not only embodies the family characteristics of BMW, but also enhances the aerodynamic performance of the vehicle. At the same time, the long and narrow headlight group is integrated with the grille, which makes the whole front face look sharper and more dynamic. Overall style, the BMW i4 adopts a streamlined body design, and the low body posture with elegant curves not only shows the sense of fashion, but also improves the aerodynamic performance of the vehicle. In addition, the rear part of the car adopts a relatively simple design language, and the long and narrow taillights echo the headlights of the car, making the whole car look more harmonious and unified.

徐州地区宝马i4降价信息!最新报价40.1万,错过就没有

The body size of BMW i4 is 4785*1852*1455mm, the wheelbase is 2856mm, the front tread is 1601mm and the rear tread is 1630mm, which provides a spacious interior space for the vehicle. The side lines of the car are smooth and dynamic, and the front face is designed with a closed kidney grille, which is very fashionable with slender LED headlights. Tyre size is the front 245/45 R18 and the rear 255/45 R18, and it is matched with an 18-inch aluminum alloy rim, which is sporty and dynamic in style.

徐州地区宝马i4降价信息!最新报价40.1万,错过就没有

The interior design of BMW i4 inherits BMW’s consistent sense of luxury and technology, and the interior space layout is reasonable, creating a spacious and comfortable driving environment. The steering wheel is wrapped in leather, which provides a good grip and support, supports manual adjustment up and down and back and forth, and is convenient for drivers to find the best driving position. The central control screen adopts a 14.9-inch touch screen, which integrates the control functions of multimedia system, navigation, telephone and air conditioning, and supports voice recognition control, which enhances the convenience of operation. The seats are made of various materials, including imitation leather, genuine leather or leather /Alcantara mix and match. The main and co-pilot seats have multiple adjustment functions, including front and rear adjustment, backrest adjustment, height adjustment (4-way), leg rest adjustment and lumbar support (4-way), and have heating function to provide a comfortable riding experience. The car is also equipped with multiple USB and Type-C interfaces to facilitate charging, and the front seats are also equipped with wireless charging function, which provides a convenient charging solution for modern mobile devices.

徐州地区宝马i4降价信息!最新报价40.1万,错过就没有

BMW i4 is equipped with an excellent motor with a maximum power of 210 kW and a maximum torque of 400 Nm, which provides drivers with a strong power output and a smooth driving experience.

The owner of car home said that the configuration parameters of Series I’s 3, 5 and X3 are almost the same, only the shell has been changed, and I want to buy the I4 for the sake of personality. Of course, it is still imported, so there is no need to do such a thing as buying it home and deducting the label. The big nostrils are not mediocre at first glance. When I drive out, everyone guesses at 600,000. I’m sorry.

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Mercedes-Benz has added "new members", with less than 1.468 million large cars.

In terms of appearance, the front air intake grille of Maibakh s560 collector’s edition has changed from a double-banner style to a vertical-banner style, which is very visually impactful with brand-new "flame headlights". On the side of the car body, the body lines of the new car are basically the same as the cash, but the newly added louver style and chrome trim on the lower side of the window make the side of the new car look more exquisite.

In terms of interior, the whole interior design is very luxurious, equipped with a large-size dual screen, internally integrated with Mercedes-Benz’s brand-new mbux intelligent interactive system, and combined with the latest style steering wheel, it creates a good sense of science and technology. The material has also been upgraded, for example, the roof, sun visor and a/b/c pillar are made of suede material, which makes the touch more delicate and soft.

The length, width and height are 5470×1921×1510mm, respectively, and the wheelbase is 3396mm, which ranks 4th in the same class. As a car, its body size does not occupy much advantage in its class, and its internal seating space is only basically enough. After all, it is limited by the length and shape of the car body. The design of skylight also increases the subjective space feeling of front and rear passengers. Among the models of the same price and class, the trunk volume of Maibakh S-class ranks 9th. The storage space in the car is quite satisfactory and basically sufficient. The interior space of the luggage compartment is relatively regular, with very good longitudinal depth and high expansibility, and the space performance is generally ideal.

