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Entrapped anti-influenza drugs

This article comes from WeChat WeChat official account:With freehand brushwork biotech (Biotech(ID：TXYBiotech), Author: Yang Yi, original title: "Anti-influenza drugs and market analysis", title map from: vision china.

The ugly SARS-CoV-19 has not been completely conquered by human beings, and the lingering influenza virus has begun to wreak havoc again. The struggle between human beings and viruses is like this."Scientific Progress-Virus Variation and Drug Resistance"It spirals up in this cycle. The periodic spread of seasonal influenza virus makes the importance of anti-influenza drug development stand out again.

Oseltamivir, which went on the market 24 years ago, is still the mainstay of anti-influenza drugs. Although the first new drug, Baloshavir, enriched the team of anti-influenza drugs, it went on the market five years ago. After learning the cruelty of SARS-CoV-19 virus, people need to make a breakthrough in the development of influenza drugs.

I. Classification of seasonal influenza

Seasonal influenza（Seasonal influenza）It is an acute respiratory infectious disease caused by influenza virus prevalent all over the world. There are four types of seasonal influenza viruses, A, B, C and D.(Chinese corresponds to influenza A, B, C and D). Influenza A and B viruses spread and cause seasonal epidemics.（seasonal epidemics）.

According to the hemagglutinin on the surface of the virus（HA， hemagglutinin）And neuraminidase（NA， neuraminidase）The combination of influenza A virus is further divided into different subtypes. At present, subtype A is transmitted among humans.（H1N1）And a（H3N2）Influenza virus. A（H1N1）Influenza virus is also written as A.（H1N1）Pdm09, because it caused a pandemic in 2009, replaced the seasonal influenza A spread before 2009.（H1N1）Viruses.

Only influenza A virus is known to cause a pandemic at present. Influenza B virus is not classified into subtypes, but can be classified into lineages. The currently popular influenza B virus belongs to B/Yamagata or B/Victoria pedigree. The detection frequency of influenza C virus is low, which usually causes mild infection, so it is not of public health importance. Influenza D virus mainly affects cattle and does not infect or cause human diseases.[1]

Second, influenza treatment

Seasonal flu patients without complications, if they have symptoms, stay at home and do their bit to reduce the spread of the virus. By means of self-monitoring, we can decide whether to seek medical treatment.

Patients suffering from serious or progressive clinical diseases related to influenza, that is, pneumonia, septicemia or clinical syndrome aggravated by chronic basic diseases, should receive antiviral drugs as soon as possible. The most common anti-influenza drugs are neuraminidase inhibitors.（Neuraminidase inhibitors）Oseltamivir（oseltamivir）. Ideally, it should be taken within 48 hours of symptoms to maximize the curative effect. It is recommended to treat for at least 5 days, but it can be extended until the clinical improvement is satisfactory.

It should be noted that corticosteroids should not be used for influenza.(corticosteroid, such as prednisone, cortisone, hydrocortisone, etc.)Unless there are other reasons.(e.g. asthma and other specific conditions)Because corticosteroids may lead to prolonged virus clearance time and double infection of bacteria or fungi caused by immunosuppression.

At present, all popular influenza viruses are resistant to adamantane antiviral drugs.(Adamantane antivirals, such as amantadine and rimantadine)Because of their drug resistance, these drugs are not recommended for monotherapy.[1]

Third, anti-influenza drugs

The main anti-influenza drugs are divided into adamantane, neuraminidase inhibitors and polymerase inhibitors.(Table 1).[2]　There are four kinds of anti-influenza drugs approved by FDA recommended by the Centers for Disease Control and Prevention: Rapivab. （peramivir），Relenza（zanamivir），Tamiflu （oseltamivir phosphate）And Xofluza（baloxavir marboxil）.[3]

Table 1. Antiinfluenza drugs

1. Neuraminidase inhibitors（Neuraminidase inhibitors）　

Neuraminidase inhibitor（NAI）Targeted neuraminidase（NA）Glycoprotein, which is second only to hemagglutinin in human body.（HA）The most abundant surface glycoprotein. Neuraminidase inhibitors can achieve antiviral effect by inhibiting the emergence of new virus particles in host cells and preventing the enzyme activity necessary for virus transmission.[4]

The four most common neuraminidase inhibitors are oseltamivir, zanamivir, peramivir and laninamivir.(Figure 1).

Fig. 1. Common neuraminidase inhibitors and their molecular structures.

Although their structures are similar, there are obvious differences in treatment schemes, routes of administration and drug resistance. The most widely used neuraminidase inhibitor is oseltamivir.(Trade name: Tamiflu)The treatment plan for adults is 75mg twice a day for 5 days. Due to zanamivir(trade name Relenza)The oral bioavailability of is low.（<5%）Therefore, it is approved as an inhalation drug, 5mg each time, twice a day for 5 days.

In 2019, intravenous zanamivir(trade name Dectova)Authorized by the European Union to be used under special circumstances.(e.g. in case of resistance to other anti-influenza drugs). Efforts to increase bioavailability and half-life have led to peramivir.(Trade name: Rapivab/Rapiacta/PeramiFlu)Development of, by intravenous infusion with a single dose of 600mg; And ranimivir (trade name Inavir), a more persistent neuraminidase inhibitor, showed therapeutic effect after a single nasal inhalation dose.[5] Paramivir and Ranimivir are allowed to be used in a few countries around the world, while oseltamivir and zanamivir are more widely approved geographically.

