Article source: authentic scenery

　　Original title: Where is the "intestine" in China the best?

　　Author: Wang Xiaolan

　　Homesickness is a shallow sausage, the taste is on the tip of the tongue, and the thoughts are in my heart. When my mother started to work hard for filling sausages, the taste of the year would be there.

　　It’s not enough to go to the market once. You have to go to see the meat inquiry every day, just like the martial arts experts in the Jianghu, waiting for the best opportunity to attack quickly and accurately. When I come home from the vegetable market with all kinds of spoils with different degrees of fat, it is the highlight of my life. I don’t consciously hold my head high when I walk, and I must greet my acquaintances warmly:

　　"How many pounds of intestines have you poured this year?"

　　"Well, the meat is expensive this year, just pour ten pounds."

　　"Winter wax and wind pickling, storage to protect against winter". Sausage was born under the simple desire of people to keep food for a long time. The minced meat was seasoned and poured into casing, and the life of food was prolonged under the power of air drying. Nowadays, sausages have traveled all over the country and become unique taste representatives. The shiny Cantonese sausages on the clay pot rice exude attractive charm; Sichuan sausage sliced into plates is an excellent appetizer; The portable Harbin sausage on the train makes the instant noodles shine … They arrive as scheduled every winter and wear "autumn pants" in an orderly way, which becomes the most delicious thing in the world at the moment of reunion.

　　Sweet? Salty? Spicy?

　　When the meat put on "autumn pants"

　　The charm of sausage lies in that "there are a thousand kinds of flavors for every one who eats food". Even sausages in the same province, different counties and even different stores will have different tastes.

　　Not only the taste is different, but also the taste depends on your preference. No matter the fat ratio of 28 to 37, even if you want to be thin and full, the boss can satisfy it. Sausages are extremely inclusive. In this matter, we can all experience a "private order".

　　Sichuan sausage: Bashi is very comfortable! "Sichuan sausage is so delicious that I didn’t find it was raw after eating the second root!"

　　Yesterday, I saw someone in the circle of friends posting such a status, which is definitely the best annotation for the excellent taste of Sichuan sausage. The charm behind simple food often comes from meticulous raw materials, such as pigs carefully kept in captivity for a year with natural feed, fresh and healthy hind leg meat, and local authentic pepper. These ingredients with local flavor are stuffed into casings and dried in the most primitive way.

　　The most correct way to punch in Sichuan sausage is to cook and slice it, without any complicated operation. A bite of meat and wine is simpler and more delicious. Just like the hearty and domineering Sichuan spice girl, there is a gentle and emotional lifestyle hidden in her irritable personality.

　　In Sichuan, where sausages are everywhere, it is superior to others to be able to fill pork ribs with sausages, and the technology of filling pork ribs with sausages must be quite mature. The ingredients that look similar, under the digestion of ribs and minced meat, taste very different.

　　If the sausage is fragrant, then the pork ribs sausage is cool, tearing and eating bones; If the sausage is a cold dish that shines on the dining table, then the pork sausage doesn’t even need to be served. When watching TV, it is an excellent and delicious snack. "Pa", it just happens to meet a brittle bone and chew it in your mouth. It feels like winning the lottery.

　　Cantonese sausage: "small and fresh" in the intestine

　　In the sausage world, Cantonese sausage is comparable to Sichuan sausage.

　　Claypot rice is the most famous spokesperson of Cantonese-style sausage. It is an attractive scenery when the oily sausage is quietly spread on the rice. The quantity does not need much. The sweetness of sausage can penetrate into the whole bowl of claypot rice. It is the most gratifying moment to find a piece of sausage in the maze of rice.

　　The beautiful appearance of Cantonese sausage can not be separated from the two soul mates, sucrose and wine. Under their nourishment, Cantonese sausage has a particularly beautiful appearance, shining with crystal light in the sun. The taste is also very unique, and the feeling of sweetness with wine makes people feel drunk, and the entrance is smooth.

　　Cantonese sausage not only has a slim face, but also has a chubby and lovely appearance. Dongguan sausage is like this. When it is tied, the interval is short, and when it is hung and dried, it becomes a half-finger-long oval meat ball. It has a lovely name called short sausage. The short sausage tastes stronger because of too many sections, and sometimes it has the urge to swallow it in one mouthful, and experience the feeling that the full minced meat breaks through the casing and explodes in the mouth.

　　In addition to the famous clay pot rice, Cantonese sausage can also be used as a dish, fried peas, scrambled eggs, and even cakes. It adds icing on the cake to many ingredients with a slightly sweet but not greasy taste. Cantonese sausage is the "small freshness" in sausage industry. With its sweet taste, it rebuilds the happiness of life.

　　Laiwu sausage: just "sauce"

　　Sausages in the north look very different from Sichuan sausages, one is full of excitement and the other is dark. Whether it is Laiwu sausage or Boshan sausage, it looks dark and not pleasing. This is due to the addition of soy sauce in the meat stuffing, which changes the color of sausage, but it is these drops of soy sauce that bring the homesickness of many northerners and the taste of their yearning.

　　If the essence of Sichuan sausage is spicy and Cantonese sausage is slightly sweet, then Laiwu sausage and many northern sausages it represents should be salty and fragrant. The use of soy sauce not only changed the appearance, but also added a little sauce flavor to the sausage. The freshly steamed Laiwu sausage looks like cream chocolate, black and milky white intersect and reflect, the fat is crystal clear and smooth, and the lean meat is chewy.

　　Wanderers in the north will freeze the sausages sent by their mothers in the refrigerator, and take them out when the spring blossoms. The moment they are on the pot, the days with their mothers seem to be coming back.

　　Smoked horse sausage: wild and delicious

　　In Ili Kazakh Autonomous Prefecture in the northwest of Xinjiang, every year in late autumn and early winter, a wild delicacy-smoked horse sausage is brewed here.

　　When Ili horse is the most plump, it is a traditional means for Kazakhs to save for the winter by killing horses and storing meat. Although the taste of directly air-dried horse meat is already amazing, it is candidly admit defeat compared with horse intestines. Horse sausage is made of horse ribs as the main material, supplemented by minced meat from other parts, which is poured into the sausage and brewed delicious in sun drying and wood fire smoking. When you eat it, you have to gnaw at the bones, meet with minced meat, and at the same time, it is attached to the skin and full of toughness. This kind of food full of nomadic pride and informality will surely satisfy all your imaginations about bones.

　　The history of the counterattack of saying "eat and eat" and bullying "cooked intestines"

　　If the charm of raw sausage lies in the happiness at the moment when it comes out of the pot, then the charm of cooked sausage lies in that it can be eaten at any time and place without waiting. They have been smoked in the process of making, and they can drink it until dawn when they are eaten.

　　The most famous of these is Harbin sausage. In the past two years, no matter where you are, there may be a Harbin sausage wrapped in vacuum packaging and red in body at your doorstep. This kind of sausage originated in Russia came to Harbin on the "free ride" of the railway. It has been quietly brewing in this brand-new land for a hundred years and has become a famous local specialty food in Harbin.

　　In Harbin, many sausages hang naked outdoors, and the north wind can’t cover its prestige. When a gust of wind rises, the smell of sausages is in the air.