Mercedes-Benz Maibakh S-Class is equipped with a combination of 6.0 twin-turbo engine (multipoint injection) and automatic manual (AT). 6.0 The engine with Maibakh S-class is quite satisfactory in dynamic performance, with weak low torque and can feel hysteresis. Maibakh’s S-Class officially measured zero-acceleration score is 4.7S, ranking 14th among the car models over 800,000.

Maibakh s-class active/passive safety configuration is complete, includingAutomatic parkingZero tire pressure endurance tireAutomatic parkingSteep slope descenthill start assist controlknee airbagHUD head-up displayAnti-lock braking (ABS)Braking force distribution (EBD/CBC, etc.)Brake assist (EBA/BAS, etc.)Traction control (ASR/TCS, etc.)Active noise reductionEngine start and stopSide safety air curtainWireless charging of mobile phonenight vision systemLED daytime running lightsForward reversing radarTire pressure monitoringSteering wheel heatingBody stability control (ESP/DSC, etc.)Rear reversing radarFatigue reminderRemote parkingChild seat interfaceLane keeping (LKAS)Equal configuration.

Among them,Automatic parkingYou can avoid stepping on the brakes for a long time or needing to pull frequently;Steep slope descentCan safely pass through steep slope road conditions at low speed;knee airbagReduce the injury of the car interior to the occupant’s knees in the secondary collision.

In order to get a more comprehensive and objective understanding of Maibakh’s S-class, you can go to the Maibakh S-class forum of Easy Car and browse the messages of users who have bought the car in history.

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Heavy posting! By 2035, China’s educational modernization will be like this.

  Cctv newsRecently, the Central Committee of the Communist Party of China and the State Council issued "China Education Modernization 2035", proposing that by 2035, a modern education system serving all people’s lifelong learning will be built, quality preschool education will be popularized, quality and balanced compulsory education will be realized, and high school education will be fully popularized … … 

  How can we achieve the above goals? Especially in the next few years, how should we proceed?

  General Offices of the General Office of the Central Committee of the CPC and the State CouncilSame dayThe "Implementation Plan for Accelerating Education Modernization (2018-2022)" issued has made detailed arrangements for this.

In 2035, the modernization of education in China is like this!

  "China Education Modernization 2035" puts forward the idea of promoting education modernization.Eight basic concepts

  The overall goal is toBy 2020, the "Thirteenth Five-Year Plan" development goal will be fully realized, the overall strength and international influence of education will be significantly enhanced, the average length of education of the working-age population will be significantly increased, and important progress will be made in educational modernization, making important contributions to building a well-off society in an all-round way. 

  On this basis, after 15 years of efforts, by 2035, a modern education system serving lifelong learning for all will be built, quality preschool education will be popularized, quality and balanced compulsory education will be realized, high school education will be fully popularized, the service capacity of vocational education will be significantly improved, the competitiveness of higher education will be significantly improved, disabled children and adolescents will enjoy suitable education, and a new pattern of educational governance will be formed with the participation of the whole society. 

Realize the modernization of education, and prepare to do so!

  Accelerate the construction of "double first-class"

  The Document requires that the transformation and development of local undergraduate colleges and universities should be continuously promoted, the innovation system of colleges and universities should be strengthened, a number of world-class national scientific and technological innovation bases should be built, applied basic research should be strengthened, and the original innovation ability of colleges and universities should be comprehensively improved. Improve the research level of philosophy and social sciences in colleges and universities, and strengthen the construction of new think tanks with China characteristics. Improve the scientific research system that is conducive to stimulating innovation vitality and promoting the transformation of scientific and technological achievements.

  The "Implementation Plan" mentioned that we should further accelerate the construction of "double first-class", promote the construction of colleges and universities to fully implement the construction plan, and study and establish a comprehensive evaluation system for the construction of "double first-class" with China characteristics.

  Strengthen the direction of college entrance examination reform

  In deepening the comprehensive reform of education in key areas, the "Implementation Plan" mentioned that it is necessary to actively and steadily promote the reform of the examination enrollment system, strengthen the direction of the college entrance examination reform, and improve the academic level examination system for ordinary high schools.In addition, we will further promote the classified examinations for academic degree and professional degree postgraduates, and improve the selection mechanism of "application-assessment" and direct doctoral students.