Different neuraminidase inhibitors show different efficacy, which mainly depends on the subtype/pedigree of influenza virus that infects patients.For example, oseltamivir versus A（H1N1）, a（H3N2）And the seasonal uncomplicated influenza caused by influenza A and B virus is more effective. However, the effect of antiviral therapy may be limited by the resistance of influenza virus to neuraminidase inhibitors. Different neuraminidase inhibitors have different drug resistance.

In view of the drug resistance of common neuraminidase inhibitors, people are now focusing on emerging drugs in research. At least two new neuraminidase inhibitors and one neuraminidase blocker are in the first and second development stages.

HNC042(Guangzhou Hengnuokang Pharmaceutical Technology Co., Ltd. and Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd.)In preclinical studies, it showed effective inhibitory activity against wild-type and oseltamivir-resistant NA-H274Y virus. HNC042 showed good safety, tolerability and linear pharmacokinetics in phase I trials in the United States.Learning (NCT04603989). HNC042 is used to prevent and treat influenza, especially for critically ill patients who need hospitalization.

AV5080(ChemRar, Russia, Viriom, USA, Figure 2)The preclinical evaluation revealed the activity against a variety of influenza viruses, including oseltamivir-resistant strains. Oral AV5080 shows good physicochemical and metabolic characteristics and good pharmacokinetic characteristics in animals.[6]

Fig. 2. chemical structure of a new neuraminidase inhibitor drug candidate AV5080.

CD388 (Cidora Therapeutics Inc., USA)It is a long-acting neuraminidase blocker, and its structure is obtained by coupling neuraminidase of influenza virus to human antibody fragment.(Fc）Proprietary variants of the domain, so as to achieve two completely different and complementary mechanisms.(Figure 3). This new method of preventing and treating virus infection is expected to provide universal protection throughout the flu season. By targeting highly conserved virus areas, CD388 can potentially protect individuals from all influenza strains, including seasonal and pandemic influenza A, influenza B and major drug-resistant viruses with clinical characteristics.（NCT05523089）.

Figure 3. Schematic diagram of CDD components. (Source: CIDARA Therapeutics)


2. Polymerase inhibitors（Polymerase Inhibitors）　

Influenza virus RNA polymerase is very important for virus gene transcription and genome replication, which makes it the main goal of targeted drug design. They are highly conserved among influenza A, B, C and D viruses.[7] Influenza virus RNA polymerase consists of three subunits: polymerase basic protein 1 in influenza A and B viruses. （PB1）Polymerase basic protein 2（PB2）And polymerase acidic protein.（PA）Or polymerase 3 protein in influenza viruses C and D.(P3) (Figure 4).

Fig. 4. Virus ribonucleoprotein (vRNP) complex model. In vRNP, the 5′ and 3′ ends of genomic antisense virus RNA (vRNA) fragment are bound by heterotrimeric RNA-dependent RNA polymerase, and the rest of vRNA is wrapped by nucleoprotein (NP). The complex is twisted into an antiparallel double helix structure, and its structure is maintained by the contact between NP monomers. The vRNA forms a loop opposite to the polymerase binding end 6. (Source: Nature)

The active sites of polymerase that bind, cleave and extend RNA are conserved in various types of influenza viruses, which is why RNA-dependent RNA polymerase is considered as the target of antiviral agents. Recently, several polymerase inhibitors have been developed for each subunit, including PB1 inhibitor favipiravir, PB2 inhibitor pimodivir and PA inhibitor baloxavir marboxil (Figure 5).

Among them, baloxavir marboxil is a relatively new drug, which belongs to hat-dependent endonuclease inhibitor.（cap-dependent endonuclease inhibitor， CENI）, a new anti-influenza drug with a new mechanism of action initiated in recent 20 years, was developed by Shionogi.（Shionogi）First developed by Pharmaceutical Co., Ltd., there is no equivalent generic drug, which has been proved to have similar symptom relief time and greater viral load reduction for healthy adults and oseltamivir.[8]　A retrospective study shows that baloxavir marboxil may reduce the hospitalization rate compared with neuraminidase inhibitors.[9]

Fig. 5. Chemical structure of anti-influenza drugs of RNA polymerase inhibitors.

The drug resistance of Baloxavir marboxil, Favipiravir and Pimodivir and other defects highlight the need to develop other polymerase targeting molecules that can widely inhibit influenza A and B viruses.

Pre-clinical studies on various PB2-targeted small molecules are under way.[10]　At least one of them（CC-42344） In the first stage（NCT05202379）, the other one（ZSP1273）In the third stage of research(NCT04024137) (Figure 7). Substitutes for nucleoside inhibitors of Favipiravir, such as molnupiravir.(Figure 6)Because it is effective against various RNA viruses, it may be beneficial to the treatment of influenza, but they may also have teratogenic side effects similar to Favipiravir, so Merck, its developer, finally gave up the development of influenza viruses and turned to Covid-19 for treatment.The development of PB1 inhibitors based on nucleoside and non-nucleoside is in preclinical stage.[11]　But there is no clinical trial at present.

Baloxavir marboxil obviously provides a broad idea for developing polymerase inhibitor anti-influenza drugs, and many patents and in vitro studies focus on compounds or variants of Baloxavir marboxil skeleton.[12] Although some of them have shown promising in vitro efficacy and pharmacodynamics in mice,[13]　However, candidate drugs such as AL-749 did not pass the Phase I test.