　　Beijing garlic sausage and Harbin sausage look like a pair of "brothers and sisters", one strong and one gentle.

　　Garlic foam is added in the filling process of garlic sausage, which retains the aroma of garlic and lacks the spicy taste of garlic. Even people who don’t eat garlic can’t help but look at garlic sausage twice. At first, they still have a fear of garlic. After aftertaste, they can’t stop.

　　In the deli in old Beijing, garlic sausage is a very popular guest, and only pine nuts and small bellies can be equally divided with it. The coat of pine nuts with small belly is made of pork belly, and the filling is filled with fragrant pine nuts. It is smoked by smoked sausage, and it is round and looks extremely cute. It is most suitable to be cut into triangles as a kind of appetizer.

　　Similar to pine nut tripe, there is also Luohan tripe, which is also filled with pork tripe. The stuffing is richer, and chicken soup, chicken, mushrooms and diced bamboo shoots can be stuffed in, which means that a big belly can accommodate. Lohan’s belly is not round, so it needs to be squashed, like a square with rounded edges and corners.

　　Dingzhou also has a kind of pork enema, also known as Dingzhou braised pork, which is different from the braised pork in the usual sense. It is made of pork and sweet potato powder and broth, each of which has arm thickness. When Dingzhou braised pork is hung together, the scene is very spectacular.

　　There are big ones and small ones. In Anshan, Liaoning Province, the heroic and hearty northeast people have made a small and lovely meat jujube sausage. The meat jujube sausage tastes very tight, and the small ones are connected together, just like jujube, so it is called "meat jujube".

　　If you can hold it, the world is yours

　　Chinese is the best at "eating". It’s not enough to put long trousers on pigs, beef and mutton, so they have the idea of more food.

　　The window is covered with silver frost, and the northeast people who go to the kang in the house must welcome the wanderers from afar with a bloody sausage. When slaughtering pigs and sheep, the delicious northeast people will not even let go of their blood. The big basin receives the blood, constantly stirs it, and the seasoning is poured into the intestines, tied tightly and bound, cooked in the pot, sliced, and the bright pig blood is wrapped in the casing and served on the table, and the entrance is instant, as soft as custard.

　　Blood sausage can also be combined with the most authentic sauerkraut in Northeast China to make a fresh and attractive stewed sauerkraut with blood sausage, which is rich in flavor, fresh but not greasy. Blood sausage with glutinous rice becomes rice blood sausage. After soaking glutinous rice soft, it is mixed with pig blood, and after adding seasoning, it is also cooked. Sliced rice sausage is black and red in color, fragrant with rice, and tastes softer and more glutinous. In addition to the northeast, many places such as Guangxi and Yunnan are popular in eating rice and blood sausage.

　　I don’t know if the taste of blood sausage is like egg custard, which inspires people. Curious foodies began to pour egg liquid into the casing. Steamed egg sausage is full of attractive orange, fresh and bright. You will also add pieces of preserved eggs to the egg liquid, which will become a double egg sausage, with orange, yellow and black and gray intertwined, like a Lego game.

　　There is also a kind of fried enema in Beijing. The most primitive fried enema actually has the blessing of pig intestines. It is made of more than 10 kinds of raw materials such as flour, red rice water, cloves and cardamom, and poured into the intestines. After cooking, it is cut into small pieces, fried in pig oil and poured with salted garlic juice. The taste is crispy and salty.

　　However, with the passage of time, most of fried enema in Beijing has lost its "intestines" and turned into a simple fried batter. If you can meet fried enema, who used to eat in the original way, you should cherish it!

　　Did you eat sausages from your hometown this year?

From October 22nd to 24th, the 16th meeting of BRICS leaders was held in Kazan, Russia. In the Kazan Declaration of the Sixteenth Meeting of BRICS Leaders, two key words have aroused widespread concern:

Cross-border payment system

"Infrastructure of Securities Depository Settlement in BRICS Countries"

What exactly do these words mean? What new progress has been made in economic and financial cooperation among BRICS countries? Tan Zhu’s exclusive dialogue with Qiang Jianxin, deputy secretary-general of the Emerging Economies Research Association and dean of the School of Economics and Finance of the Institute of International Relations, takes you to understand the new changes in economic and financial cooperation among BRICS countries.

(1) What is the cross-border payment system and settlement infrastructure?

The cross-border payment system is a cross-border financial infrastructure. We can use a "highway network" as a metaphor. Just like all kinds of trucks and buses are flowing on the expressway network, the cross-border payment system is actually the "expressway" in the international financial field, in which monetary funds flow.

A complete cross-border payment system includes payment instruments, payment institutions (mainly banks) and clearing system. Payment refers to the transfer of monetary funds, or the process of transferring acceptable monetary claims from the payer to the payee. The complete payment process mainly includes three links: transaction, clearing and settlement, and clearing and settlement are specific links in the payment process. Settlement refers to the final transfer and delivery process of monetary funds between the payee and the payer. In the face of a large number of transactions, we can’t settle accounts one by one, so we have to set up a clearing system among countries to settle accounts. Liquidation is the process of matching, transmitting, collecting and sorting out payment information and data, that is, the process and method of clearing off creditor’s rights and debts in multilateral currencies.

The Kazan Declaration dealt with the cross-border payment system according to different links and elements, from the payment currency, the agent bank network for cross-border payment to the "Securities Depository Settlement Infrastructure in BRICS countries", which is actually a specific link from easy to difficult. From this, we can see that the BRICS countries have not only macro and ambitious system goals, but also concrete measures with strong operability and reality.

(2) What are the current cross-border payment systems in the world?

The current cross-border payment system is actually a composite system, which mainly includes two parts: the cross-border payment system denominated in domestic currency and the cross-border payment message information transmission system. The former is represented by the clearing house interbank payment system (CHIPS) in New York, and the latter is represented by the Society for Worldwide Interbank Financial Telecommunications (SWIFT).

Cross-border payment system involves central banks and commercial banks in various countries, as well as related information and technical support institutions. The interbank payment system (CHIPS) of Clearing House in New York, USA, is the largest private payment and settlement system for US dollars in the world at present, handling about 95% of global cross-border US dollar transactions. The SWIFT system does not play the role of paying or transferring monetary funds, but its main function is the transmission of transaction information. Therefore, the cross-border payment systems in various countries need such a message information transmission system to form a complete cross-border payment system.

(3) What are the main problems in the current cross-border payment system?

First of all, the cost of the mainstream cross-border payment system is higher now, because there are so many nodes involved in the whole process. For example, if an enterprise between the two countries wants to conduct a transaction, it must at least involve the central banks, commercial banks and other agencies and complex links between the two countries. This also indirectly leads to the problem of low efficiency.

Secondly, the existing cross-border transactions involve the issue of currency selection, and the vast majority of transactions are conducted in US dollars. For countries whose transaction currency is not their own currency, there is a risk of exchange rate changes, which may affect financial stability.

In addition, the current cross-border payment system also shows the problem of insufficient inclusiveness. This is mainly because the mainstream cross-border payment system is highly dependent on the functions of banks and requires the popularization of bank outlets in business operation. Therefore, in many small villages and some underdeveloped areas in the world, especially in low-income countries, their banking networks are often not so developed, resulting in many people unable to use this system for cross-border transactions.