  Vigorously develop public kindergartens

  The "Document" points out that it is necessary to improve the popularization level of preschool education with rural areas as the focus, and establish a more perfect preschool education management system, garden management system and investment system. Vigorously develop public parks and accelerate the development of inclusive private kindergartens. Improve the consolidation level of compulsory education, and improve the responsibility system for dropping out of school.

  Promote the integration of the enrollment treatment of the accompanying children in the same city.

  The "Document" requires that the level of equalization of compulsory education be further improved, the balanced development of compulsory education in urban and rural areas be promoted, the enrollment treatment of migrant children be promoted in the same city, the supply of urban degrees be expanded in an orderly manner, and the examination system for children of floating population to enter higher schools in different places be improved.

  At the same time, the "Implementation Plan" proposes to incorporate compulsory education for migrant children of migrant workers into urban development plans, strengthen care and protection for left-behind children, and organize the implementation of special education promotion plans.

  Accelerate the development of modern vocational education

  The Document proposes to accelerate the development of modern vocational education and constantly optimize the structure and layout of vocational education. Promote the organic connection and deep integration of vocational education and industrial development, and concentrate on building a number of high-level vocational colleges and majors with China characteristics.

  The "Implementation Plan" points out that the standards of vocational education system will be established and improved, and a series of systems and standards such as school setting, professional teaching, teachers’ team, student internship, funding input and information construction will be improved, and the per capita funding system for vocational colleges will be formulated and implemented. Establish a joint conference system for vocational education in the State Council.

  Teachers’ morality becomes the first criterion for evaluating teachers’ quality.

  The "Document" makes it clear that it is necessary to vigorously strengthen the construction of teachers’ morality and style, take teachers’ morality and style as the first criterion for evaluating teachers’ quality, and promote the long-term and institutionalized construction of teachers’ morality. Improve the teacher qualification system and access system. Improve teachers’ professional titles, posts and evaluation system. Cultivate high-quality teachers.

  The "Implementation Plan" also pointed out that the construction project of teachers’ morality and style will be implemented.

  Improve the political, social and professional status of teachers.

  The Document calls for improving teachers’ social status, improving the guarantee system for teachers’ treatment, improving the long-term linkage mechanism for primary and secondary school teachers’ salaries, and fully implementing the living allowance policy for concentrated contiguous areas with special difficulties. Strengthen the recognition of teachers and strive to improve their political, social and professional status.

  In terms of ensuring teachers’ salaries and benefits, the "Implementation Plan" is clear: improve the long-term linkage mechanism of primary and secondary school teachers’ salaries, make overall consideration of the actual income level of local civil servants when approving the total performance salary, realize synchronous adjustment with the salary income of local civil servants, and improve the approved distribution method and internal distribution method of the total performance salary of primary and secondary school teachers.

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Guangzhou BMW i5 price reduction news! The discount is 93,000, and the discount waits for no one.

[car home Guangzhou Preferential Promotion Channel] Specially recommended, this luxury electric car is setting off a grand price reduction storm in Guangzhou. As a high-profile model, BMW i5 is currently in the process of preferential treatment, with the highest preferential rate reaching an astonishing 93,000 yuan, which has brought tangible car purchase benefits to consumers. The starting price has been adjusted to 352,900 yuan, which undoubtedly provides a rare opportunity for potential buyers in Guangzhou. Friends who want to seize this preferential opportunity, don’t miss it, and quickly click the "Check Car Price" button in the quotation form to get a higher car purchase discount.

广州宝马i5降价消息!优惠9.3万,优惠不等人

The design of BMW i5 is full of dynamic and technological sense. The front face adopts the iconic kidney grille of BMW brand, with exquisite LED headlights, showing the combination of strength and elegance. Smooth body lines extend to the rear of the car, creating an aerodynamic beauty, and the overall style highlights BMW’s aesthetic pursuit for future travel.