Cap-dependent endonuclease inhibitor TG-1000 (Dongyangguang Pharmaceutical)And GP681(Jiangxi Qingfeng and Yinxingshu Pharmaceutical Co-developed)Recently completed the second phase of the experiment.（NCT04706468、NCT04736758), and the recruitment of ZX-7101A phase 1 research is under way.（NCT05217732）. Various small molecules and peptides that disrupt the important protein-protein interaction between components of polymerase complex, including the key contact between PA and PB1 or between PB1 and PB2, are in the preclinical development stage.[14]

Fig. 6. Chemical structure of a new polymerase inhibitor molnupiravir.

Fourth, the global market of anti-influenza drugs

According to the latest report released by Growth Plus Reports, the global influenza drug market is expected to reach US$ 1.51 billion by 2030, and it will grow at a compound annual growth rate of 4.8% during the forecast period. The number of influenza cases increases sharply every year, which is expected to promote the sustained growth of the influenza drug market.[15]

North America accounts for most of the global influenza drug market.The high diagnosis rate of influenza, the wider basis of drug discovery and development, the wide availability of treatment methods, and the more significant medical expenditure contribute to the dominant position of influenza drugs in the North American market. The Asia-Pacific region has the second largest market share of influenza drugs in the world. The high prevalence rate, the government’s measures to control diseases, and the increase in health care expenditure have affected this growth.

Due to the increasing incidence of diseases and the existence of considerable influenza-related risk factors in the general population, it is expected that the European market will also see significant growth. NCBI(National Biotechnology Information Center)According to a new study, there are 27,600 respiratory deaths related to seasonal influenza in 28 EU countries every winter, of which 88% are people over 65. The mortality rate of this age group is about 35 times that of people aged 65 and under.

The main participants in the development and sales of influenza drugs include: Sanofi, Lupin, Teva, Shionogi, Macleods, Alvogen, AstraZaneca, BioCryst, La Roche, Novartis, Vitaris, etc.

V. Summary　

Although it is not as ugly as SARS-CoV-2 virus, influenza virus also kills many people, and treating influenza is still an arduous challenge for human beings. Like other antiviral drugs, the development of influenza drugs faces the difficulty of virus resistance. Baloxavir marboxil is the first new drug, which shows activity against some oseltamivir-resistant strains, and there is no significant difference in safety and effectiveness from the recently known drugs used to treat influenza. The listing of Baloxavir marboxil also brings new opportunities for combined treatment with two drugs with different mechanisms of action. Although this kind of research has not been carried out systematically, it provides a valuable new direction for influenza treatment.

In addition to Baloxavir marboxil, there are many drugs under research at different clinical stages.(Figure 7)They will be optimized in pharmacology, drug resistance, pharmacokinetics, etc., and stand on the shoulders of a few influenza drugs at present to launch a unremitting struggle against influenza virus.

Fig. 7. Overview of anti-influenza drugs in development. (Source: Antiviral Research)

References:

[1] WHO. Influenza (Seasonal). 12， 01， 2023. ↑[] Jones， J. C. et al. Influenza antivirals and their role in pandemic preparedness. Antiviral Research. 2023， 210， 105499.　

[2] Influenza (Flu) Antiviral Drugs and Related Information. FDA. 08， 12， 2022.　　

[3] Monto， A. S. et al. Influenza pandemics: history and lessons learned. Webster， R. G. et al (Eds.)， Textbook of Influenza (2 ed.)， Wiley Blackwell， West Sussex， United Kingdom (2013)， pp. 20-36　　

[4] Sugaya， N. et al. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob. Agents Chemother. 2010， 54， 2575-2582

[5] Ivachtchenko， A. V. et al. Novel oral anti-influenza drug candidate AV5080. J. Antimicrob. Chemother. 2014， 69， 1892-1902.　　

[6] Peng， Q. et al. Structural insight into RNA synthesis by influenza D polymerase. Nat Microbiol. 2019， 4， 1750–1759.　　

[7] Hayden， F. G. et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescentsN. Engl. J. Med. 2018， 379， 913-923.　

[8] Komeda， T. et al. Comparison of hospitalization incidence in influenza outpatients treated with baloxavir marboxil or neuraminidase inhibitors: a health insur ance claims database studyClin. Infect. Dis.， 2021， 73， e1181-e1190.　

[9] Chen， W. et al.　 Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit. Drug Discov. Today. 2022， 27， 1545-1553.　

[10] Hou， L. et al. Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins. Acta Pharm. Sin. B. 2022， 12， 1805-1824.　　

[11] Stevaert， A. et al. The influenza virus polymerase complex: an update on its structure， functions， and significance for antiviral drug design. Med. Res. Rev. 2016， 36， 1127-1173.　

[12] Ivashchenko， A. A. et al. Synthesis， inhibitory activity and oral dosing formulation of AV5124， the structural analogue of influenza virus endonuclease inhibitor baloxavir. J. Antimicrob. Chemother. 2021， 76， 1010-1018.　

[13] Massari， S. et al. Inhibition of influenza virus polymerase by interfering with its protein-protein interactions. ACS Infect. Dis. 2021， 7， 1332-1350.

[14] Influenza Medication Market – Global Outlook & Forecast 2022-2030. Growth Plus. 11， 10， 2022.　

This article comes from WeChat WeChat official account:With freehand brushwork biotech (Biotech(ID：TXYBiotech), author: Yang Yi

Na Ying joined ＂Like a Shadow＂ and decided not to sing ＂Reunion＂ for a new song in the Spring Festival Evening.

Na Ying sang the theme song for the film.


