Original Zhao Bei Ten-Point Science

Because of the aging immune system, vaccines are less effective for the elderly. Scientists believe that it is more important and more widely used to develop drugs that can enhance the immune function of the elderly than to develop vaccines for the elderly.

Along with skin aging, there is also the immune system. | Figure worm creativity

Author | Doctor of Immunology, Zhao Bei

Recently, many deaths caused by influenza vaccine in Korea have attracted attention. As of October 31st, the death toll rose to 83, of which 71 were over 70 years old (accounting for 85.5%). In addition to the possible quality problems of the vaccine itself, it also reminds us of the fact that the role of the vaccine for young people and the elderly is different.

This is also a difficult point in the development of COVID19 vaccine.

Increasing age, and aging immune system

As people get older, we experience a series of physical changes, such as hearing loss, skin relaxation, joint injury and so on, and even the vitality of the immune system gradually decreases. This phenomenon is called "immune aging". This is also the reason why the elderly have become the main targets of infection and death in Covid-19.

In the face of the out-of-control epidemic in COVID-19, USA, and the emergence of the second round of epidemic peak in Europe, vaccine research and development is in full swing in various countries, which is expected to be a life-saving straw to reverse the situation.

However, vaccines, a means of "actively mobilizing the human immune system to prevent real virus attacks", are usually far less effective in the elderly population-the immune response of the elderly to vaccines is often weaker. That is, the immune system of the elderly is more difficult to be mobilized by vaccines.

This means that vaccines may not protect those who need protection most.

So, how does the immune system age?

Our bodies are naturally resistant to most pathogens. Although the environment is full of pathogens, we still live well most of the time.

The human immune system is divided into innate immunity and acquired immunity. The former is universal immunity. When the body encounters foreign objects (such as skin and mucous membrane), innate immunity will respond quickly. However, although it responds quickly, its ability is limited and it is often broken. For example, when it meets Covid-19, it can’t hold on.

The latter is the acquired immunity of the body, that is, for some pathogens that have not been seen before, the body must first fight with it and learn from it before it can gain immunity to it. The power of acquired immunity is very powerful. As long as the body can withstand the attack of pathogens in "learning" and meet the same pathogens in the future, it will not be a problem at all. For example, infectious diseases such as smallpox and chickenpox, if you get it once, you will generally not get it again.

When the body is invaded by foreign pathogens, such as viruses, innate immunity and acquired immunity will cooperate to resist.

In the innate immune system, immune cells, such as phagocytes and natural killer cells, will recognize or even devour the virus first, and secrete a large number of cytokines to summon more immune cells with different functions to join the battle. Some of these cells, such as phagocytes and dendritic cells, will also transmit the antigens of these viruses (substances that can cause antibody production) to the subsequent T cells and B cells, which are representatives of acquired immune cells.

T-cells and B-cells (shown here as antibodies produced by B-cells) are representatives of immune cells, and they are named after mature parts. The former is mature in thymus (English) and the latter is mature in bone marrow (English). Both are star immune cells. | Figure worm creativity

These two kinds of cells can not only produce antibodies and cytokines to quickly destroy the virus, but also form specific memory cells, so that they can respond quickly after encountering the same virus again.

When the immune system destroys the virus, immune cells will gather locally in the body, forming redness, swelling and heat pain, which is what we usually call inflammation. Proinflammatory factors secreted during this period, such as interleukin -1 and tumor necrosis factor α, can promote the elimination of pathogenic microorganisms, but excessive inflammation may lead to cytokine storms and even life-threatening. Another kind of anti-inflammatory factor, such as interleukin -10, can prevent excessive inflammation and maintain the balance of the body environment.

These factors together constitute our immunity.

And what will happen to our immune function as we get older? What is the impact on vaccine development?

Compared with young people, the immune aging of the elderly is mainly manifested in two aspects:

The initial number of T cells and B cells decreased. Vaccine mainly stimulates B cells to produce antibodies. Only when there are a large number of B cells with high diversity of receptors in the body, the greater the probability of recognizing antigens, and the targeted (directional) antibodies and memory B cells can be formed. -The decrease of B cells will undoubtedly weaken this effect.

Chronic low-grade inflammation is easy to occur after vaccination. The aging and necrotic cells in the elderly can not be removed in time, which will stimulate the immune system continuously, causing immune cells (such as macrophages) to continuously secrete pro-inflammatory cytokines, and the immune response cannot be terminated. The consequence is that the immune system can’t respond the next time the pathogenic microorganism attacks the human body, that is, immune dysfunction.

These lead to different effects of vaccines in the elderly and young people.

Vaccine research and development under "immune aging";

A special vaccine or an auxiliary drug to reverse aging?

For Covid-19, there are about 50 kinds of vaccines being tested in the world, but scientists are still not sure whether the vaccines are equally effective for the elderly.

One of the vaccines "mRNA-1273" being developed by Moderna, a biological company located in Cambridge, Massachusetts, USA, produced antibody levels similar to those of younger subjects in 40 subjects over the age of 56.

However, Pfizer and BioNTech, pharmaceutical companies located in Mainz, Germany, found in the first phase of the experiment that the antibody level induced by the vaccine "BNT162b2" was only half that of young people. It is certain that the antibody level produced by the elderly after vaccination is higher than that caused by the virus infection of their peers, but this is still not enough to explain whether the antibody induced by "BNT162b2" is enough to protect the elderly from the real virus attack.

Most of the vaccines being developed have elderly subjects, but more than half of the 18 latest candidate vaccines have no elderly subjects in clinical trials, which greatly increases the potential risks of vaccines to the elderly.

Some vaccines are being developed, which may have hidden dangers for the elderly. | Figure worm creativity

Facing the phenomenon of immune aging of the elderly, scientists are also actively looking for strategies.

Mainly includes the following two aspects:

(1) The first is how to enhance the immune response of the elderly induced by vaccines.

According to the experience in the research and development of influenza vaccine, the elderly are usually treated by increasing immune stimulating components (such as adjuvants) or increasing the dose of virus antigen to achieve the expected antibody level.

Other scientists have turned to developing drugs to enhance the immune system function of the elderly, that is, supplementing drugs at the same time of vaccination. This way aims to promote the rejuvenation of the immune system of the elderly, even reverse immune aging, and can also resist the virus more effectively when it is infected.

In the above two schemes, the research on reversing age, especially immune aging, has made some progress. In the past 20 years, scientists have found some key small molecular targets. One kind of anti-aging drugs acts on the protein molecule mTOR in the cell growth regulation pathway. Experiments show that inhibiting the expression of mTOR can prolong the life of Drosophila and even mice.