On the other hand, over-reliance on a single payment system also has security problems. Once the cross-border payment system is cut off, it is equivalent to the "highway" of a country’s foreign trade being cut off.

(4) What problems will the BRICS countries focus on in economic and financial cooperation?

To further promote cooperation in the economic and financial fields among BRICS countries, it is necessary to consider improving the existing payment system, give full play to the advantages of latecomers, and use the more advanced technologies to overcome the problems existing in the current system.

Ushakov, foreign policy adviser to the Russian President, said in an interview that the cooperation among BRICS countries in cross-border payment system will be based on advanced tools such as digital technology and blockchain. This will effectively solve the problems of low efficiency, high cost and insufficient inclusiveness in the current cross-border payment system. The establishment of a common cross-border payment system in BRICS countries will be a steady and gradual process, and its prospects need further observation.

The following article comes from the old urchin, and the author said that the old urchin

The old urchin said.

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Translated by Alva Wang, Xiong Muzhao, Cai Linguo and Yang Ping.

Novel coronavirus can cause immune response after being infected with human body. However, in addition to being infected with pathogenic microorganisms, human body can also produce immune response without being infected, that is, aseptic inflammation. Aseptic inflammation is an important factor leading to chronic diseases and individual aging. Recently, it has been found that there is an obvious correlation between cytoplasmic DNA and the activation pathway of aseptic inflammation. On October 28th, 2021, Prof. Peter D. Adams from Sanford burnham Presby Institute of Medicine and Prof. João F. Passos from Mayo Medical Center published a review entitled "Cytoplasmic DNA: Sources, Sensing, and Role in Aging and Disease" on the Cell, focusing on the formation of cytoplasmic DNA and the potential molecular mechanism of its related functions, providing new ideas for finding strategies to treat chronic diseases.

Abstract

Endogenous cytoplasmic DNA (CytoDNA) has been proved to be a key inflammatory mediator in many physiological and pathological processes. Although the role of cytoplasmic DNA in innate immune activation has been clarified, cytoplasmic DNA itself is often lacking in characteristics and difficult to be recognized, and its formation mechanism, functional scope and its role in diseases are not completely clear. In this paper, the author summarizes the research progress in this rapidly developing field, focusing on the similarities and differences between different cytoplasmic DNA, the potential molecular mechanism of their formation and function, the interaction between cytoplasmic DNA pathways, and the potential application in the treatment of aging-related diseases.

Jieshao

As the main medium for storing biological information, DNA is distributed in specific compartments of eukaryotic cells and separated from other cellular components. This kind of compartment, which exists in the nucleus or endosymbiont organelles (i.e. mitochondria and chloroplasts), can specialize and compartmentalize the main DNA functions and cell processes, thus regulating gene expression, genome replication and the repair of damaged DNA. In addition, cellular responses have evolved the functions of sensing, destroying and transmitting signals of exogenous DNA, and these functions are partly realized according to the information that they have located in cells that usually do not contain DNA. In the cells of multicellular animals, the above cellular reactions are part of the innate immunity of organisms and can be activated by various stimuli (such as virus and bacterial infections).

A similar pathway may also be activated by misplaced endogenous cytoplasmic DNA, thus driving the cell’s autonomous response without infection. Endogenous cellular DNA is a trigger of aseptic inflammation. The so-called aseptic inflammation is inflammation without pathogenic infection, which is related to the occurrence and development of many chronic diseases, including cancer, cardiovascular diseases and neurodegenerative diseases. The change of immune function, such as aseptic inflammation, is considered as an important sign of aging process, also known as "inflammatory aging". Although the interaction between viral DNA and host defense has been thoroughly studied, the role of cytoplasmic DNA in aging and chronic diseases has not been recognized until recently. In this review, the author focuses on four kinds of endogenous cellular DNA: micronucleus, cytoplasmic chromatin fragment, mitochondrial DNA and retrotransposon, and also evaluates the main types of endogenous cellular DNA, clarifying the mechanisms related to the formation, function and pathology of cytoplasmic DNA.

Micronucleus

Micronucleus (Mn) is a complete chromosome or chromosome fragment wrapped by nuclear membrane in cytoplasm, which may be directly separated from the nucleus, or is usually thought to be caused by mitotic defects.

Formation of micronucleus

The formation of micronucleus occurs under the background of cell division, which is related to two related mechanisms of chromosome error division, including: (1) Mitotic defects include metaphase or defective metacentric-kinetochore assembly or anaphase abnormality, and (2)DNA repair abnormality (Figure 1A). Although mitotic defects are related to the wrong separation of the whole "lagging" chromosome in the later stage, abnormal DNA repair is related to the wrong separation of chromosome fragments. These fragments can be formed by the fusion of chromosome fragments caused by unrepaired DNA double strand breaks (DSBs) or the wrong repair of telomere ends of DSBs. The former can lead to the wrong segregation of chromosome fragments lacking centromere, while the latter can lead to the formation of chromosome bridges. The fusion chromosome containing two centromeres breaks during cytokinesis, or can persist in the later stage of mitosis, and forms a bridge structure between the two newly formed nuclei. The breakage of this bridge leads to the extensive rearrangement of the bridge region through non-homologous terminal connection, and the formation of chromosome fragments lacking centromere or with other centromere defects. These abnormal chromosomes can produce micronucleus in the next round of cell division. In this case, the wrongly separated nuclear DNA will form a single nuclear membrane and become micronucleus, which will affect the cell function and fate.

Function of micronucleus

Micronucleus is initially surrounded by nuclear membrane, which separates micronucleus from cytoplasm. However, the integrity of the nuclear membrane may be lost spontaneously, leading to rupture (Figure 1B). Micronuclei carry defective nuclear membrane components, which are characterized by the lack of nuclear pore complexes and the weakening of nuclear transport capacity, which will affect many biological processes in micronucleus, such as the defects of replication and repair of micronucleus DNA. The loss of nuclear membrane integrity of micronucleus is also related to the rupture of micronucleus and the induction of micronucleus DNA by cell DNA receptors.

Although many DNA receptors have been reported, the most thoroughly studied cytoplasmic DNA receptor is cyclic GMP-AMP synthetase (cGAS). After recognizing DNA, the activated cGAS uses ATP and GTP as substrates to generate the second messenger loop GMP-AMP(cGAMP), which will bind and activate IFN gene stimulator (STING). STING oligomerization induced by cGAMP provides a signal platform for the recruitment and activation of TANK-binding kinase (TBK1). STING can also be used as a scaffold for phosphorylation of IRF3 by TBK1 and subsequent dimerization of IRF3. The dimerized IRF3 will enter the nucleus and trigger the type I interferon response. STING-related TBK1 also promotes the activation of nuclear factor κB(NF-κB) mediated by dsDNA to promote the transcription of inflammation-related genes. Gene knockout studies in mice show that cGAS is necessary for DNA ligand and virus-induced interferon response, which indicates that cGAS is the main cytoplasmic DNA receptor in these cases. Similarly, cGAS activation due to the rupture of micronucleus nuclear membrane is considered to be the main trigger of interferon-based inflammatory response.