广州宝马i5降价消息!优惠9.3万,优惠不等人

With its slender body design, the size of BMW i5 is 5175mm * 1900mm * 1520mm, which shows an elegant body proportion. The wheelbase reaches 3105mm, providing passengers with spacious interior space. The car’s side lines are smooth and dynamic, with a front track of 1621mm and a rear track of 1658 mm. Careful adjustment of these parameters ensures the stability of the car. Tyre size is 245/45 R19, with fashionable rim design, which not only provides good grip, but also increases the visual appeal of the vehicle.

广州宝马i5降价消息!优惠9.3万,优惠不等人

The interior design of BMW i5 fully embodies the fusion of luxury and technology. The exquisite leather steering wheel not only feels excellent, but also is equipped with electric up and down+front and rear adjustment function to ensure that the driver can always find the most comfortable grip position. The 14.9-inch central control screen stands in front, full of science and technology, and supports multimedia system, navigation, telephone and air conditioning control to meet the driver’s demand for infotainment and practical functions.

The seat part is made of imitation leather, which not only feels comfortable, but also has good durability. The main and passenger seats have four-way adjustment, including front and rear, backrest, height and lumbar support, to ensure the comfort of long-term driving. The front seats are equipped with heating function, which further enhances the riding experience. The driver’s seat is also equipped with electric seat memory function, which is convenient for daily use. In addition, the car is equipped with a Type-C interface and a wireless charging function of the mobile phone to provide passengers with convenient charging and data connection. Generally speaking, the interior design of BMW i5 not only pays attention to practicality, but also pays attention to details and luxury, creating a comfortable interior environment for drivers and passengers.

广州宝马i5降价消息!优惠9.3万,优惠不等人

The powerful power of the BMW i5 comes from a high-efficiency engine, with a maximum power of 210kW and an astonishing peak torque of 410Nm. This engine not only provides excellent performance output, but also takes into account fuel economy, ensuring that drivers can enjoy driving pleasure while also experiencing energy-saving and environmental protection driving experience.

To sum up, car home car owners are full of praise for the interior of BMW i5, and the gorgeous atmosphere and exquisite ambience lamp design he mentioned have brought great enjoyment to drivers. At the same time, he spoke highly of the functionality of the middle and back stage, which is not only beautiful, but also practical. This comprehensive experience has undoubtedly enhanced the overall charm of BMW i5, making it an ideal car with both aesthetic feeling and practicality of interior and exterior decoration.

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Chongqing Willanda is offering a discount, the latest offer is 133,800! Preferential treatment waits for no man.

[car home Chongqing Preferential Promotion Channel] Recently, a large-scale preferential promotion activity is being carried out in Chongqing, with a maximum discount of 40,000 yuan, which makes many consumers feel excited. At present, the minimum starting price of Willanda has dropped to 133,800 yuan, which has brought more car purchase options and benefits to consumers. If you are interested in Willanda, you may wish to click "Check the car price" in the quotation form, strive for higher discounts and enjoy more car purchase benefits.

重庆威兰达正在优惠,最新报价13.38万!优惠不等人

Willanda has adopted a brand-new design, with smooth lines on the front face and large-size hexagonal design on the air intake grille, which shows a steady atmosphere. The headlights use LED light source, which is perfectly integrated with the air intake grille, enhancing the fashion sense of the whole vehicle. The overall lines of the car body are tough and dynamic, which shows Willanda’s sense of strength and movement. The rear part adopts a simple design style, and the taillight has a unique shape, which improves the visual effect of the whole vehicle. On the whole, Willanda’s design is not only fashionable and dynamic, but also reveals a steady atmosphere, which meets the aesthetic needs of modern consumers.

重庆威兰达正在优惠,最新报价13.38万!优惠不等人

Willanda adopts a streamlined body design with the length, width and height of 4665mm, 1855mm and 1680mm respectively, and the wheelbase is 2690mm, which provides spacious interior space for drivers and passengers. The side lines of the car are smooth and dynamic. The front and rear wheel tracks are 1605mm and 1620mm respectively, which ensures the stability and handling performance of the vehicle. Willanda is equipped with 225/60 R18 tires and fashionable rim style, which not only enhances the sense of movement of the vehicle, but also enhances the grip and driving stability.