Joan Mannick, one of the founders of resTORbio, a biotechnology company in Boston, Massachusetts, USA, said that "mTOR participates in many biological regulation mechanisms, especially the process of human aging and organ dysfunction".

During his work at Novartis Institute in Cambridge, Massachusetts, Mannick published a study on mTOR protein in 2018, trying to answer the question "Can reducing the content of mTOR protein in the elderly improve the immune system function of the elderly?". 264 participants in the study received low-dose mTOR inhibitor or placebo respectively, and after six weeks, the infection rate of influenza virus and the effect of influenza vaccine were followed up. It was found that the number of people suffering from influenza in the elderly who received mTOR inhibitors decreased significantly, and the immune response caused by influenza vaccine was stronger.

Another study shows that mTOR inhibitor RTB101 can enhance the immune response of the elderly after coronavirus infection, and the elderly who receive mTOR inhibitor have lower coronavirus load and recover faster. At present, resTORbio is testing the preventive or therapeutic effect of RTB101 on Covid-19 infection in 550 elderly people over 65 years old in nursing homes.

In addition, at least four research teams are studying the therapeutic effect of rapamycin, another more mature mTOR inhibitor, on the elderly over 60 years old infected with COVID-19.

In addition, metformin, a drug for the treatment of type 2 diabetes, also inhibits the activity of mTOR protein. Clinical data from China and the United States show that diabetic or obese patients who take metformin have less symptoms of Covid-19 infection and lower mortality.

Carolyn Bramante, a researcher at the University of Minnesota in the United States, pointed out that people with diabetes and obesity show immune deficiency very similar to that of the elderly. At present, Bramante and his colleagues are conducting a study involving 1,500 people to explore whether taking metformin can prevent Covid-19’s infection or alleviate its symptoms. Although the mechanism is not clear, decades of clinical data show that metformin has high safety, can be used in children and even pregnant women, and the cost is very low, which are the advantages of metformin.

(2) The second key is how to avoid causing or how to terminate chronic inflammatory reaction.

Studies have found that losmapimod, an anti-inflammatory drug used to treat muscular dystrophy, can inhibit chronic inflammatory response and improve the body’s response when viruses or bacteria invade. A biological company in Cambridge, Massachusetts, USA recruited 400 volunteers to verify the therapeutic effect of losmapimod on patients with COVID-19. The drug may be able to treat symptoms such as respiratory failure after Covid-19 infection, thus saving patients’ lives.

Many scientists say that it is more important to develop drugs to enhance the immune function of the elderly than to develop COVID-19 vaccine for the elderly, and the latter is more universal, which can improve the protection effect of influenza vaccine, COVID-19 vaccine and even other vaccines in the future. A deep understanding of immune aging and its regulation mechanism and the development of related drugs will also have far-reaching implications for the treatment of other diseases such as diabetes and cancer.

In short, although there are always difficulties in vaccine development, known or unknown, scientists have been working hard and believe that methods will always be found.

(Editor Gao Peiwen)

Original information:

Cassandra Willyard, Nature vol 586, 15.10.2020

Reference information:

1. Anderson E. J.et al., N. Engl. J. Med., 2020

2. Walsh E. E. etal., Preprint at medRxiv https://doi.org/10.1101/2020.08.17.20176651 (2020)

3. Helfand B. K. I. et al., JAMA Intern. Med., 2020

4. Mannick J. B. et al., Sci. Transl. Med., 2020

5. Luo P. et al., Am. J. Trop. Med. Hyg., 2020

6. Bramante, C. et al., Preprint at medRxiv https://doi.org/10.1101/2020.06.19.20135095(2020)

7. Vukmanovic-Stejic M. et al., J. Allergy Clin. Immunol., 2018

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Original title: "Immune aging that cannot be underestimated: old age may lead to ineffective vaccines"

Read the original text

On November 27, 2009, Cai Jian [2009] No.853

　　

Shanghai, Jiangsu, Zhejiang, Anhui, Fujian, Jiangxi, Hubei, Hunan, Guangdong, Guangxi, Hainan, Chongqing, Sichuan, Guizhou, Yunnan, Tibet, Heilongjiang, Jilin, Inner Mongolia, Liaoning Province (autonomous regions and municipalities directly under the Central Government) Finance Department (bureau), Grain Bureau, China Grain Reserve Management Corporation, COFCO Group Co., Ltd., China Hualiang Logistics Group Company,

　　In order to give full play to the role of market mechanism, stabilize the domestic corn market price, and protect the interests of grain farmers, with the approval of the State Council, after the newly-produced corn in Northeast China (including Heilongjiang, Jilin, Liaoning and Inner Mongolia, the same below) was listed in 2009, the central government gave a one-time fixed-fee subsidy to the southern feed-consuming provinces that purchased the newly-produced corn in Northeast China and transported it to the local area. In order to do a good job in subsidy management, we hereby print and distribute the Measures for Financial Management of Subsidies for New Corn Production in Northeast China in 2009 to you, please implement them carefully.

　　Attachment: Financial Management Measures for Subsidies of New Corn Production in Northeast China in 2009 by Southern Feed Consumption Provinces

　

　　Cc: General Office of the State Council, Shanghai, Jiangsu, Zhejiang, Anhui, Fujian, Jiangxi, Hubei, Hunan, Guangdong, Guangxi, Hainan, Chongqing, Sichuan, Guizhou, Yunnan, Tibet, Heilongjiang, Jilin, Inner Mongolia, Liaoning (autonomous regions and municipalities directly under the Central Government) People’s Government, Development and Reform Commission, Agricultural Development Bank branches, and the Ministry of Finance in Beijing, Shanghai and Inner Mongolia.

　　

Attachment:

Southern feed consumption provinces purchase new corn produced in Northeast China in 2009.

Measures for the financial management of expense subsidies

　　

　　In order to give full play to the role of market mechanism, stabilize the domestic corn market price, and protect the interests of grain farmers, with the approval of the State Council, after the newly-produced corn in Northeast China (including Heilongjiang, Jilin, Liaoning and Inner Mongolia, the same below) was listed in 2009, the central government gave a one-time fixed-fee subsidy to the southern feed-consuming provinces that purchased the newly-produced corn in Northeast China and transported it to the local area. To this end, these measures are formulated.