However, the exact relationship between micronucleus rupture, DNA damage and cGAS sensing is still unclear. In view of the fact that some cGAS are usually located in nucleosomes, and the activation of cGAS by DNA/ chromatin binding is highly regulated (see prospect and conclusion for details), micronucleus breakage alone is not enough to activate cGAS. Similar to nuclear rupture, micronucleus rupture is related to extensive DNA damage, which may be due to the exposure of micronucleus to cytoplasmic factors, such as exonuclease TREX1 or other nucleases, so DNA damage may directly or indirectly promote cGAS activation. The perception of micronucleus by cGAS plays an environmentally dependent role in inflammatory signals and tumorigenesis. Mackenzie and others speculate that cGAS recognition of micronucleus DNA may be used as an intracellular immune monitoring mechanism to monitor a series of tumor induction processes (that is, micronucleus induction is a tumor inhibition mechanism). Harding et al.’ s research also suggests that cGAS/STING’s perception of micronucleus has tumor inhibitory effect, which may be mainly in the early stage of disease progression. Therefore, cancer cells usually inactivate cGAS-STING pathway to avoid immune monitoring.

Dysfunction of micronucleus

Although micronucleus is thought to be activated as a tumor inhibition pathway, it also drives genome instability through chromosome fragmentation, and plays a pathogenic role in the evolution and metastasis of cancer genome. Chromosome fragmentation is a widespread process of chromosome breakage, and some of it is considered to occur through the cycle of broken fusion bridges and the accumulation of DNA damage in micronucleus. Compared with micronucleus, the nucleoplasmic bridge formed between daughter nuclei has similar defects in nuclear membrane assembly, which leads to replication and repair defects and eventually rupture. This breakage and subsequent cell division can start the cycle of micronucleus formation, damage and reintegration into the genome through non-homologous terminal connection, further aggravating the genomic instability of chromosome fragmentation and evolution. In addition, the abnormal activation of STING-dependent NF-κB signal will also promote tumor metastasis due to micronucleus rupture.

Therapeutic target of micronucleus

The micronucleus activation of cGAS-STING signal is the internal mechanism of monitoring genomic instability, which is of great significance for cancer treatment. Therefore, activating the signal pathway downstream of micronucleus, especially STING, is a potential target in cancer immunotherapy. However, we need to pay attention, because in some cases, the activation of cGAS-STING pathway or other candidate micronucleus receptors is tumor-promoting. For example, in breast cancer and lung cancer, inhibiting chromosome instability and related cytoplasmic DNA can reduce the metastasis of cancer cells. This may be related to the environment-dependent utilization of cGAS-STING downstream pathway in changing immune function, the participation of other cell DNA receptors, the role of tissue environment in different environments or some combinations of these factors. In the case of chronic STING activation in aging cells near the tumor, STING activation may also promote tumor occurrence, which suggests that other environments of cytoplasmic DNA biology in non-tumor cells must also be considered for drug targeting of STING and cGAS.

Fig. 1 Micronucleus formation mechanism

(a) Micronucleus is caused by chromosome segregation defect, which is caused by chromosome segregation error or DNA repair error during mitosis. The formation of abnormal chromosomes may directly lead to the formation of micronucleus or nuclear bridge. The fracture and reassembly of nuclear bridge can form micronucleus in the next round of cell division. (b) Micronucleus is characterized by nuclear membrane instability, and nuclear membrane rupture leads to cGAS activation.

Cytoplasmic chromatin fragment

Cell senescence is one of the inducing factors of age-related aseptic inflammation and diseases, which is a stress response of cells to severe stimuli, mainly manifested in morphological and metabolic changes, permanent exit from the cell cycle, cell death arrest, and the formation of inflammatory aging-related secretory phenotype (SASP). There are chromatized micronucleus-like structures in the cytoplasm of aging cells. However, unlike real micronucleus. Many of these structures are formed independently of the cell cycle process. Its formation mode is that chromatin bubbles and enters the cytoplasm from the nucleus, and contains different molecular markers (Table 1), which indicates that the formation mechanism of these cytoplasmic chromatin fragments (CCF) is different from the real micronucleus.

Formation of CCF

CCF is characterized by a series of chromatin modifications, including the existence of heterochromatin-related H3K27me3 and the deletion of euchromatin-related H3K9Ac. This shows that CCF is formed by heterochromatin, although the genomic sites where these changes occur are not clear. The formation of CCF is related to the loss of nuclear membrane integrity in aging. To some extent, the integrity of the nuclear membrane depends on the nuclear fiber layer (a network structure composed of fibrin between A, B1, B2 and C, which supports the nuclear membrane). The loss of lamin B1 is also a recognized feature of cell senescence. The formation of CCF is also related to autophagy, which is a series of life activities to maintain intracellular homeostasis and is used to transport and degrade macromolecules and cellular components. The formation of CCF is also related to the autophagy degradation of Lamin B1 in aging cells. However, it is not clear whether the down-regulation of Lamin B1 is the cause or consequence of CCF formation. It is known that the knock-out of Lamin B1 can promote the formation of CCF-like lesions, and the over-expression of Lamin B1 can delay the aging process, which indicates that the loss of Lamin B1 may be the upstream regulatory factor of CCF formation. However, the formation of CCF in aging fibroblasts requires the interaction between Lamin B1 and LC3B (an autophagic substrate transfer protein) in the nucleus, and then Lamin B1 containing CCF in the cytoplasm undergoes autophagy degradation. This shows to some extent that,CCF is the carrier for degradation of Lamin B1. In addition, there is evidence that the mRNA level of Lamin B1 in aging cells is decreased, which indicates that there are many mechanisms to regulate the expression of Lamin B1 during aging. Clarifying the kinetics of Lamin B1 expression and degradation in aging cells will help to explain the relationship between CCF formation and autophagy.

CCF is strongly positive for DNA damage marker γH2AX, but it lacks a typical negative regulator of CCF formation, namely co-located DNA repair protein 53BP1. The observation that CCF is strongly positive for γH2AX shows that DNA damage plays an important role in the formation of CCF. DNA damage, especially the formation of DSB, is a powerful inducer of cell aging. Part of DNA damage is related to the change of mitochondrial function in aging cells through positive feedback loop and the continuous DNA damage caused by nuclear-mitochondrial (anterograde) and mitochondrial-nuclear (retrograde) pathways. Compared with cells in normal proliferation period or quiescent period, the mitochondrial mass of aging cells increases, the mitochondrial membrane potential decreases, the mitochondrial phagocytosis function may change, and the mitochondrial reactive oxygen species level increases. Interestingly, removing mitochondria from aging cells or inhibiting the formation of mtROS will inhibit SASP and prevent the formation of CCF, which indicates that mitotic nuclear pathway plays a role in the formation of CCF. It is reported that mtROS can activate stress-activated kinase JNK1/2 interacting with CCF inhibitor 53BP1 in mechanism. 53BP1 is a scaffold protein related to DNA damage, which recruits DNA repair factors into the DSB of DNA and inhibits the excision of the DSB end, which indicates that the formation of CCF requires the excision of the DSB end of DNA, and the inhibition of MRE11 by mirin also prevents the formation of CCF (Figure 2).Recently, similar mechanisms have been found in the genome instability models of human brain and Drosophila.