"Like a Shadow" Chen Xiao


1905 movie network news Na Ying, the diva of Chinese music, officially announced today that she has joined Jianqi Huo to direct the new film "Like Shadows". She will sing two theme songs for the film, and a poster of "Na Ying X Years Like Shadows" will be exposed. In the picture, Na Ying looks gentle, changing her big sister’s domineering attitude in the past, and her warm eyes seem to greet old friends. This time, that sister personally participated in the creation of movie songs, cooperated with the beautiful pictures directed by Jianqi Huo, and the wonderful performances of the leading actors and actresses Chen Xiao, Du Fu and Wang Jia, which will definitely please the audience and satisfy the long-lost fans. How the real characters of the two songs of that elder sister quickly aroused fans’ guesses on Weibo, which made the audience’s expectations for new songs and movies soar.

　Rhododendron "Like a Shadow"


Na Ying has performed countless popular Chinese classics, and her songs tell a lot about love and looking for a marriage’s love-hate relationship. The warning record of marriage and love "Like a Shadow" is a transformational work prepared by director Jianqi Huo for ten years. It is adapted from the emotional record of urban emotional expert Anton, starring Chen Xiao, Du Fu and Wang Jia, and gathering many stars to join in the cross-border business. The film focuses on the topic of marriage and love that attracts the most attention of urban men and women. Na Ying’s joining is also following the golden song "Silence" and "Sansheng Sanshi"After that, I sang for the movie again. Tianhou holds hands with famous director’s new work,The golden combination will create the most resounding movie music. The elder sister said frankly：This joining is attracted by the high quality of the film and the strong love story.,As for what you can sing,You will hear it when Valentine’s Day comes.


　"Like a Shadow" Wang Jia


On the occasion of joining the movie "Like a Shadow", some media reported that Na Ying would be on the Spring Festival Evening of the Year of the Dog, and after a lapse of 20 years, she would sing with Faye Wong. Na Ying confirmed that she will bring a new song to CCTV Spring Festival Gala this year. As for which song and what kind of performance Faye Wong will perform, everything has yet to be decided. However, it is certain that the Spring Festival Evening song is not "Reunion" or "Meet 2018". As can be seen from the posters issued by the film company, Na Ying will release two theme songs on the two Valentine’s Days, which will really satisfy the fans. It can be seen that this year Na Ying will share with the public her 20 years from "Meet 98" to "Time flies like a shadow", and I believe that it will definitely set off the feelings of urban men and women and set off a wave of memories of 20 years.


Mercedes-Benz GLE shopping guide when 2.5L meets automatic manual (AT)= more fuel-efficient.

First of all, let’s take a look at the overall design of this model according to the routine. The car body lines continue the family design concept, the front face of the whole car looks exquisite, the design of the headlights on both sides is quite beautiful, and the headlights look very energetic after lighting. From the side of the car body, the new car adopts the side design, which prolongs the visual effect of the car to a certain extent. The double five-spoke shape is unique and the visual effect is acceptable. At the same time, the reasonable proportion of luggage compartment cover and enclosure also gives the tail a rounded visual center of gravity, and the design of split taillights is also interesting, which shows great personality after lighting.

Coming to the interior of the car, the simplicity of the interior of Mercedes-Benz GLE gives people the feeling that it is bright at the moment. The three-position steering wheel is full of movement. In the embracing center console and the door handle, a lot of plastic, leather and metal materials are used to cover and wrap it. The 12.3-inch central control screen with high touch is simple in screen design, but fully functional. The front row is also equipped with a dual-temperature automatic air conditioning control system, which can freely debug the most comfortable space atmosphere. The leather seat looks very comfortable.

The length, width and height are 4927×2018×1797mm respectively, and the wheelbase has reached 2995 mm. In the same class, the wheelbase of Mercedes-Benz GLE ranks 13th. 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 Mercedes-Benz GLE ranks third. 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 GLEGLE 450 4MATIC luxury model uses a 2.5 engine, with a maximum horsepower of 367 and a peak torque of 500, matching the automatic manual transmission (AT). The whole power parameters are superior in power performance among engines of the same class, which can provide better power performance. Mercedes-Benz GLE’s official measured zero-acceleration score is 5.9S, ranking 32nd among 400,000-800,000 SUV models.

The active/passive safety configuration of Mercedes-Benz GLE is complete, includingAutomatic parking、Zero tire pressure endurance tire、Automatic parking、Steep slope descent、hill start assist control、knee airbag、HUD head-up display、Anti-lock braking (ABS)、Braking force distribution (EBD/CBC, etc.)、Brake assist (EBA/BAS, etc.)、Traction control (ASR/TCS, etc.)、Active noise reduction、Engine start and stop、Side safety air curtain、Wireless charging of mobile phone、night vision system、LED daytime running lights、Forward reversing radar、Tire pressure monitoring、Steering wheel heating、Body stability control (ESP/DSC, etc.)、Rear reversing radar、Fatigue reminder、Remote parking、Child seat interface、Lane 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 addition to the above description, we can also go to the Easy Car Forum to browse more real car feedback from actual buyers, or use our experience.

Didi responded positively to the ＂flight attendant hitchhiking＂ case for the first time： the platform has loopholes

　　China Central Broadcasting Network Beijing May 22 news, according to the voice of China "news vertical and horizontal" report, these days, Zhengzhou stewardess Didi Hitch case caused widespread discussion in the community, what are the loopholes in the management of the Didi platform? In the end is it safe to take Didi Hitch? Didi Chuxing company recently responded positively for the first time, chief development officer Li Jianhua admitted that the alleged offender in the case Liu illegally used his father’s account to receive orders and commit crimes, indicating that the platform did have loopholes before.