重庆威兰达正在优惠,最新报价13.38万!优惠不等人

Wilanda’s interior style is simple and fashionable, and the central control area is equipped with a 10.25-inch central control screen, which enhances the sense of science and technology. The steering wheel is made of plastic material, which supports manual adjustment up and down and back and forth, increasing driving comfort. The car is also equipped with a USB interface, which is convenient for passengers to charge electronic equipment. The seat is made of fabric. The main driver’s seat has the functions of front and rear adjustment, backrest adjustment and height adjustment. The co-pilot seat also supports front and rear and backrest adjustment. The second row of seats also supports backrest adjustment, and the rear seats support proportional tilting, which is convenient for storage.

重庆威兰达正在优惠,最新报价13.38万!优惠不等人

Willanda is equipped with a 171 HP inline four-cylinder engine with a displacement of 2.0L, with a maximum power of 126kW and a maximum torque of 206 N m.. The matching CVT continuously variable transmission can provide a smooth shifting experience and simulate the effect of 10 gears.

Car home car owners have a positive evaluation of Willanda. He especially pointed out that the white color is very beautiful, and the design of the front and rear of the car conforms to the aesthetics of young people, which makes Willanda not only perform well in driving performance, but also win the favor of young consumers in appearance design.

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Fans pick on the thorns for the drama version of "Hua Qiangu": "Abstinence from immortality" becomes a warm man

The immortal drama "Hua Qiangu" that thousands of original fans have been waiting for has finally gone LIVE the night before! This eighteen-episode "fancy sadomasochistic" story of "Pretty Apprentice of the Arrogant Master" has been very popular on the Internet, and the first night of the drama "Go LIVE" has brushed out an amazing discussion peak of 1.40 billion people on Weibo. Huo Jianhua’s "abstinence" Xianbaizi painting, Zhao Liying’s "act cute" girl Hua Qiangu, Marco’s "narcissistic" devil killing Qianmo, and the producer’s self-proclaimed cute pet "Sugar Treasure" made with "definitely not fifty-cent special effects"… have all become hot topics.

  That night, Rao Jun, the screenwriter of "Hua Qiangu", also watched the audience’s comments with the media reporters. Rao Jun jokingly said, "What would you do if I said that I killed my sister (the Great Demon King killed Qianmo) and fell in love with (abstinence from immortality) Baizi painting?" God! The original fans, if the story really turned out like this, would you want to immediately pick up the guy and talk to the screenwriter about life?

  A popular science

  What is the story of "Hua Qiangu"?

  "Hua Qiangu" is considered to be a sadistic and upgraded version of Yang Guo and the little dragon girl’s "forbidden teacher-student love": the goddess of god-level Mary Sue (little apprentice) and the immortal master of the abstinence system disobeyed heaven and started a "master-apprentice love", which caused a series of disasters in the world… The whole story goes through the little apprentice’s secret love and the immortal master’s abstinence; the little apprentice does not give up, and the immortal master resolutely abstinents from sex; the little apprentice gets into a big disaster, and the immortal master gives up the immortal bone to be punished for the little apprentice; the little apprentice goes out to save the master with blood, and the immortal master refuses to welcome it; the little apprentice finally gives up, and the immortal master regrets it; after the little apprentice becomes a demon god, he asks the immortal master to sleep with him so as not to wash the world with blood. The immortal master agrees in order to save the world… In Finale.

  Just such a sadomasochistic story of "Immortal Master abused me thousands of times, and I treated Immortal Master like my first love" caused a frenzy of popularity after being serialized on the Internet. After the physical book was published in 2009, it was even printed in three editions in mainland China. It also launched a traditional Chinese version of Taiwan, as well as a Vietnamese version and a Thai version. Therefore, since the TV series "Hua Qiangu" announced the start of filming last year, its popularity on social networking sites has remained high, and it finally ushered in a climax when it went LIVE the night before yesterday.

  B Focus

  How suitable is Huo Jianhua for portraying white paintings?