Fig. 2 Mechanism of CCF formation

The loss of Lamin B1 leads to the loss of nuclear membrane integrity through autophagy or other ways, and promotes the formation of CCF. Mitochondria can activate JNK1/2 signal pathway by producing mtROS, and participate in the formation of CCF. In the nucleus, 53BP1, as an inhibitor of CCF formation, may play a role by inhibiting MRE11-dependent double-stranded DNA cleavage. The markers of CCF include DNA damage marker γH2AX, heterochromatin marker H3K27me3, topoisomerase 1 cleavage complex (Top1Cc, which can enhance the binding of DNA to cGAS) and Lamin B1.

Functions of CCF

CCF will be induced by cGAS-STING pathway after entering cytoplasm (Figure 2). However, whether the DNA in CCF is a good substrate for cGAS activation and whether it can be obtained by cGAS remains to be studied. The activation of cGAS-STING leads to the activation of NF-κB of SASP gene downstream of STING, but not interferon gene, which may be due to the inhibition of interferon gene by p38 mitogen-activated protein kinase (MAPK) in aging cells. Under the condition of acute stress, aging cells, as an effective tumor inhibition mechanism, prevent cell growth and promote the elimination of potential malignant cells through SASP-dependent immune system activation. By observing the autophagic degradation of Lamin B1 in CCF, it is found that CCF may be the "reservoir" of nuclear autophagy substrate. At present, many other autophagy substrates have been found in aging cells. However, the direct role of CCF in this process is still unclear. In fact, CCF contains many chromatin-related proteins, but their fate in cytoplasm, such as autophagy degradation, independent signal transduction of cGAS and even cell secretion, is rarely reported. The correlation between γH2AX and CCF indicates that CCF is a by-product of DNA repair process. Most DNA repair factors are down-regulated in aging cells, which leads to the decrease of repair activity, especially the decrease of homologous repair pathway activity. This shows that,Removal and degradation of failed and potentially unstable repair intermediates (such as CCF) may be a mechanism to protect genome integrity or inhibit excessive DNA damage response, DDR) signal.

Table 1 molecular markers of cytoplasmic DNA

CCF and disease treatment

In addition to the functions of CCF and SASP mentioned above, these signals may also have harmful effects on human health. In some cases (such as aging), the failure to clear aging cells will lead to their accumulation and chronic SASP inflammation. A large number of studies show that aging cell accumulation and chronic SASP are the main factors leading to aging and related diseases. Therefore, the removal of aging cells by genetic or pharmacological "anti-aging" methods can prolong the life span of aged mice and prevent the occurrence of aging-related diseases. However, taking some anti-aging drugs for a long time may "accidentally injure" non-aging cells and produce toxic and side effects. As an alternative method, reducing SASP by "pathogenic" or "pathogenic" method may have lower toxic and side effects, and many studies have suggested that this method is effective in animal models.

Targeting the formation of CCF through the downstream targets of JNK signaling pathway or cGAS-STING pathway inhibitors can provide more strategies for the development of anti-aging drugs. Recent studies have shown that histone deacetylase inhibitors (HDACiS, such as voronostatin, an HDA CI approved for the treatment of some cancers in humans) can indirectly inhibit the formation of CCF and SASP by activating the mitochondrial function in aging cells and mice’s liver, which indicates that this method can play a targeted role in the treatment of aging in vivo. Further research on related mechanisms can find more targets (such as JNK1/2 and MRE11) to reduce human SASP, chronic inflammation and related chronic diseases. In view of the role of aging cells in promoting aging-related diseases, it is of great significance to analyze the interaction between mitochondrial function, autophagy and various cytoplasmic DNA during aging and the therapeutic potential of regulating these interactions (see prospect and conclusion for details).

Other forms of cytoplasmic DNA related to DNA damage

In addition to micronucleus in splinter cell and CCF formation in aging cells, there are several other cytoplasmic DNA labeled as micronucleus or CCF with unclear formation mechanism. These include cells from ataxia telangiectasia patients and cytoplasmic DNA； in Dnase2a deficient mouse model; Cytoplasmic DNA of CCF-like structure mediated by telomere damage, nuclear abnormality related to HGPS disease and cytoplasmic DNA in chromosome instability caused by excessive excision of Exo1; And small cytoplasmic DNA fragments related to DNA damage. The formation of these cytoplasmic DNA is directly or indirectly related to DNA damage marker γH2AX. However, it is not clear how these formation mechanisms are related to the specific mechanisms of micronucleus and CCF formation mentioned above. Despite these obvious differences, these cytoplasmic DNA types related to DNA damage have been confirmed to participate in the activation of cGAS-STING pathway. However, in aging T cells, cytoplasmic DNA can be sensed by KU complex (independent of cGAS-STING pathway), and they may also play an important role in physiology and diseases.

mitochondrial dna,mtdna

DNA(mitochondrial DNA, mtDNA) has thousands of copies in each cell and is densely packed into nucleoid. These nucleoids consist of a copy of mtDNA and various protein, such as mitochondrial transcription factor A (TFAM, a protein responsible for nucleoid structure, abundance and separation). Mitochondrial DNA is usually located in the matrix of mitochondria and encodes 37 genes: 13 kinds of mRNA (translated into some subunits of oxidative phosphorylation system), 2 kinds of ribosomal RNA and 22 kinds of transport RNA.

Fig. 3 release mechanism of mitochondrial DNA

(a–c) The release of mitochondrial DNA occurs through the following channels: (A)BAK and BAX channels provide the possibility for the inner membrane of mitochondria to pass through the outer membrane to form a protruding structure, and further allow matrix components such as mitochondrial DNA to escape; (b) mPTP channels in the inner membrane of mitochondria and oligomeric VDAC pores in the outer membrane of mitochondria; or (c) the outer membrane of mitochondria is broken due to the expansion of mitochondria mediated by mPTP. Once released, mitochondrial DNA can be sensed by DNA receptors. TFAM can enhance cytoplasmic cGAS induction.

Mechanism of mtDNA cytoplasmic release

Mitochondrial DNA in cytoplasm is related to the process of cell apoptosis. After receiving the apoptosis signal, pro-apoptosis proteins BAX and BAK are activated, and large holes are formed in the outer membrane of mitochondria, which leads to the increase of mitochondrial outer-membrane permeability (MOMP) (Figure 3). After the appearance of MOMP, the pores of BAX and BAK gradually widened, allowing the inner membrane of mitochondria to squeeze into cytoplasm. Then the prominent intimal permeability increased, which promoted the release of mitochondrial DNA. At first, MOMP was considered as an all-or-nothing event. All mitochondria in the cell showed MOMP, and pro-apoptotic proteins (such as cytochrome C) were released from the membrane gap, which eventually led to cell death. However, studies have shown that under sublethal stress, MOMP will occur in a small number of mitochondria, but it will not induce cell death. This phenomenon is called MOMP(minority MOMP, miMOMP). Therefore, mitochondrial DNA can also exist in the cytoplasm of cells that do not undergo apoptosis. Other mitochondrial stresses may also lead to cytoplasmic mitochondrial DNA leakage. For example, the decrease of TFAM expression leads to abnormal packaging, recruitment and distribution of mitochondrial DNA, which is finally released into cytoplasm.