　　Although the Didi Hitch case has passed for many days, the loopholes exposed in the case are still thought-provoking. What is the security situation of the Didi platform, and how should the safety net of Hitch and online car-hailing be woven?

　　According to China Central Radio and Television CCTV, Didi Chuxing said that in order to ensure safety, taking the hitch accident as an example, it has set up five gates, including real-name verification registration, virtual middle contact phone number, facial recognition when the first order is placed, itinerary sharing, and one-click alarm. Among them, real-name verification registration is the first hurdle for driver and vehicle identity confirmation. Didi requires hitch drivers to be at least one year old. When registering, drivers must upload their ID cards, driver’s licenses, and driving licenses to the platform for three-certificate verification.

　　But the alleged offender, Hitch driver Liu, only got his license at the end of December. According to the situation of the alleged offender Liu, Didi said that he must not pass the review of Didi’s driver qualification. The reason why he passed the review was because his father’s three certificates were uploaded when the account was registered.

　　In addition, facial recognition must be carried out before receiving the first order after registration. Is it the father or the son who passes the facial recognition of this first order? Li Jianhua, chief development officer of Didi Chuxing, said that the registered car owner, the father of the alleged offender Liu, is compared through the facial recognition of the first order.

　　However, the person who actually took the order and drove it became the son – the alleged offender Liu. "The problem is that we didn’t find that the driver who took the order was either the registered person or his father," said Li Jianhua. "But it’s not particularly clear who picked up each order."

　　So, the people and cars in actual operation are not the same as when they were registered. Is it an accident in this case?

　　On May 11, the day Didi issued its statement, at around 6 PM, through the Didi platform, a reporter made an appointment for an express train in Beijing, but another car arrived.

　　Reporter: Master, is your tail number 98962?

　　Driver: Internet Finance Center.

　　Journalist: Yes.

　　Driver: Get in the car!

　　Reporter: But this one is written as 98962.

　　Driver: I’ve changed again, tail number M5.

　　It is not uncommon to encounter people and cars when ordering a car through the Didi platform. Some cars are not registered cars, and some people are not registered people. Didi driver told reporters: "I can be a car and a person. I just log in with one account, then take the order and pull it."

　　Citizen 1: I found out that it was another car, which was different from the phone number and license plate number on the software. I didn’t pay much attention at the time.

　　Citizen 2: He will say that I have this limit number, or that I have changed a car, which is easy to prevaricate.

　　According to the drivers, no matter which car it is, no matter which person it is, as long as you log in with your registered account, the platform system will automatically assume that it is the registered person and car for dispatch and checkout. If the registration is Zhang San driving but becomes Li Si, can the Didi platform find out in this situation? Li Jianhua, chief development officer of Didi Chuxing, responded: This case shows that the platform has previously had loopholes.

　　So, why did all these "barriers" to ensure safety fail in this case? Didi said that the company is now growing rapidly and on a large scale. In 2017, there were about 21 million car owners on the Didi platform. Wang Sixin, deputy director of the Department of Cultural Studies at Communication University of China, pointed out that no matter how large and fast the development scale of the enterprise, the main responsibility of the enterprise should always be put first.

　　On May 16, Didi Chuxing announced rectification measures, including: all personalized tags and comment functions in the offline ride-hailing business, drivers must perform facial recognition before each order, and at the same time launch prizes for reporting people and cars that do not match on all major platforms. In addition to Didi’s self-rectification, the next step is to further strengthen supervision for the problems of people and cars that appear on the online ride-hailing platform, which is also the focus of the competent authorities.

The Central Radio and Television General Station publishes and distributes the excellent programs celebrating the centenary of the founding of the Party, ethnic languages and audio-visual products in

　　The release ceremony of the national language and Minnan dialect version of the excellent program celebrating the centenary of the founding of the Party by the Central Radio and Television General Station was held in Beijing on July 21. Shen Haixiong, Vice Minister of Publicity Department of the Communist Party of China, Director and Editor-in-Chief of Central Radio and Television Station, attended and launched the launch.

　　On the occasion of celebrating the centenary of the founding of the Communist Party of China (CPC), the Central Radio and Television General Station broadcast live the celebration meeting and the awarding ceremony of the July 1st Medal, created, recorded and broadcasted the literary performance Great Journey, and launched a number of excellent programs such as Armageddon and Crossing the Yalu River, which won wide acclaim at home and abroad. At the request of the broad audience, the audio-visual products of these excellent programs in Mongolian, Tibetan, Uygur, Kazakh, Korean and Minnan languages are published and distributed to the public by China International Television Corporation, which is affiliated to the General Station.

　　△中央广播电视总台副台长 蒋希伟

　　中央广播电视总台副台长蒋希伟在致辞中表示，习近平总书记指出，文化是一个民族的魂魄，文化认同是民族团结的根脉。中央广播电视总台充分发挥多语言优势，制作推出庆祝中国共产党成立100周年精品节目民族语言以及闽南话版音像制品，让广大受众通过自己熟悉的语言身临其境地感受党的庆典、人民的节日，能够增强中华民族大家庭的自豪感，进一步弘扬伟大建党精神，激励全国各族人民向着实现第二个百年奋斗目标奋勇前进。

　　据介绍，庆祝建党百年精品节目民族语言及闽南话版音像制品将于近期在全国近百家省市级新华书店、音像商城和网络电子商城上线销售。中国国际电视总公司还将为党政机关、企事业单位、院校、社会团体、博物馆、红色旅游地等定制相关产品。截至目前，中国国际电视总公司已倾力打造了32种庆祝建党百年主题出版物，涵盖普通话、粤语、闽南话、五种少数民族语言以及多语种外语。

　　中央广播电视总台编务会议成员刘晓龙、王晓真，总台相关部门负责人及媒体代表参加了发行活动。（摄影：谢云飞）

How will new energy vehicles run in the next 15 years？ This document points out a new path of development.