  For fans of the original novel, the first priority when watching the adaptation is to check whether the male and female protagonists have destroyed the original novel. As it turns out, fans of the original novel are quite satisfied with the performance of Huo Jianhua and Zhao Liying, especially Huo Jianhua’s portrayal of Bai Zi Hua. During the premiere, social media was flooded with similar comments: "Shangxian’s perfect sideways face is really… let me watch it quietly for a while." "His Majesty is really handsome!" "The female disciple next to you, don’t be so obvious, okay, that should be my play…"

  Abstinence handsome guy

  The perfect side face cut by knives and axes, the clear eyes like grapes, and the long eyelashes that are gentle enough to make people tremble… These are all the capital of Huo Jianhua to harvest the girl’s heart. In fact, Bai Zi Hua is not the first time Huo Jianhua has played a male god of abstinence. In "Legend of Immortals and Swords and Heroes 3", he plays Xu Changqing, the eldest disciple of Shushan Mountain, who is a cold male god who does not eat human fireworks, but he will occasionally be cute. And Bai Zi Hua is high without any impurities! Cold! A handsome face is full of words "This world has a relationship with me", and his every move seems to be free of dust.

  In real life, Huo Jianhua is also single-minded about his work, so he can even give up his relationship. In 2003, Huo Jianhua and Chen Qiaoen fell in love because of their collaboration on "100%", but Huo Jianhua later confessed in an interview that Chen Qiaoen wanted a lot, but he only wanted a career. The two have different perceptions. After the filming, the relationship will come to an end… Is this exactly the same as the feelings of Bai Zihua and Xia Zixun in the play?! In an interview with a reporter from Yangcheng Evening News, Huo Jianhua also said that he enjoyed the happiness brought by the rise of his career more than his feelings. Not long ago, there were a few photos of Huo Jianhua on the set circulating on the Internet – in order to stay awake, he actually stabbed his body with an awl, a real awl!

  sadomasochistic professional household

  Do you still remember Xu Changqing, who was reincarnated three times in "Immortal 3" and still decided to forget Zixuan Fairy in the rivers and lakes? Do you still remember Liu Liancheng, who sacrificed his life for Ma Fuya in "Concubine of Fallen Times"? That’s right, Huo Jianhua is a "sadomasochistic professional". This time, he used Baizi paintings to abuse everyone again. In the play, the misunderstanding between him and his little apprentice Hua Qiangu can be called a thousand twists and turns, until the gods, demons and ghosts can’t stand it anymore, and he still refuses to say "In fact, I have you in my heart".

  Huo Jianhua’s own love history is also very bumpy. According to netizens, Huo Jianhua dated his first girlfriend, Yoyo, when he was 20 years old. At that time, he thought that he would naturally enter the marriage hall. As a result, Yoyo cheated on someone else at the most unsatisfactory time in his life. When he got to his second girlfriend, he actually went out with Huo Jianhua without telling his boyfriend. It was not until his real boyfriend came to the door that Huo Jianhua knew that he was "mistress". According to rumors circulating outside the world, Huo Jianhua’s girlfriend also has Tang Yan, Ye Xuan, and Lin Xinru, but his attitude has always been non-responsive. Including when Li Chen "tore" his ex-girlfriend Zhang Xinyu not long ago, the incident revealed that Huo Jianhua was the object of Zhang Xinyu’s cheating, and he just said: "Don’t talk so much, just focus on filming."

  Cold noodle big warm man

  In the face of the cute and infatuated little apprentice Hua Qiangu, Bai Zihua seemed cold and indifferent, but his heart had already been deeply rooted in love. For Hua Qiangu, he was even willing to abandon his immortal bones and suffer from illness every day. "As long as you are always by my side, it is not a curse if you don’t hurt or die, but a divine grace." How many little girls’ tears were deceived by this disgusting sentence!