Besides the lack of miMOMP and TFAM, another mechanism that may mediate the release of mitochondrial DNA into cytoplasm is the opening of mitochondrial permeability transition pore (MPTP) (Figure 3). MPTP is a transmembrane protein located in the inner membrane of mitochondria, which is usually opened by calcium accumulation in mitochondrial matrix, oxidative stress and other stressors. Although it has been proved that mPTP does not play a role in mitochondrial DNA leakage during apoptosis, a study shows that mitochondria will release mitochondrial DNA fragments by briefly opening mPTP in irradiated mouse brains. Another study shows that inducing oxidative stress in mitochondria isolated from rat hepatocytes can lead to the release of mitochondrial DNA fragments, and this process is partly mediated by the opening of mPTP. The above research shows that only mitochondrial DNA fragments will be released through mPTP, which is consistent with the fact that mPTP only allows molecules smaller than 1.5 kDa (smaller than mitochondrial DNA nucleoids) to be transported. However, the structural opening of pores may also lead to the expansion of mitochondria, the destruction of intima and the release of mitochondrial DNA cytoplasm, but further research is needed to confirm this conclusion. Interestingly, a recent study proposed a voltage-dependent anion channel (VDAC).The role of oligomerization in mitochondrial DNA release into cytoplasm. Studies have shown that mouse fibroblasts lacking mitochondrial endonuclease γ have more mitochondrial DNA, while mitochondrial endonuclease γ shows higher oxidative stress, which can be compensated by knocking out VDAC 1 and 3.

The dynamic changes of mitochondrial regulatory network also promote the release of mitochondrial DNA to cytoplasm. Mitochondrial DNA in TFAM-deficient fibroblasts increased, and mitochondria were elongated and highly fused. Mitochondrial division is very important for ensuring correct nucleoid distribution and removing damaged mitochondrial DNA. Consistent with this, the author found that the increase of mitogen 1 (MFN1) in TFAM-deficient cells was related to the decrease of the expression of interferon-stimulated genes (ISGs), which indicated that the destruction of mitochondrial regulatory network also affected the expression of interferon gene induced by mitochondrial DNA. A recent study also showed that knocking out GTP enzyme MxB located in the inner membrane of mitochondria would lead to mitochondrial breakage, inner membrane breakage and increase of mitochondrial DNA in cytoplasm. This result can support the viewpoint that the imbalance of homeostasis in mitochondrial regulatory network is the reason for the release of mitochondrial DNA into cytoplasm.

Function of cytoplasmic mtDNA

Mitochondrial DNA and bacterial DNA have many common characteristics. For example, mitochondrial DNA is hypomethylated compared with nuclear DNA. The unmethylated CpG motif in bacterial DNA is an effective trigger for inflammation. Interestingly, the similarity between mitochondrial DNA and bacterial DNA at the structural level probably reflects the bacterial origin of mitochondrial DNA, and is even considered as the basis of the joint action in immune signals. Mitochondrial DNA is considered as an exogenous substance outside mitochondria, and may cause inflammatory reaction. For example, in TFAM-deficient cells, the existence of mtDNA in cytoplasm is related to the increased expression of ISGs and depends on cGAS-STING-IRF3 pathway (Figure 3). In addition, the accumulation of cytoplasmic mitochondrial DNA caused by mitochondrial endonuclease γ deficiency has also been proved to induce the expression of ISGs in mouse fibroblasts, which indicates that cytoplasmic mitochondrial DNA is a major trigger of inflammatory reaction.

Cytoplasmic mitochondrial DNA has also been proved to play a role after virus infection. For example, although cGAS is more specific to cytoplasmic DNA than RNA, RNA virus can also activate cGAS-STING pathway. A study showed that the infection of human cells with dengue virus (DENV-2) led to the increase of mitochondrial DNA in cytoplasm and the activation of cGAS, which explained the mechanism of RNA virus activating innate immune signals. Consistent with the role of mitochondrial DNA in initiating antiviral immune response, TFAM-deficient cells showed high expression of type I interferon and ISGs when infected with herpes simplex virus 1 (HSV-1), and it was more resistant to infection than wild-type cells. Treating TFAM-deficient fibroblasts with dideoxycytidine, ddC) can eliminate the antiviral initiation and resistance to virus infection. ddC can inhibit the replication of mitochondrial DNA in these cells and reduce the stress of mitochondrial DNA, which indicates that cytoplasmic mitochondrial DNA enhances the antiviral innate immunity. Interestingly, another recent study showed that microbial infection induced the cytoplasmic release of miMOMP and BAX/BAK-dependent mitochondrial DNA, which would lead to the activation of cGAS-STING and the secretion of pro-inflammatory cytokines.Blocking the signal of sublethal apoptosis can damage the ability of cells to resist pathogenic infection, which means that the release of mitochondrial DNA cytoplasm mediated by BAX/BAK is an effective immune defense mechanism.

In addition to triggering inflammation through cGAS-STING recognition, cytoplasmic mitochondrial DNA can also activate other receptors in cells, eventually leading to downstream inflammation. For example, mitochondrial DNA has been proved to activate NLRP3 inflammatory corpuscles. A study shows that treating cells with mitochondrial dysfunction with lipopolysaccharide or ATP will lead to the increase of mitochondrial DNA level in cytoplasm, which is helpful to secrete interleukin (IL)-1β and IL-18 through NLRP3 inflammatory corpuscles. The author also suggested that NLRP3 not only acts as a downstream receptor of cytoplasmic mitochondrial DNA, but also promotes the release of mitochondrial DNA by promoting the formation of mPTP in mitochondrial inner membrane. Another study showed that during the process of macrophage apoptosis, oxidized mitochondrial DNA was released into the cytoplasm and combined with NLRP3 inflammatory body to activate. In addition, a recent study also showed that macrophages triggered the new synthesis of oxidized mitochondrial DNA fragments and activated NLRP3 inflammatory bodies, which indicated that NLRP3 was more likely to bind to oxidized mitochondrial DNA.

Cytoplasmic mitochondrial DNA and disease treatment

It has been reported that mitochondrial DNA circulating in plasma is related to several specific age-related diseases. For example, studies have shown that the level of mitochondrial DNA in plasma and joint fluid of patients with rheumatoid arthritis is significantly increased. Rheumatoid arthritis is a disease characterized by chronic inflammation, with a high incidence among the elderly. The levels of pro-inflammatory factors tumor necrosis factor alpha (TNF-α) and mitochondrial DNA in blood circulation of patients with type 2 diabetes mellitus are increased, and the latter is related to insulin resistance. In addition, high levels of circulating mitochondrial DNA in plasma were found in patients with ovarian cancer, testicular cancer, prostate cancer and lung cancer. The concentration of mitochondrial DNA was also increased in plasma and bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis (IPF). Plasma mitochondrial DNA level is related to disease progression and has been proved to predict mortality. In addition, normal human lung fibroblasts treated with isolated mtDNA will express high levels of α -smooth muscle actin, which is a characteristic of fibrosis diseases, indicating that mitochondrial DNA plays a role in the pathophysiology of IPF.