　　New Energy Automobile Industry Development Plan (2021&mdash; In 2035), it is proposed that the core technology of China’s new energy vehicles should reach the international advanced level in 2035, and the quality brands have strong international competitiveness, and it is pointed out that it is necessary to improve the infrastructure system and improve the service level of charging infrastructure &mdash; &mdash;

　　Reporter Li He

　　New energy vehicles have become the main direction of the global automobile industry transformation and development, and also an important engine to promote the sustained growth of the world economy. For China, developing new energy vehicles is the only way to move from a big automobile country to a strong automobile country, and it is also a strategic measure to cope with climate change and promote green development. Since 2010, China’s new energy vehicles have grown rapidly at an average annual rate of double. In 2019, 1.06 million new energy passenger cars were sold, ranking first in the world for five consecutive years. With the development plan of energy-saving and new energy automobile industry (2012&mdash; After the end of 2020), how should China’s new energy automobile industry develop?

　　On November 2nd, General Office of the State Council announced the Development Plan of New Energy Automobile Industry (2021&mdash; 2035) (hereinafter referred to as "Planning") emphasizes the need to seize strategic opportunities, give full play to the advantages in infrastructure, information and communication, continuously enhance the core competitiveness of the industry, and promote the high-quality and sustainable development of the new energy automobile industry.

　　With strong competitiveness, the core technology has reached the international advanced level.

　　The Plan is divided into eight chapters, including five key tasks, five column tasks and five "three 5s" of safeguard measures. Xin Guobin, vice minister of the Ministry of Industry and Information Technology, said that as a programmatic document of the new energy automobile industry, the main highlights of the Plan can be summarized as "four new ones", namely, adapting to the new situation, adapting to new requirements, proposing new development paths and defining new development directions.

　　The new situation means that with the vigorous development of the new round of scientific and technological revolution and industrial transformation in the world, new energy vehicles integrate new energy, new materials, Internet, big data, artificial intelligence and other revolutionary technologies to promote the transformation of vehicles from simple means of transportation to mobile intelligent terminals, energy storage units and digital spaces, and promote the optimization of energy consumption structure, the improvement of transportation system and the intelligent level of urban operation; Emphasizing "market leading" requires giving full play to the decisive role of the market in resource allocation, strengthening the dominant position of enterprises in the selection of technical routes and the construction of production and service systems, giving full play to the role of the government in strategic planning and guidance, formulation of standards and regulations, quality and safety supervision, maintenance of market order, and green consumer guide, so as to create a good environment for industrial development.

　　The Plan proposes that by 2025, the competitiveness of China’s new energy vehicle market will be significantly enhanced, and the sales volume of new energy vehicles will reach about 20% of the total sales volume of new vehicles, and the long-term goal of "in 2035, the core technology of China’s new energy vehicles will reach the international advanced level, and the quality brands will have strong international competitiveness".

　　Xin Guobin said that at present, there is still a certain gap between new energy vehicles and traditional fuel vehicles in terms of purchase cost and charging convenience. To promote the goal that the sales volume of new energy vehicles will reach about 20% of the total sales volume of new vehicles in 2025, it needs to be promoted from both the supply and demand sides. On the supply side, it is necessary to continuously strengthen technical research around key factors such as reducing costs and improving safety, develop advanced, applicable and reliable products, and accelerate the formation of greater market competitive advantages; On the demand side, it is necessary to strengthen policy guidance, introduce preferential policies to encourage the use of new energy vehicles, optimize classified traffic management measures, encourage business model innovation such as power exchange, accelerate the electrification of vehicles in public areas, increase the promotion of new energy vehicles to the countryside, and continuously improve the user experience.

　　Cui Dongshu, deputy secretary-general of the National Passenger Car Association, said that in terms of power consumption, the Plan proposed that by 2025, the average power consumption of new electric passenger cars would be reduced to 12 kWh/100 km. This is 1 degree higher than the 11 kWh/100 km of its exposure draft. In essence, it is to encourage the development of high-end new energy and should give it more room for development.

　　Driven by innovation, deepen the "three verticals and three horizontals" R&D layout

　　Xin Guobin said that China’s new energy automobile industry has developed to this stage, and there are still problems such as weak core technology innovation ability, quality assurance system to be improved, lagging infrastructure construction, service model to be innovated and improved, imperfect industrial ecology, and increasing market competition.

　　Telly, director of the High-tech Department of the Ministry of Science and Technology, said that from the whole development experience of new energy vehicles, the supporting and leading role of scientific and technological innovation in its development is very obvious.

　　In order to promote the realization of the goal, the Plan puts forward the basic principle of "innovation drive" and the special chapter of "improving the ability of technological innovation", and also emphasizes deepening the layout of "three verticals and three horizontals". "Three verticals" refer to pure electric vehicles, plug-in hybrid electric vehicles and fuel cell vehicles, and "three verticals" refer to power batteries and management systems, drive motors and power electronics, networking and intelligent technologies.