  In fact, the cold-faced and warm man is also Huo Jianhua’s true colors. Take his attitude towards fans, can you imagine it? He will say to fans very seriously: "We are not relatives, even if you don’t like me, it doesn’t matter." For fans who call themselves "brain-dead fans", Brother Hua is also very puzzled: "Why can’t you be a good fan if you want to be a’brain-dead fan ‘?" And the most famous thing is that in an interview show, when the host asked: "What would you think if Hua fans gave you luxury cars like other fans give idols?" Huo Jianhua actually replied: "Kill her!" He also added seriously: "How do you explain to your parents? What is this? Volcano’s filial son? So my fans can’t give me things, not within my scope! "Fans also reported that Huo Jianhua’s fans would never accept money, do not hold support clubs, or sell peripheral products, even if Huo Jianhua paid for the meeting himself. Therefore, on the surface, he was very strict with fans, but in fact he was very caring.

  C picky

  How can Shangxian be so handsome to complain?

  Due to the high degree of fit between Huo Jianhua and Baizi’s paintings, fans of the original novel couldn’t bear to criticize the "five-cent special effects" of "Hua Qiangu" and the large-scale adaptation of the original novel. What "Jade Lake First See" became "Hero Saves Beauty", what "Godzilla Vs Dragon", can’t match the handsome face painted by "Immortal" Baizi.

  Picky 1

  "First See in Yaochi" Become a Hero to Save Beauty

  In the original book, the first encounter between Bai Zi Hua and Hua Qiangu is full of Mary Su-style fantasies. The fourth time in the book, the first time Yaochi sees him, he is a high-ranking immortal, and she secretly turns into a bug and lies on the tree, but is blown by the wind and falls into his wine glass…

  In the TV series, the male and female protagonists met at 3:50 in the first episode, and it was an old-fashioned "hero saves beauty" scene. After 5 minutes and 50 seconds, she knew she had fallen in love with him. In addition, Hua Qiangu, who was 12 years old in the original book, was also changed to 16 years old. Fans of the original book generally expressed a little regret but understanding for these two changes. If it is completely according to the book, Shangxian will not come out until the fourth episode, how can fans wait?

  Picky 2

  "Abstinence from immortality" becomes a cold-faced warm man

  "Keep the Immortal for a Long Time" Baizi’s painting, in the original work, is the master who does not eat human fireworks at all, "Immortal is beautiful, cold and dusty, long hair is like a waterfall, eyes fall on stars, and his style is peerless. In this world, I am afraid that there is no painting that can hold his immortal posture, his appearance, his style, and his temperament…"

  In the TV series, Huo Jianhua fully interpreted the otherworldly, but at the same time it was a little more tender. For example, as soon as he appeared, he rode Sun Wukong’s somersault cloud to come to the hero to save the beauty, and also helped the female master of "Bad God" to repair the house, which is really down-to-earth! And seeing the part of Bai Zi painting accompanying Hua Qiangu to eat buns on her birthday, the original party simply burst into tears: The little dragon girl of the new "Divine Condor" eats buns every day, and now Hua Qiangu also eats buns. Is Xiaolongbao a stem that Mango Station can’t skip?

  Picky 3

  "The First Beauty of the Six Realms" becomes Venus

  Although the male and female protagonists escaped the complaints of the original fans, the corner of the Lord of the Demon World "Killing Qianmo" caused a lot of controversy. In the original book, this is a stunner who is indistinguishable from male and female. Because he is too narcissistic and handsome, he is also regarded as "sister" by Hua Qiangu.

  "Kill Qianmo" in the play is played by the new generation actor Marco, who was born in 1990. The young man has worked hard to grasp the imposing and enchanting manner of the Great Demon King, but because the side is too much like the "Poisonous Tongue Teacher" Jinxing, he let the audience play every minute. Some netizens shouted: "What about the first beauty in the Six Realms? Jinxing, go away and kill my sister!"

  Picky 4

  "Sugar Treasure" shape changed to "Kill Matt"

  At the screening of "Hua Qiangu" before, the filmmaker once patted his chest and said: "We are definitely not a special effect!" But it turned out that the scenes of "Godzilla vs. Dragon" in the domestic Xianxia novel were also drunk. And the long-term footage of Shangxian stepping on the somersault clouds into the sky and the earth, if paired with the music of "Journey to the West", there is no sense of incompatibility. And the caterpillar "Sugar Treasure", which captured the hearts of thousands of girls in the original book, turned out to be a "Killing Matt" look, wearing smoky makeup, and having short legs!