Although it is not clear whether circulating mitochondrial DNA is related to age-related diseases, due to its powerful pro-inflammatory properties, cytoplasmic and extracellular mitochondrial DNA may promote the development of diseases to some extent. Therefore, mitochondrial DNA and its release mechanism may be potential therapeutic targets for improving or preventing diseases related to the elderly. For example, studies have shown that the expression of Bax in alveolar epithelial cells of IPF patients is increased, which indicates that MOMP is involved in the occurrence and development of the disease. Consistent with this, the treatment of IPF mouse model with BAX-inhibiting peptide V5 (BIP-V5) can inhibit the activation of BAX in cytosol, reduce inflammation, improve lung pathology and improve the survival rate of experimental mice. In addition, the deletion of Bax gene has been proved to improve the ovarian function of elderly female mice, and promote the significant improvement of many age-related phenotypes, such as increasing bone density and intensity, better maintaining weight and reducing anxiety. Another study showed that the inhibition of BAX by two small molecule BAX channel inhibitors, Bci1 and Bci2, had protective effects during cerebral ischemia in gerbils. After reperfusion, the administration of BAX inhibitor can effectively inhibit MOMP, which shows that the release of cytochrome C in neuronal cytoplasm is reduced and the hippocampal damage is significantly reduced. These studies show that inhibiting MOMP by targeting BAX may be a valuable therapeutic strategy, which can improve the phenotype of age-related decline and prolong healthy life. Besides,In the mouse model of systemic lupus erythematosus, inhibiting VDAC oligomerization by using inhibitor VBIT-4 has been proved to reduce mitochondrial DNA release and IFN signal transduction, and improve the severity of the disease, which indicates that inhibiting VDAC oligomerization and mPTP may be an effective therapeutic strategy and can improve related diseases involving mitochondrial DNA release in cytoplasm.

All kinds of SASP play a role in paracrine way, inducing the aging of surrounding cells, which is considered as a mechanism of aging-related tissue dysfunction caused by aging cells. IL-1β is a major SASP factor, which can induce the release of mitochondrial DNA and then activate pro-inflammatory reaction. This may be one of the mechanisms by which aging cells stimulate the release of mitochondrial DNA in the cytoplasm of neighboring cells, thus aggravating inflammation, but further research is needed to confirm this hypothesis. A recent study shows that aging cells are the main source of extracellular mitochondrial DNA accumulated with aging. The pharmacological action of removing aging cells from aged animals significantly reduced circulating mitochondrial DNA, improved age-related inflammation and prolonged the survival time of mice receiving organ transplantation from aged animals. Although the mechanism of mitochondrial DNA release into extracellular space has not been fully clarified, this study shows that cell aging is an important factor for the increase of circulating mitochondrial DNA with age. In addition, damaged mitochondria in aging cells may contribute to the release of mitochondrial DNA and promote chronic inflammation related to aging, which is a subject worthy of further study. Eliminating aging cells has been proved to be an effective strategy to improve many age-related diseases. Although the role of mitochondrial DNA in this respect remains to be determined, targeting aging cells or simultaneously targeting the release of mitochondrial DNA from aging cells is another intervention strategy worth trying.

Retrotransposon

Transposable elements, TEs) is a mobile DNA sequence discovered by Barbara McClintock in 1950. Transposons account for 50% of the human genome, and contribute significantly to genetic variation at the population level. There are two types of transposons: one is a class II transposon called DNA transposon, which codes for protein transposase, allowing these transposons to mediate insertion and excision functions in the genome through the "cut and paste" mechanism. The other is class I transposons or retrotransposons, which rely on RNA mediators to transfer their transposons to other parts of the genome because they do not encode transposase. Retrotransposons are the main transposons in human genome, which can be divided into two types: LTR retrotransposons, including long terminal repeat at both ends, and non-LTR which does not contain these repetitive sequences. Non-LTR can be subdivided into long scattered repetitive sequences (LINEs) and short scattered repetitive sequences (SINEs). SINEs includes Alu family sequence, which is about 300 bp in length, and has more than one million copies in the genome, accounting for 11% of the human genome. In contrast, the length of LINE-1(L1) family sequence can reach 6 KB, and the number of copies exceeds 500,000, accounting for 17% of human genetic material. It is the most abundant human LINE. In addition, the L1 family includes the only endogenous autonomous reverse transcription factor that still retains the ability of autonomous reverse transcription transposition.Its protein products (ORF2p and ORF1p) are also responsible for mediating the reverse transcription transposition of sinusoidal involuntary elements.

Activation of retrotransposon and formation of cytoplasmic retrotransposon cDNA

After activation, LINEs are transcribed by RNA polymerase II, and the resulting mRNA is transcribed into cytoplasm, where it is translated into two kinds of protein: ORF1p (an RNA binding protein) and ORF2p as an endonuclease and a reverse transcriptase (Figure 4). These two proteins form a complex with mRNA transcripts and then relocate back to the nucleus. In the nucleus, the reverse transcription transpositional time occurs by target-primed reverse transcription (TPRT) when the target is not determined. In the process of TPRT, some people think that the endonuclease encoded by L1 cuts the negative sense chain of the target DNA and exposes a 3′-terminal hydroxyl group, which can be used as a primer for ORF2p to reverse transcribe L1 mRNA. After the synthesis of the second strand DNA, the mechanism of the reinsertion process has not been clarified. Although TPRT occurs in the nucleus, under some conditions, L1 cDNA is also found in the cytoplasm, such as autoimmune reaction. Here, we discuss the possible mechanisms that two kinds of L1 cDNA exist in cytoplasm: (1) The accumulation of a large number of L1 mRNA and L1 protein in cytoplasm may lead to reverse transcription without standard DNA template, thus leading to the increase of cytoplasmic cDNA elements; (2) In the process of TPRT, the generated cDNA will not be reintegrated into the genome, but will leave the nucleus and enter the cytoplasm through an unknown process.

DNA damage is related to the activation of retrotransposon. Studies have shown that the exposure of mouse and human cells to DNA damaging agents, such as etoposide, ultraviolet rays and γ-radiation, will lead to an increase in the expression level of AlRNA and an increase in reverse transcription translocation. In fact, after X-ray irradiation, new insertion of SINE and LINE-1 was detected in mouse germ cells. Although the mechanism of DNA damage promoting reverse transcription transposition is not clear, it may be that the change of transcription factor expression after DNA damage induction promotes the transcription of these elements. Epigenetic changes caused by some genotoxic stresses may also provide another mechanism of reverse transcription transposition induced by DNA damage. For example, methylation of CpG site at 5’UTR site will hinder the activity of L1 promoter and prevent reverse transcription transposition. The finding that MeCP2 can inhibit L1 expression and reverse transcription transposition also supports this view. Studies have shown that oxidative damage reduces the affinity of MeCP2 with damaged methylated DNA. Therefore, the oxidative damage near L1 element may show inhibition. Since the accumulation of DNA damage is one of the characteristics of cell aging and individual aging, the increase of DNA damage may contribute to the reactivation of retrotransposons observed in aging cells and aging tissues.