　　"For the power battery, the core component of new energy vehicles, it will be deployed in advance in terms of new systems, new materials, new processes and new structures, and promote the development of power batteries in the direction of high specific energy and high safety; For fuel cells, we will focus on supporting core materials such as proton exchange membranes, catalysts and carbon paper, as well as key technologies related to hydrogen energy, and work hard on high performance, long life and low cost of fuel cells. " Telly said that around intelligence, networking and lightweight, we will speed up the layout of a new generation of information technology and focus on promoting the development of autonomous driving technologies and equipment such as vehicle control operating systems and computing platforms and vehicle-level chips; Strengthen the technical layout of new materials and support the research and development of silicon carbide power devices, lightweight materials and low-cost rare earth permanent magnet materials. We will increase support for scientific and technological innovation platforms such as the National New Energy Vehicle Technology Innovation Center, build a national strategic scientific and technological force for the national new energy vehicle industry, and provide support for the research and development of common key technologies in the industry.

　　Xin Guobin said that in addition to strengthening innovation drive, it also pays attention to standard guidance, which will promote the formation of a technical standard system based on vehicle-road coordination and reflecting Chinese characteristics. Accelerate the deployment of 5G communication base stations, promote the transformation and upgrading of intelligent roads, and organize manned loading tests and large-scale application demonstrations.

　　Improve infrastructure and promote the construction of charging and replacing network

　　China has built the largest charging network in the world. As of September this year, 42,000 charging stations and 525 power stations have been built nationwide, with 1.42 million charging piles of various types, and the ratio of vehicles to piles is about 3.1: 1.

　　"Charging and replacing electricity infrastructure is a key link in the development of new energy vehicles and an important support for industrial promotion. On the whole, compared with the promotion and application scale of new energy vehicles, the construction and development of charging facilities still cannot meet the needs of consumers, and it is necessary to increase construction efforts and optimize structural layout. " Xin Guobin said.

　　The Plan proposes to "improve the infrastructure system", promote the construction of the charging and replacing network, scientifically arrange the charging and replacing infrastructure, and strengthen the overall coordination with urban and rural construction planning, power grid planning and property management, and urban parking. Relying on "internet plus" smart energy, we will improve the level of intelligence, promote the charging service mode in residential areas with intelligent and orderly slow charging as the mainstay and emergency fast charging as the supplement, accelerate the formation of expressways and urban and rural public charging networks with moderate advance, fast charging as the mainstay and slow charging as the supplement, encourage the application of power exchange mode, and improve charging convenience and product reliability.

　　According to the data provided by the Ministry of Finance, in order to support local governments to speed up the construction of charging infrastructure, from 2014, the central government will give incentives to local governments to carry out charging infrastructure construction. So far, the central government has issued a total of 4.5 billion yuan of incentive funds, forming a development pattern of coordinated promotion between the central and local governments.

　　"In the past, users had mileage anxiety, and driving new energy vehicles could not run far, so they could only run in the city. Now, some expressways have built networked charging and power exchange facilities. " Xin Guobin said that to solve the mileage anxiety, in addition to continuing to increase the construction of charging piles, it is also necessary to consider the problem of making full use of existing charging piles. The existing information management technology can be used to bring all charging piles into a management platform and share them as much as possible. With the continuous expansion of market capacity, the construction layout of charging piles will be more scientific and standardized.

　　The Plan also proposes to improve the service level of charging infrastructure. Guide enterprises to jointly establish a charging facility operation service platform to realize interconnection, information sharing and unified settlement. Strengthen the research and development of technologies such as safety monitoring and early warning of charging equipment and distribution system, improve the safety, consistency and reliability of charging facilities, and improve the level of service guarantee.

2024 China Daqing First International Youth Cross-country Skiing Short Distance Race was held.

On January 20th, the 2024 China Daqing First International Youth Cross-country Skiing Short Race was held in Sanyong Lake, Daqing, under the guidance of China Skiing Association, sponsored by Daqing Sports Bureau and Daqing Longfeng District Government, undertaken by Daqing Karhu Sports Culture Co., Ltd. and Beijing Sanbei Aoxue International Competition Management Co., Ltd., and co-organized by Daqing Longfeng District Culture, Sports and Tourism Bureau and Daqing Longfeng District Education Bureau.

The competition was established: 10 km for men/women aged 17-18, 5 km for men/women aged 15-16, 2.5 km for men/women aged 13-14 and 1.5 km for men/women aged 11-12. In addition, in order to encourage the public to participate in the competition, a 10-kilometer freestyle skiing competition for men and women was added.

This competition attracted 60 young athletes from Russia, the Republic of Russia, the Republic of Sakha, Kazakhstan and France, and nearly 500 cross-country skiers from China. The settlement of this event in Daqing will inject new vitality into the revitalization and economic growth of the ice and snow sports tourism industry in Daqing and build a bridge of friendship for sports and cultural exchanges between European and Asian countries.

After fierce competition: the men’s 10km champion was won by Russian Filipoff &bull; For Ole and sergeyevich, Russian Lebedev &bull; Slavic Evgenyevich of Wache won the runner-up, and Russian player Stramilav &bull; Gregory &bull; Romanovic won the third place.

The women’s 10km champion was given to Gina &bull by Russian player Nini; Alina &bull; Vidaliyevna picked it. China’s Chen Jiayi won the runner-up, Russian Mirnikova &bull; Sophia alekseev won the third place.

The men’s 5km champion was won by China’s Zhong Guoqiang and Kazakh’s Garasbek &bull; Azimu won the runner-up and China’s Jin Yuchen won the third place.

The women’s 5 km champion was won by Russian player Goncearuc &bull; Sophia &bull; Vidaliyevna won, Russia’s Skupoyeva &bull; Uriana &bull; Alekseev Na won the runner-up, Russian player Sambuyeva &bull; Ye Li Zaveta &bull; Ba Li Lovna won the third place.