  However, "Hua Qiangu" is still worthy of praise in terms of set and picture. The play uses aerial photography mode, with the karst landforms in Guangxi as the background, to restore the fairyland in the original novel. In the first episode, the scene of Hua Qiangu leaning under the peach blossom tree on the edge of the cliff is very magnificent, and the scenes such as Changliu Mountain and the Immortal Pavilion also left a deep impression on the audience. Producer Tang Lijun said: "Unlike many domestic costume TV series," Hua Qiangu "uses the modern ink painting style for the first time in its entirety. It is elegant and refined, elegant and secluded, and with the poignant and beautiful story core of the play – this is a love story with a real Chinese soul." (Reporter, Zhang Yue)

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The maximum discount can reach tens of thousands of yuan! 2023 Zhongshan Spring Auto Show has many highlights.

On the morning of March 17th, the 2023 Zhongshan Spring Auto Show sponsored by Zhongshan Daily and Zhongshan Automobile Distribution Association was held in Zhongshan Expo Center under the guidance of Zhongshan Municipal Bureau of Commerce. As the first large-scale indoor auto show subsidized by Zhongshan Municipal Bureau of Commerce in the first quarter, this auto show covers an area of about 10,000 square meters and lasts for three days (March 17-19), attracting nearly 80 auto dealers and over 30 auto brands from all over the city.


On March 17th, 2023 Zhongshan Spring Auto Show opened in Zhongshan Expo Center. Reporter Miao Xiaojian photo

Nearly 80 automobile dealers and over 30 automobile brands participated in the exhibition.

At 10 o’clock in the morning, people came to Zhongshan Expo Center to watch the exhibition in an endless stream. The car brands participating in the exhibition basically cover the mainstream hot-selling new energy and fuel vehicles on the market, and the new models with beautiful colors and smooth lines are very eye-catching.


Various new models are very eye-catching. Reporter Miao Xiaojian photo

It is understood that,Nearly 80 automobile dealers and over 30 automobile brands came to the exhibition.Among them, there are mainstream models of Japanese and European joint venture brands, and many first-line brands in China, such as Changan and Geely, as well as new energy vehicle brands (such as Nezha, Zero Run, etc.), which can meet the needs of different customers in an all-round way.

At the auto show, many exhibitors offered discounts such as limited time reduction, trade-in, and gift packages. In order to attract consumers’ attention, some exhibitors also made lemon tea, distributed small gifts and launched promotional activities such as smashing golden eggs.


Citizens get on the bus and experience it for themselves. Reporter Miao Xiaojian photo

With the help of the government, we will continue to promote consumption activities.

In order to vigorously carry out automobile consumption promotion activities and fully promote the expansion of automobile consumption in Zhongshan, the subsidies provided by Zhongshan Municipal Bureau of Commerce for the 2023 Zhongshan Spring Auto Show includeParticipating car dealers (subsidizing participation fees and sales incentives) and car buyers (consuming red envelopes), of which a total of investment was made.Spend 10 million yuan on red envelopes.In addition, customers who successfully bought cars during the auto show can also participate in the lucky draw provided by the organizer on the spot, and the winner can get the highest prize.1000 yuan fuel card.

It is reported that consumers can enjoy the most when buying a car during this auto show."Car dealer discount+consumption red envelope+on-site lottery"Triple discount,The maximum amount can reach tens of thousands of yuan..


The Municipal Bureau of Commerce subsidized the "2023 Auto Show Consumption Red Packet" for this auto show.

It is understood that Zhongshan Municipal Bureau of CommerceThis year, we will continue to support at least two large-scale auto shows held throughout the city.In addition, the "Zhongshan Tesco" series of consumer promotion activities will continue to be carried out, making car purchase concessions more "intimate" and "effective".

[Exhibition Guide]

Exhibition location:Zhongshan Expo Center

Exhibition time:March 17-19, 9: 00-17: 30.