　　I. Scope of subsidies

　　(1) The southern feed consumption provinces include 16 provinces (autonomous regions and municipalities) such as Shanghai, Jiangsu, Zhejiang, Anhui, Fujian, Jiangxi, Hubei, Hunan, Guangdong, Guangxi, Hainan, Chongqing, Sichuan, Guizhou, Yunnan and Tibet.

　　(II) Under the leadership of the provincial people’s government, the local grain reserve companies and corn feed processing enterprises in the above-mentioned provinces are entrusted by the provincial grain administrative department and the financial department to purchase the newly-produced corn in China in 2009 in Northeast China under the principle of voluntary and independent declaration and at their own risk, and each province (autonomous region, city) entrusts 1-2 enterprises with the qualification of grain operation, and then uniformly transports them back to the local area and applies for subsidies. The list of specific enterprises should be announced to the public in a timely manner.

　　(III) The corn purchased by the grain enterprises directly under the central government (including the enterprise headquarters) in the above-mentioned provinces in the northeast and transported back to the above-mentioned provinces, as well as the corn purchased by the central reserve enterprises in the above-mentioned provinces from the northeast and used for reserve rotation, enjoy the same subsidy policy. The specific enterprise list shall be examined and determined by the enterprise headquarters, and the enterprise headquarters shall uniformly organize and apply for subsidies.

　　(four) the relevant provinces and enterprises directly under the central government shall report to the Ministry of Finance, the State Grain Bureau and other relevant departments for the record after selecting and determining the specific enterprise list; The State Grain Bureau shall make a summary and make it public in time. Once the list of enterprises is published, it will not be adjusted.

　　Second, the subsidy conditions and standards

　　(five) enterprises included in the scope of subsidies shall meet the following conditions when applying for subsidies:

　　1 enterprises entrusted by the provincial administrative department of food jointly with the financial department shall have the qualification of food business and the entrustment documents jointly issued by the local provincial food and financial departments. Grain enterprises and reserve enterprises directly under the central government need to be audited and confirmed by the enterprise headquarters.

　　2. The price purchased by enterprises from farmers in Northeast China shall not be lower than 0.76 yuan/kg in Inner Mongolia and Liaoning, 0.75 yuan/kg in Jilin and 0.74 yuan/kg in Heilongjiang (third class in the national standard, the same below). When purchasing third-class corn higher or lower than the national standard, the purchase price can be raised or lowered by 0.02 yuan/kg for each grade raised or lowered according to the national standard.

　　3. The purchased corn must be the newly produced corn in China in 2009.

　　4. The procurement period for enjoying the expense subsidy is from December 1, 2009 to April 30, 2010.

　　5. The purchased corn must be delivered to this province (autonomous regions and municipalities) before June 30, 2010.

　　6 enterprises applying for subsidies must be consistent with the goods receiving unit of the transport certificate.

　　7. The total amount of corn purchased by the central reserve enterprises applying for subsidies shall not exceed the reasonable annual rotation plan for the local subsidy period issued by the relevant state departments and China National Grain Storage Corporation.

　　(VI) The corn actually purchased by the enterprise according to the above provisions and transported back to the province (autonomous regions and municipalities) shall be subsidized by the central government at a one-time fixed cost of 0.035 yuan per catty according to the number of corn converted into standard products (moisture ≤14% and impurities ≤1%). The subsidized corn is sold by the enterprise itself and is responsible for its own profits and losses.

　　(seven) enterprises included in the scope of subsidies, one of the following acts, once found, cancel all financial subsidies of the enterprise, and through social media and other public notification:

　　1 enterprises will not yet arrived in the province (autonomous regions and municipalities) to apply for subsidies for corn.

　　2. The enterprise will apply for subsidies for the corn purchased within the non-subsidized procurement period or the corn newly produced in Northeast China in 2009.

　　3. The enterprise fails to submit the monthly statistical report of purchase, sale and storage to the local administrative department of grain according to the provisions of the statistical system, and the grain and oil processing enterprise fails to submit the statistical report of grain and oil processing industry according to the provisions, and refuses to report false statistical data.

　　4 other acts of obtaining state subsidies through fraud.

　　(eight) according to the monitoring results of the relevant state departments, when the price of corn directly purchased from farmers in Northeast China rose to an average of 0.8 yuan/kg (third-class national standard), the central government stopped subsidizing it.

　　Third, the starting and ending period of subsidy policy

　　(9) The subsidized corn shall be purchased in Northeast China from December 1, 2009 to April 30, 2010 and delivered to the provinces (autonomous regions and municipalities) where the grain purchasing enterprises are located before June 30, 2010.

　　(10) The procurement time shall be based on the time when the procurement contract is signed.

　　(eleven) the arrival deadline refers to the time of transportation to the province where the grain purchasing enterprise is located. According to the date indicated on the legal transportation documents, it is determined according to the following principles:

　　1. Direct inter-provincial railway transportation shall be based on the date when the goods arrive at the platform;

　　2. The combined transport of hot metal and public water shall be based on the date of arrival at the loading dock;

　　3. Direct road transportation shall be based on the date when the goods arrive at the destination.

　　Iv. application for subsidy funds

　　(12) Time of application. Enterprises enjoying this subsidy need to submit an application before July 15, 2010, and local procurement enterprises shall submit the subsidy application and valid vouchers to the provincial grain administrative department according to the above-mentioned prescribed time limit; Enterprises affiliated to the central government shall submit subsidy applications and valid vouchers to the enterprise headquarters. The subsidy application includes all materials for corn procurement and transportation, as well as the sales and inventory of corn transported back to the province (autonomous regions and municipalities).

　　(thirteen) the subsidy application materials include:

　　1. Voucher of purchasing link: For direct purchase from farmers in Northeast China, there should be a unified invoice (copy) for grain and oil purchase uniformly printed by the local tax department, and this invoice should have an audit stamp stamped by the tax department. Unified procurement from grain enterprises in Northeast China should have a legal procurement contract and a special invoice for local tax value-added tax (copy). A new grain certificate issued by the county-level grain administrative department or quality inspection unit where the purchase is located. At the same time, the purchaser of the small ticket or the buyer of the purchase contract must be the subsidy application enterprise announced by the State Grain Bureau to the public.

　　2. Vouchers for transport links: waybills and delivery vouchers uniformly printed by railway, transportation and shipping departments. Among them, the place of dispatch is Northeast China, the place of arrival is the subsidized province stipulated in these Measures, and the consignee is a subsidy application enterprise made public by the State Grain Bureau.