The men’s 2.5km champion was won by Russian player Putintsev &bull; Dmitry &bull; Alexeyevich won, Russian player Lu Dehe &bull; Sergey &bull; Alexeyevich won the runner-up, Russian Krymukin &bull; Nigada &bull; Sergeyevich won the third place.

The women’s 2.5 km champion was won by Kazakhstan’s Trevor Onava &bull; Valeria won, Russia’s Kolaxin &bull; Balina &bull; Evgenyev Na won the runner-up, Russian player Malkova &bull; Anna &bull; Alekseev Na won the third place.

The men’s 1.5km champion was won by Russian player sakr &bull; Andre &bull; Jurjevic won, Russian Leochiev &bull; Mikhail &bull; Alexeyevich won the second place, and the third place belongs to Russian player Durbanov &bull; Yegaoer &bull; Vladimirovich won the third place.

The women’s 1.5km champion was won by China’s Zheng Xunuo, Russian player Gusheva &bull; Yekaterina &bull; Aleksandrovna won the runner-up and China’s Zhang Xinyao won the third place.

The purpose of this competition is to cultivate the development concept of "ice and snow are also Jinshan Yinshan" and vigorously develop the ice and snow sports industry. Conscientiously implement the requirements of accelerating the development of ice and snow economy in the province, accelerate the development of ice and snow industry, and make social responsibility of Heilongjiang Province.

On the occasion of the successful bid for the 2025 Harbin Asian Winter Games, we will take sports as a link and cross-country skiing as a bridge to enhance the exchange and mutual learning between sports and cultures of Asian and European countries, so as to "gather the light of sports for march towards a great future together’s future".

The day after the New Year’s Day holiday, Zhou Bianyou became the mainstream of travel.

　Sichuan News Network-First Screen News Chengdu December 31st (Reporter Dai Luling)On the second day of the New Year’s Day holiday in 2024, the reporter learned from the Sichuan Provincial Department of Culture and Tourism that as of 15: 00 on the 31st, 832 A-level scenic spots in the province had received 3,318,200 tourists, achieving a ticket income of 33,095,200 yuan, up by 25.2% and 49.66% respectively compared with yesterday, up by 71.85% and 99.66% respectively compared with the same caliber in the same period in 2023.
Five-year-level tourist attractions in the province (16 parks opened normally) received 249,700 tourists and realized ticket income of 9,466,800 yuan, up by 63.75% and 85.48% respectively compared with yesterday, and up by 111.75% and 97.78% respectively compared with the same caliber in the same period in 2023. Libraries, cultural centers and museums in the province received 684,500 people.
Zhou Bianyou has become the mainstream of New Year’s Day travel
On the second day of New Year’s Day holiday, cloudy days predominated in most parts of the province. Tourists mostly chose open scenic spots, ancient towns and museums near their homes, and go on road trip, family tours and parent-child tours became the mainstream. The top five scenic spots in the province are Chengdu Joy City (78,000 person-times), Luodai Ancient Town (71,000 person-times), Qionghai Lushan Scenic Area (63,500 person-times), Chengdu Shuangliu District Seaside City Scenic Area (59,000 person-times) and Chengdu Wuhou Temple Museum (57,900 person-times). The popularity of traveling in museums has not diminished, and the reservations for visiting Sanxingdui Museum and Chengdu Museum have reached the upper limit.
Ice and snow hot spring tour continues to be hot.
The ice and snow hot springs were sought after during New Year’s Day. The annual reception volume of Bipenggou Scenic Area exceeded the million mark for the first time today, and the number of tourists in Wawu Mountain Scenic Area reached the maximum carrying capacity. Hailuogou Scenic Area ushered in the reception peak (0.34 million person-times) after the earthquake, which was three times higher than yesterday. Among ski resorts, Emei Mountain Scenic Area (45,200 person-times), Bashan Grand Canyon Scenic Area (21,000 person-times), Zengjia Mountain Scenic Area (17,500 person-times), Bipenggou Scenic Area (17,400 person-times) and Xiling Snow Mountain Scenic Area (13,000 person-times) all exceeded 10,000 people, which promoted the "cold resources" to become a "hot economy". Among the hot spring scenic spots, the top three scenic spots are Luofu Mountain Scenic Area (17,700 person-times), Jiulongshan-Lutangshan Tourist Area (15,900 person-times) and Huashuiwan Hot Spring Resort Tourist Area (7,000 person-times).
All kinds of cultural tourism activities meet the needs of the masses
Local cultural and tourism departments and scenic spots have launched online and offline activities around the New Year, so that people can enjoy the feast of cultural tourism. Deyang City launched the New Year’s Eve activity of "Temple Fun, Leisure and Virtue", Nanchong City launched the New Year’s Eve activity of "Cultural Travel Consumption, Enjoy Nanchong", and Maoxian County held a cultural performance and a non-legacy market activity to welcome New Year’s Day, which not only met the needs of the masses but also effectively promoted holiday consumption. On New Year’s Eve, many theaters in Chengdu held New Year’s Eve concerts, Yibin held the 2024 Stars New Year’s Eve Concert, Zigong Fangte Dinosaur Kingdom held the theme activity of "Fangte Flying Snow New Year’s Eve", and Yingjing County launched the Taiji Park New Year Fireworks Show to welcome the New Year. Guangyuan Grottoes Research Institute innovatively launched the New Year’s Day live broadcast of "Grottoes in Guangyuan, Accompany You in the New Year’s Eve" to show the historical and cultural charm of grottoes during the New Year holiday.
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