　　3. Payment voucher: the grain purchase voucher or bank remittance voucher printed by the tax department. Among them: the payer and the payee of the payment voucher must correspond to the buyer and the seller of the purchase contract; At the same time, the payment before June 30, 2010 must exceed 80% of the contract amount.

　　4. Sales inventory certificate: sales contract and special VAT invoice (copy), inventory statistics.

　　5 central reserve corn storage enterprises, but also need to provide the relevant state departments and China Grain Storage Corporation issued the annual rotation plan documents.

　　When applying for subsidies, all vouchers are provided with photocopies (which must be stamped with the official seal of the unit), but the applicant enterprise must keep the vouchers for verification. The application materials provided by the enterprise shall be registered and tabulated, and shall be responsible for the authenticity of all materials. At the same time, the enterprise shall keep all the original documents by itself, and the relevant departments shall conduct random inspection when auditing and checking.

　　V. Audit of subsidy funds

　　(fourteen) the audit of the application materials of local procurement enterprises. The provincial food department shall timely summarize, sort out and preliminarily examine the application materials for enterprise subsidies, and report them to the provincial finance department for review within 15 working days. The provincial finance department shall complete the review within 15 working days, and submit an application report for pre-allocation of subsidy funds to the central finance, and send a copy of the application report to the local financial Ombudsman office of the Ministry of Finance for examination and confirmation. The provincial food department and the financial department shall be responsible for the authenticity and completeness of the application materials of enterprises (after the preliminary examination by the provincial food administrative department in Tibet, the provincial financial department shall review and report on its own).

　　(fifteen) the audit of the application materials of enterprises directly under the central government. Enterprise headquarters shall, after timely summarizing, sorting out and preliminary examining the application materials for enterprise subsidies, submit an application report for pre-allocation of subsidy funds to the Ministry of Finance before the end of July 2010, and send a copy of the application report to the Office of the Financial Ombudsman of the Ministry of Finance in Beijing for examination and confirmation. The enterprise headquarters shall be responsible for the authenticity and completeness of the application materials of the directly affiliated enterprises.

　　(sixteen) the Office of the Financial Ombudsman shall, on the basis of the audit of the relevant departments at the provincial level and the headquarters of the enterprise, review the application materials, and at least select 1~2 enterprises for on-the-spot verification. The Office of the Commissioner shall submit the examination results to the Ministry of Finance within 30 working days after accepting the application report.

　　Six, the allocation of subsidy funds

　　(seventeen) the Ministry of Finance shall, according to the application report of subsidy funds submitted by the provincial financial department and the enterprise headquarters, allocate the amount of corn subsidies determined by the Office of the Financial Ombudsman and the subsidy standards. Subsidies from local enterprises are allocated by the central government to provincial financial departments; Subsidies from enterprises directly under the central government shall be allocated by the central finance to the enterprise headquarters.

　　(eighteen) after receiving the central financial allocation, the provincial financial department shall directly allocate it to the subsidy application enterprise within 10 working days.

　　VII. Supplementary Provisions

　　(nineteen) the subsidy funds allocated by the central government, as subsidy income, shall be managed and used by enterprises according to the current accounting requirements.

　　(twenty) business disputes, accidents, etc., which occurred during the subsidy period, shall be settled by the enterprise according to the relevant laws and regulations.

　　(twenty-one) enterprises included in the scope of subsidies must conscientiously implement national policies, accurately and timely fill in relevant statistical statements, and truthfully submit subsidy application materials according to regulations. Relevant regions and departments should earnestly perform their duties of supervision and inspection, and it is strictly forbidden to resort to deceit or falsely report the subsidy funds.

　　(twenty-two) the Ministry of Finance shall be responsible for the interpretation of these Measures.

CCTV News:In Wonsan, the eastern city of North Korea, there is a famous factory that produces leather shoes. The "Yingfengshan" brand leather shoes produced here have excellent workmanship and fashionable styles, which are well received by the Korean people. This factory is Yuanshan Leather Shoes Factory.

At the North Korean National Footwear Exhibition in 2018 and 2019, a leather shoes brand named "Yingfengshan" made a big splash for two consecutive years and won the first prize and the special prize respectively. This brand came from Yuanshan Leather Shoes Factory.

Yuanshan Leather Shoes Factory was founded in 1959 and has a history of 60 years. Kim Jong-un, the current top leader of North Korea, came to Yuanshan Leather Shoes Factory five times since 2014, and it was from 2014 that the development of Yuanshan Leather Shoes Factory entered the fast lane.

CCTV reporter Dong Haitao:This pair of shoes on the exhibition platform was produced in 2007, while this pair of shoes on this side was produced in 2017. It can be seen that there are great differences in texture, design and workmanship between them in the past ten years.

Independent research and development, independent manufacturing and self-reliance

According to the factory commentator, the entire production system of the factory is independently developed by North Korea, and the raw materials for shoemaking are also independently produced by North Korea, while the electricity is provided by national power stations such as Yuanshan Military and Civilian Power Station. They are at the forefront of North Korea’s footwear industry in implementing national policies and realizing self-reliant production, and factory employees are particularly proud.

Zhao Mingshi, head of technical department of Yuanshan Leather Shoes Factory:We received many favorable comments and won the special prize at this spring national footwear exhibition in North Korea.

Cui Hua, a female worker in Yuanshan Leather Shoes Factory:I am a shoe-maker, and I like the ladies’ sandals produced by our factory best. Sandals are women’s favorite footwear products in summer, and we have successfully controlled the weight of women’s sandals within 250 grams.

Nowadays, the vast majority of shoemaking employees in the factory have more than 5 years of shoemaking experience, and the factory will arrange different kinds of leather shoes production plans according to the season, personnel arrangement and product demand.

CCTV reporter Dong Haitao:I’m at the end of the production line of Yuanshan Leather Shoes Factory, where all kinds of leather shoes are displayed. I’m going to have a try now. Let’s try on this pair of pointed leather shoes first. They look very fashionable. The sole is solid and powerful, and it walks steadily. It is a good pair of shoes.

Leather shoes factory is looking forward to expanding production.

Since 2014, the quality of "Yingfengshan" brand leather shoes has been continuously improved, but the price is very close to the people. Take the pair of leather shoes that I just tried on as an example. The ex-factory price is only 25,000 yuan, which is equivalent to about 20 yuan, which is quite good and cheap. The factory commentator told me that the supply of factory products to the Korean people is already in short supply, and they hope to expand production in the future and strive to make "Yingfengshan" brand leather shoes go global.

Albinism is a kind of hereditary leukoplakia caused by melanin deficiency or synthesis disorder of skin and accessory organs due to tyrosinase deficiency or functional decline.

According to clinical manifestations, albinism can be divided into three categories: ocular albinism (OA), ocular skin albinism (OCA) and albinism-related syndrome, among which ocular skin albinism (OCA) is the most common and albinism-related syndrome is the rarest.

This paper mainly expounds the clinical manifestations, genetic causes and genetic counseling of OA and OCA.

Clinical manifestations of OA and OCA

Only the eye pigment in OA patients is reduced or lacking, while the eye, skin and hair in OCA patients are obviously reduced or lacking.

1, eye performance

① Iris transillumination defect (TID)-91% ~ 100% albino patients have TID.

② nystagmus

③ Fundus hypopigmentation —— It is caused by the decrease of retinal pigment epithelium and/or choroidal pigmentation, which often leads to obvious choroidal vessels in the posterior pole. It is reported that more than 94% patients with albinism have fundus hypopigmentation.

④ hypoplasia of fovea-characterized by the continuation of the inner layer of retina behind fovea and the decrease of cone photoreceptor specialization.

⑤ optic nerve abnormality

⑥ ametropia

2. Skin manifestations

The skin and hair color of albino patients may change with age.

① Skin and hair pigmentation score

Skin and hair pigmentation scores help to objectively determine the influence of hypopigmentation.

② Skin diseases

Including all albinos, regardless of skin color, the risk of ultraviolet (UV) light-related skin diseases will increase. The most important of these is skin cancer, which includes squamous cell carcinoma, basal cell carcinoma, melanoma and less common Merkel cell carcinoma.

Genetic causes of OA and OCA

The following table summarizes the genes known to be related to nonsyndromic OCA and OA. All nonsyndromic OCA are inherited by autosomal recessive mode. OA (always non-syndrome) is inherited in an x-linked manner.

The following table summarizes the genes known to be related to OCA syndrome:

Genetic counseling

1. Inheritance mode

Nonsyndromic ocular skin albinism (OCA) caused by pathogenic variation in TYR, OCA2, SLC45A2, SLC24A5, LRMDA (C10orf11) or DCT (TYRP1) is inherited in autosomal recessive way.

Ocular albinism (OA) caused by pathogenic variation in GPR143(OA1) is inherited by X linkage.

If an individual suffers from a specific syndrome related to OCA (such as Hermansky-Pudlak syndrome or Chediak-Higashi syndrome), genetic counseling is needed for this disease.

2. Autosomal recessive inheritance-risk to family members

Parents of the proband:

The parents of the affected children are presumed to be heterozygotes causing the pathogenic variation of OCA.

If molecular diagnosis has been established in the proband, it is suggested that the parents of the proband should be tested for molecular genes to confirm that both parents are heterozygotes causing the pathogenic variation of OCA and allow reliable recurrence risk assessment.

If the pathogenic variation is detected only in one parent, and the parental identity test has confirmed biological motherhood and parent-child relationship, one of the pathogenic variations identified in the proband may occur as a newborn event in the proband or as a zygote in the mosaic parent. If the proband seems to have homozygous pathogenic variation (that is, the same two pathogenic variations), other possibilities to be considered include:

The deletion of single exon or multiple exons in the proband was not detected by sequence analysis, which led to artificial homozygosity;

Parental chromosomes and single parent homomorphism of pathogenic variation lead to homozygosity of pathogenic variation among proband.

Heterozygotes (carriers) are asymptomatic and have no risk of developing the disease.

Siblings of the proband:

If it is known that both parents are heterozygotes of pathogenic variants that cause OCA, each sibling of the affected individual has a 25% chance of being affected at conception, a 50% chance of becoming asymptomatic carriers, and a 25% chance of inheriting any familial pathogenic variants.

Heterozygotes (carriers) are asymptomatic and have no risk of developing the disease.

Descendants of the proband:

The offspring of autosomal recessive OCA individuals are obligate heterozygotes (carriers) that cause the pathogenic variation of OCA.

Other family members:

Every brother and sister of the proband’s parents has a 50% risk of becoming the carrier of OCA’s pathogenic variation.

Carrier detection:

It is necessary to identify the pathogenic variation that causes OCA in the family in advance for carrier detection of at-risk relatives.

3. X-linked inheritance-risk to family members

Parents of male proband:

The father of the affected man will not suffer from this disease, nor will he be a hemizygote of the pathogenic variant GPR143; Therefore, he does not need further evaluation/testing.

In a family with more than one affected individual, the mother of the affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives, and if family pathogenic variation cannot be detected in her white blood cell DNA, she is likely to have germline chimera.

If the male is the only affected family member (i.e., a simple case), the mother may be heterozygote, the affected male may have new pathogenic variation (in this case, the mother is not heterozygote), or the mother may have somatic/germline chimera.

It is suggested that the mother should be tested for molecular genes to confirm her genetic status and make a reliable recurrence risk assessment.

Brothers and sisters of male proband:

The risk of siblings depends on the mother’s genetic status:

If the proband’s mother has the pathogenic variation of GPR143, the chance of transmission in each pregnancy is 50%.

Men with genetic disease variation will be affected;

The female with genetic pathogenic variation will be heterozygote (i.e. carrier). Heterozygotes are usually unaffected, although they can show iris penetration defects, "mud splash" fundus appearance and fovea hypoplasia.

If the proband represents a simplex case and the pathogenic variation cannot be detected in the mother’s leukocyte DNA, it is assumed that the risk of sibs is low, but the risk is higher than that of the general population because of the possibility of maternal lineage mosaic.

Descendants of male proband:

The affected men spread the disease-causing mutation of GPR143 to all their daughters, but not to their sons.

Other family members:

Menstruation and maternal cousins of the male proband may be at risk of GPR143.

Note: Molecular genetic testing may be able to identify family members with new pathogenic mutations, and this information can help determine the genetic risk status of large families.

Heterozygote detection:

To identify female heterozygotes, it is necessary to identify the pathogenic variation of GPR143 in the family in advance.

Note: As carriers of this X-linked disease, women are heterozygotes, which are usually not affected, but they may show iris penetration defects, "mud splash" fundus appearance and fovea hypoplasia.

Source | Metz Medical official website

Write | ｜Anna.An

Original title: Inheritance and Manifestation of Albinism

Read the original text

Lord Yue Zun has taken on a new job.

Recently, a new drama in Dylan was launched. This drama is the costume drama "Floating Figure" starring him and Yukee Chen’.

Because of the popularity of Dylan, I heard that the number of reservations for this drama exceeded one million before it started.

To say how hot Dylan is, since the launch of "Freesia Tactics" a while ago, Yue Zun’s adult has been out of the circle almost every day, and 800 hot searches directly build a nest and settle down on the hot search every day.

In addition, these two days, the new drama began to broadcast, and the hot topics were one after another. There was a kind of entertainment that seemed to have no one but him.

01 New Drama Controversy

Speaking of the new drama "Floating Picture", this is his first work since the popularity of "Freesia", so it has attracted everyone’s attention.

However, after the play was broadcast, the comments were polarized. Some netizens think that the plot of this drama is novel and it is a cool drama without delay. However, some viewers think that Dylan’s makeup and hair styling is still ugly, and her acting skills are a little off-line. The acting skills of the hostess are even more complicated, and the audience’s comments are mixed.

Some people have given the play a five-star praise, and feel that the setting is novel and has a sense of humor, which will give people the desire to watch it.

In view of the appearance of the male host and the acting skills of the female host, many people directly made a one-star bad review, and their words were sharp.

Judging from the broadcast episodes, the hostess is clever, happy and cute, but the netizens’ comments on Yukee Chen”s acting skills are almost meaningless. A pair of beautiful and moving eyes are not the case when put into the performance. Because of the eye play, Yukee Chen’ was also crowned as "Wood Beauty" before.

Just look at this photo, please analyze the psychological activities of the characters.

Option 1: A group performance in front of the hostess made an incredible and amazing move.

Option 2: When the hostess went out, she suddenly remembered that she had locked her key at home.

Option 3: The hostess is about to be locked up in the tower, and she will take a last look at the world with the attitude of death.

The correct answer is the last one.

But the first two options seem to be more in line with Yukee Chen”s eyes at this time.

Therefore, many netizens complained that Yukee Chen’ Yan value, the heroine, was online, but her acting skills were dull and she stared like two bells, which made people very dramatic.

The netizen said that he thought that the hostess’s hip-pulling performance could be made up by Dylan, but he never imagined that he also overturned the car.

It may be that his role in "Freesia" is so amazing that Xiao Duo’s role is eclipsed.

Everyone knows that Dylan’s face is the most attractive thing. I don’t know whether it’s a stylist’s standard or a character setting. The hat Dylan wears on his head makes him look a little strange.

Coupled with a purple costume and a makeup that doesn’t match, I have to say that this makeup was shot at some death angles, which greatly reduced the handsome degree of Yue Zun’s adult.

In terms of acting skills, netizens commented that Dylan was too dull. In many plots, he prefers to talk with his neck stuck. Moreover, only the male and female actors are dubbing in the whole play.

02 Lucky Resource Coffee?

In others’ eyes, Dylan seems to be a very lucky existence in the entertainment circle, and some even call him Resource Cafe. But looking back on Dylan’s career, he has actually been working hard. After all, it’s so hot now. If we only rely on luck, Dylan probably won’t be where he is today.

Dylan once participated in the reality show variety Superdimensional Idol and starred in the mainland versions of Meteor Garden and Night Two, but none of them aroused much splash.

Until then, I took the play yu long. The heat was there at that time, but it was a uniform stigma.

Dylan has become synonymous with the ugly man in ancient costume and acting skills, and the tucao video at a certain station has reached millions of broadcasts.

Even so, he took the characters seriously. During the broadcast of yu long, Dylan printed his book list on Weibo. It seems that I have thought a little bit about the plot. At the same time, this has also been questioned by netizens: Who knows if this is "pretending"?

There are also actresses who play against him, saying that he will recite the other party’s words in order to be more smooth and substitute.

There is no idol burden to participate in the variety show, and it also presents the scene of watermelon head’s fame.

Later, with the drama "Freesia Tactics", Dylan’s popularity increased, and the director also stood up and praised him.

After the fire, Dylan was as busy as a bee.

Take on a new play as the leading actor.

All kinds of attendance activities, invited to participate in the GQ ceremony of the red carpet shine.

Even the big show of luxury brand LV invited Dylan to be present.

But even so, he has no airs, and he still tries to seize the opportunity to advertise himself, asking the producers and directors to find their own films. This kind of Dylan can be regarded as a down-to-earth and real person.

In addition to acting in a down-to-earth manner and working hard, he is also a rare real person in private.

Dylan’s family is average, and his father sells fried skewers. Before that, he often went home to help his family sell fried skewers.

Even Eric Wang, who has always been serious, praised him on the show: "He is essentially a rare person in this era, and he goes straight to that kind …".

You have to speak with acting skills and works.

Looking back at the stars of entertainment flow, YiBo, Dylan, Leo, Zhao Lusi … Nowadays, one after another, the flow is rising, dividing up the cake of entertainment circle. When someone comes in, someone will eat less or go out. In fact, they are not disturbing the water in the pool, but to increase the vitality of the water in the pool, but the increase of one person’s flow will inevitably affect another person’s exit.

In addition, some netizens spit out that the status quo of entertainment artists is that they pull their legs on the stage, dance and paddle, get together and act, and they are not good at acting, doing things that they were not good at, and they can’t figure out their position. Therefore, the current traffic stars are still full of various controversies.

Chen Daoming, a veteran actor, once said at a symposium: The so-called stars are not from the literary and art circles, but from the traffic circle. They are plastic actors hyped by packaging. Although it is also active in this industry, it has affected the reputation and reputation of many excellent creators.

Indeed, it seems that the acting level and personal problems of the entertainment personnel still need to be improved. After all, the artists in the entertainment circle have subverted the public’s cognition again and again, so that we can’t see the bottom line of entertainment.

Nowadays, Dylan’s new drama "Floating Edge Map" has been launched, although the controversy continues, but the popularity has not diminished. There is also a modern drama "Taking Love as a Camp" to be broadcast. I don’t know what comments these follow-up netizens will give, but what is certain is that his challenge is still not small.

Dylan’s hope of becoming popular will not be just a flash in the pan, but how far he can go still depends on whether he can keep up with the works and enthusiasm in the future, and how he can keep it. Besides, there are still many voices questioning Dylan. If you want to prove your strength, you will ultimately depend on the quality of your works.

And his explosion has brought a lot of pressure to other artists. I hope everyone will not relax their vigilance, or they will work harder.

In a word, having the chassis depends on how Dylan will go in the future.

On the evening of March 19th, the 2023 performance report was disclosed.

In 2023, the operating income reached 372.6 billion yuan, up 5.0% year-on-year, and the net profit returned to the mother reached 8.2 billion yuan, up 12% year-on-year, achieving double-digit increase for seven consecutive years; The return on net assets reached 5.1%, achieving a good level in recent years; The capital expenditure is 73.9 billion yuan, and the network investment shows an inflection point.

Over the past year, we have focused on the coordinated development of the two main businesses, successfully achieved effective improvement in quality and reasonable growth in quantity, and laid a solid foundation for long-term development. Behind this is always solidly promoting the deepening of the strategic system, focusing on both scale growth and value enhancement.

Responsible for the main business, fruitful business performance has reached a new high.　　

In recent years, with the promotion of national policies,Data application promotion, etc., the number of Internet users continues to expand.,It has promoted emerging forms such as artificial intelligence and big data to continuously empower the development of traditional industries.,The continuous emergence of industrial digital integration application results has promoted the continuous release of data traffic market demand. As a leading enterprise in the field of communication, it has ushered in broad development opportunities.

Under the wave of digital economy development,Actively embrace the strategic opportunities brought by the same frequency resonance between Chinese modernization and the new generation of digital revolution.In 2023, innovation and transformation will continue to deepen. The business of computing network and intelligence realized a revenue of 75.2 billion yuan, which brought more than half of the new income to the company.

Among them, "Unicom Cloud" business continued to grow steadily, achieving a revenue of 51 billion yuan, a year-on-year increase of 41.6%. The sales of cloud resources exceeded one million cores, a year-on-year increase of 186%, and the coverage of cloud resources has exceeded 230 cities. In 2023, innovations were made in technological innovation and ecological co-construction, the level of independent research and development was further improved, and the dual-engine bases of "virtualization" and "cloud native" were continuously optimized. More than 3,300 sets of self-developed operating system CULinux2.2 were deployed.

With the empowerment of 5G technology, the large-scale development of digital intelligence applications has also achieved remarkable results. There are 30,000 application projects in the 5G industry, covering 71 categories of the national economy, serving over 8,500 customers of 5G private networks, and forming a leading edge in key industries such as industrial Internet, digital government and car networking.

In the 2024 work conference, it was pointed out that it is necessary to solidly promote high-level security. In the past year, we focused on key directions such as network security, data security and information security, and strengthened the strategic business layout of big security. Not only did it build the first digital security operation center for super-large cities in China for customers, but it also landed more than 50 benchmark projects, and actively promoted open cooperation in security ecology, supporting the growth of network security income by 120% year-on-year.

Today, the industry share of data services has exceeded 50% for five consecutive years, leading the industry. With the rapid development of the network intelligence service, the network communication service has also made steady progress.

In 2023, the revenue of networked communication business was 244.6 billion yuan, and the scale of connection was further expanded, with more than 1 billion networked communication users, an increase of about 140 million compared with the end of 2022. Among them, the number of mobile users reached 333 million. In 2023, the net increase of users increased by 90% year-on-year, and the penetration rate of 5G package users also increased by 12 percentage points to 78% compared with last year. The "basic disk" was further consolidated.

Scientific and technological innovation speeds up and the dividend level reaches a record high.

This year’s government work report not only clearly puts forward "vigorously developing the digital economy", but also puts forward clear requirements for "accelerating the development of new quality productive forces" and "promoting industrial innovation with scientific and technological innovation". As one of the three major operators, it is timely and timely to develop new quality productivity.

It is said that the field of artificial intelligence has become an important strategic direction. The company is accelerating the layout of emerging industries of artificial intelligence, combining its advantages in computing network infrastructure, rich business scenarios and extensive customer contacts, and making efforts to create a large model development and application paradigm with Unicom characteristics. At the Mobile World Congress, the "Yuanjing" large model system was launched, and multi-parameter versions were arranged according to different functional requirements to promote the large model to better empower the real economy application scenarios. Relevant achievements were selected as "Wu Wenjun Artificial Intelligence Science and Technology Award", and the innovation ability was further enhanced.

At the same time, it is emphasized that the overall layout of satellite communication will be further accelerated in the later period, and the industrialization and systematic development of integrated communication between heaven and earth will be actively promoted.

In 2023, we will actively promote key core technology research, focus on promoting industrial innovation with scientific and technological innovation, and continuously enhance core competitiveness. During the year, 2,287 patents were granted, up 37% year-on-year, and attention was paid to the construction of scientific and technological innovation talents, whose proportion reached 40%. Standing at a new starting point, scientific and technological innovation has been further intensified, and it has actively become a national strategic scientific and technological force and a "vanguard" for developing new quality productive forces.

With the arrival of the computing power era, the long-term prospects of the company are further optimistic by investors. It also actively gives back to the trust and support of investors. The annual report shows that in 2023, the final dividend per share will be 0.0524 yuan (including tax), together with the already distributed interim dividend of 0.0796 yuan per share, and the total annual dividend per share will be 0.132 yuan, up 21.1% year-on-year, significantly higher than the growth of basic earnings per share of 11.5%, and the cash dividend level will reach a record high.

Talking about the key work in 2024, Chairman Chen Zhongyue said that he would persist in striving for progress while maintaining stability, and thoroughly implement the five strategies of strengthening enterprises through science and technology, talents, reform, digital intelligence and brand, and thoroughly implement the nine key action plans of networking communication development, computer network integration development, digital intelligence application development, internationalization development, big data innovation, artificial intelligence innovation, new digital infrastructure, high-quality service and network information security, and accelerate to become. We are confident that we will continue to maintain steady growth in operating income and double-digit growth in total profits.

[Global Network Technology Comprehensive Report] On the evening of August 8, Alibaba Group officially announced the brand-new membership plan of "88VIP" at the "88 Member Annual Stars Festival" in Guangzhou, redefining the traditional membership system.

According to reports, "88VIP" is a "all-in-one card" integrating Ali’s new retail ecology and multi-membership status, covering almost all the core services of Alibaba, and also providing a series of compound rights and interests in conjunction with 88 domestic and foreign brands among the 150,000 brands on Tmall. These exclusive discounts run through the whole year, even in double 11, and "88VIP" can be discounted and then discounted.

Users who have spent money on Ali retail platforms such as Taobao and Tmall in the past year will automatically become 88 members, and each member will correspond to different naughty values. If you are a naughty svip with a value of over 1000, you can only use 88 yuan to get this "88VIP" that non-members have to spend 888 yuan to buy. After preliminary calculation, the value of "88VIP" running through Ali’s ecological rights and interests is nearly 2000 yuan.

After becoming "88VIP", not only can you enjoy the annual "credit" of double 11 discount, but also the high-quality goods from Tmall Supermarket, Tmall International Direct Marketing and 88 brands around the world are all 15% off for the whole year; You can also enjoy annual exclusive discounts on imported milk, imported rice and other necessities; What’s even more surprising is that "88VIP" enjoys the exclusive status of "Eat, Drink and Play in One Train" under Ali, and is automatically upgraded to annual card members including Youku, Hungry, Shrimp and Taobao Film. In this way, according to the average user’s consumption level, becoming "88VIP" can save nearly 2000 yuan a year.

Take a bottle of Newsland fresh milk from 49 yuan as an example. "88VIP" can enjoy 72-hour direct fresh milk from New Zealand Ranch for only 19.9 yuan.

Roughly calculate, suppose a white-collar worker with a monthly salary of 5,000 yuan spends 888 yuan to become an "88VIP", and according to the average user consumption level, he can save 1,596 yuan, which is equivalent to getting 708 yuan for nothing. If it happens to be 88 svip, he only needs 88 yuan to get the "88VIP" status, which is equivalent to getting 1,508 yuan for nothing. Suppose a student party with limited pocket money can save its card fee in one month after spending 88 yuan as an "88VIP", and the following 11 months are pure "bonus hunter".

"Naughty value" is still the cornerstone of Alibaba’s membership system and the basis for the classification of Ali members. Naughty value of 1000 is a demarcation point. Those below 1000 are called 88 members, and those above 1000 are 88 svip. Besides enjoying the special price of "88VIP", they have distinguished privileges in daily shopping, payment and entertainment.

Ali’s new retail ecosystem is continuing to add more value and services to its members. Different consumption and life scenes face the same crowd. They not only order take-away food on the top every day, shop in Taobao Tmall, but also listen to shrimp on the way to and from work and watch the World Cup in Youku. They live in the ecology of Ali’s new retail every day. Compared with the traditional membership mechanism focusing on a certain field, "88VIP" has created a brand-new membership system based on Ali Ecology.

Those senior "hands-on parties" who are naughty and worth more than a thousand dollars have increased their sense of identity and belonging to the Ali ecological platform through the opening of the membership system. They are no longer entangled in the opening, renewal and maintenance of individual membership rights. As long as they have an "88VIP" card, those scenes that are frequently used in daily life can communicate with each other, which not only saves worry and money, but also makes the experience smoother.

This highly integrated Alibaba ecosystem is bringing great value to enterprises and promoting them to better carry out brand operation, user management, channel expansion and product development. For a wide range of merchants active in Ali’s new retail platform, the upgrading and opening of membership systems of different platforms can make them more deeply bound with consumers, not only further opening up online and offline, but also greatly expanding the original membership system.

Today, I took the time to go to the 4S shop and test drive the two-wheel drive version. To tell the truth, after reading so many photos online, it’s better to actually experience the real car.

The appearance of this car is very charming, the front face is full, the silver logo is added, and there are quite a few decorative strips on the wheel hub cover, which is a high-end feeling as a whole.

The interior workmanship can be felt very fine. In addition to the leather bag near the door and the central control, the roof is also wrapped with suede material, which is very comfortable to the touch. The triple screen and head-up display are also very easy to use. Let’s sum up the space in one sentence. People and things are enough.

At present, I have visited several 4S stores, and the prices are different. If you buy a car, I suggest shopping around more. At present, the price is calculated. The most expensive loan is 16w, and the cheapest loan is 14.9w I am going to grind it again and book one at the full price. # China Star Let the World See Dongfang Yao # Geely Automobile #L # Xingyue L Dongfang Yao # Good Car Recommendation # Test Drive

The Beijing News Shell Financial News (Reporter Lin Zi) On April 15th, the Star Era Night and Star Era ET Pre-sale Conference was held. There are two kinds of pure electric versions and extended range versions of ET in this Star Age, namely REEV series: 199,000 yuan for Plus, 219,000 yuan for Pro and 239,000 yuan for Pro, and BEV series: 239,000 yuan for Pro, 249,000 yuan for Pro Four-wheel Drive, 259,000 yuan for Pro City Smart Drive, 289,000 yuan for Max and 329,000 yuan for Ultra32.9

The longest cruising range of Xingjiyuan ET pure electric version is 760km, and the comprehensive cruising range of extended range version is over 1500km.

The extended-range version adopts a special engine with the highest thermal efficiency of 44.5% in industrial mass production developed by Chery, with a rated power of 115kW, achieving 1L oil power generation of 3.65kWh and WLTC feed fuel consumption of 5.2L/100km.

The pure electric version is equipped with Contemporary Amperex Technology Co., Limited Shenxing rechargeable battery, with a peak charging power of 420kW, which can achieve a battery life of 475km for 11.5 minutes. Even in the low temperature environment of-20℃, it only takes 24 minutes for the SOC to change from 20% to 80%. When the SOC is only 20%, the peak output power still reaches 280kW.

Editor Jiang Fan

Proofread Jia Ning

1905 movie network news At the end of January, the high-profile announcement of remarriage was good news, and his wife was pregnant. A few days ago, the husband and wife made a high-profile appearance at the airport and flew to Hungary together. Their beloved wife will accompany him to film here. Song Joong Ki, who hasn’t shared her recent life for a long time, updated the IG news on February 19th, and published her first PO article after remarriage.

Song Joong Ki exposed his daily life in Hungary. He was in a sunny bathroom, enjoying a pleasant time with his dog in his arms and pouting and kissing. Although my beloved wife didn’t appear, it is not difficult to see the silhouette of a woman from the reflection on the wall. Some netizens speculated that it should be Katie in love plus.

It is reported that Song Joong Ki went to Hungary this time to shoot a new film "The End of Roadbed". Originally, it was speculated that Katie would give birth in South Korea. Unexpectedly, the two of them appeared at the airport on the 16th, and Katie also took her dog abroad. A family of four made a surprise appearance and became the focus of the spotlight.

"Lu Jiwan" tells the love story of Lu Jiwan, a defector who arrived in Belgium with the last glimmer of hope, meeting and breaking up with Mary, a Korean woman who lost her reason to live. In the film, Song Joong Ki plays Lu Jiwan, a defector from the North, and strives for refugee status in Belgium. According to the plan, the film will be finished in June this year.