More and more evidences show that extensive epigenetic changes during cell aging and individual aging explain the reactivation of retrotransposons. In fact, a previous study showed that the increase in L1 transcription observed during cell aging was mediated by the decrease in the expression of RB1 and the increase in the expression of transcription activating factor FOXA1, in which RB1 is a transcription inhibitory factor that promotes heterochromatization of L1 elements. Another mechanism of age-related retrotransposon activation is the decrease of SIRT6 expression, which is a histone deacetylase and has been proved to regulate life span. SIRT6 inhibits L1 activity by binding to the 5’UTR of L1 element, and promotes heterochromatization by promoting the interaction between KAP1 and heterochromatin factor HP1α, thus making L1 element lose its transcriptional activity. However, in the process of cell aging and in the brain of aged mice, SIRT6 at L1 locus is deleted, which allows L1 expression and reverse transcription transpositions to occur. Consistent with this, SIRT6-deficient mice showed an accelerated aging phenotype, and the expression of L1 increased in many tissues. SIRT7, another member of sirtuin family, is also responsible for the epigenetic regulation of LINE1. LINE-s tends to locate in the protein-related domains of the nuclear laminae, which are mainly located in the periphery of the nucleus. Importantly, SIRT7 mediates the deacetylation of H3K18 in L1 element, thus promoting its association with nuclear laminin.Keep it in a transcriptional active state. One possibility is that in the aging process, due to the lack of Lamin A/C, SIRT7 can’t fix L1 element on the nuclear fiber layer, thus starting the expression of LINE-1 and reverse transcription transpositions.

Reversing the function of transposon

The inhibition of reverse transcription transposition will be relieved in some physiological processes. For example, during preimplantation development, when methylation modification is absent, the expression of retrotransposon is relatively high in late oocytes and early embryos of mice, and decreases in later stages. Evidence of L1 reverse transcription transposition was also reported during human early embryogenesis. In addition, reverse transcription transposition may also occur in the process of neuronal differentiation and affect the fate of cells. In addition, many stressors can induce the expression and translocation of retrotransposons, such as genotoxic stress, heat shock, viral infection and heavy metals. Retrotransposon activation can also be found in aging cells. In aging cells, the chromatin structure of many retrotransposon families becomes looser, which increases their transcription and eventually leads to the occurrence of retrotransposon of these elements, such as Alu, SVA and L1. Nevertheless, it is not clear whether the activation of retrotransposons is beneficial. However, the programmed activation of retrotransposons in aging cells and the subsequent activation of cGAS-STING-dependent IFN-I response and pro-inflammatory phenotype are beneficial to tumor inhibition related to cell aging.

Fig. 4 Mechanism of cytoplasmic DNA production caused by retrotransposon activation.

After transcriptional activation, polyadenylation (polyA) LINE-1 mRNA will encode ORF1p and ORF2p, which will be transported to the cytoplasm for translation. ORF1p and ORF2p combine with mRNA to form a ribonucleoprotein (RNP) complex. Reverse transcription and L1 nuclear integration are completed by TPRT mechanism which depends on the annealing reaction of thymidine nucleotide poly(A) tail in nuclear DNA. In addition, reverse transcription may also occur in cytoplasm. L1 cDNA accumulates in cytoplasm during aging and diseases, and is detected by nucleic acid sensor.

Retrotransposon dysfunction

The unrestricted movement of L1s in genome may be harmful, and more than 60 human genetic diseases are attributed to the insertion of retrotransposons. Therefore, the transcription of retrotransposons is strictly regulated and silenced at many levels, including epigenetic modification, premature termination of transcription, miRNAs(micro-RNAs), siRNAs(small-interfering RNAs) and post-transcriptional modification.

Some studies provide new evidence that the increased expression of retrotransposon gene is related to aging and diseases. For example, the expression of different retrotransposons and retrotransposable events in Caenorhabditis elegans, yeast, Drosophila melanogaster, mice and human cells increased with age. In the aging model of Saccharomyces cerevisiae, with the increase of age, the mobility of Ty1 in the yeast population increases, and this reverse transcription transposition is related to chromosome rearrangement. In addition, the expression of Cer1 retrotransposon in Caenorhabditis elegans increases with age, while in Drosophila, the increase of age-related gypsy and non-LTR retrotransposons R1 and R2 is related to the loss of neuronal function and the decline of cognitive ability. In mammals, the expression of retrotransposon is increased in the liver and skeletal muscle of aged mice, which leads to the occurrence of retrotransposon in elderly individuals. Interestingly, these phenomena can be weakened by calorie restriction, which has been proved to prolong the life span of a large number of organisms and reduce the burden on aging cells. Retrotransposon activation is also observed in mammalian cells lacking typical aging markers and aging model organisms that do not show cell aging, which indicates that retrotransposon activation is an inherent and conservative feature of aging process.

The activation of retrotransposons has also been proved to promote age-related chronic inflammation. In the later stage of senescence, the reactivation of LINE-1 element is accompanied by the accumulation of L1 cytoplasmic cDNA, which is partly due to the decrease of exonuclease’s TREX1 level and the activation of cGAS-STING-dependent IFN-I response and pro-inflammatory phenotype. Consistent with this, SIRT6 knockout mouse fibroblasts showed L1 activation, L1 cDNA accumulation in cytoplasm and increased expression of type I IFN gene. Immunocoprecipitation analysis of these cells showed that the abundance of L1 DNA bound to cGAS increased, which confirmed that L1 DNA in cytoplasm bound to cGAS and activated IFN-I reaction. Using nucleoside reverse transcriptase inhibitor (NRTIs) to inhibit the synthesis of L1 DNA in cytoplasm or knock down the expression of L1 by shRNA can reduce the activation of IFN gene and the level of SASP, which indicates that the accumulation of L1 cDNA in the cytoplasm of aging cells is an important factor to maintain the pro-inflammatory phenotype. Interestingly, increased expression of cytoplasmic L1 DNA and IFN genes has been observed in the tissues of many aged mice.

Transcription intermediates independent of reverse transcription and derived from retrotransposons are also related to the development of age-related diseases. It has been shown that in an age-related macular degeneration called geographic atrophy, GA), the decrease of the miRNA processing enzyme DICER1 in retinal pigment epithelium (RPE) cells leads to the accumulation of AlRNA. The latter then activates the inflammatory corpuscles of NLRP3, stimulates the production of cytokines and the cytotoxicity of RPE cells induced by MyD88, which leads to map atrophy. In addition, the study found that L1-derived mRNA was highly expressed in synovial fluid of patients with rheumatoid arthritis, suggesting that L1 activity may play a role in the invasive phenotype of rheumatoid arthritis.

Study on targeted therapy of retrotransposon

The most widely studied treatment to inhibit L1 reverse transcription transposition is to use nucleoside analogue reverse transcriptase inhibitor (NRTIs), which is a kind of antiviral compound that inhibits nucleic acid polymerase, including reverse transcriptase, and is also used to treat AIDS. A study of LINE-1 retrotranspositional test in vitro shows that L1 retrotranspositional can be inhibited by many reverse transcriptase inhibitors with different effects. Consistent with this, another group of studies showed that reverse transcriptase inhibitors can effectively inhibit the reverse transcriptase activity of L1 protein ORF2p, thus reducing reverse transcription transpositions. In addition, NRTIs has been proved to eliminate the accumulation of cytoplasmic L1 DNA in aging cells. Based on the IFN-I reaction triggered by cytoplasmic L1 DNA, which leads to age-related inflammation, NRTIs can be used as a potential treatment for age-related diseases. In fact, the treatment of aged mice with NRTIs effectively reduced L1 cytoplasmic DNA and subsequent inflammation in various tissues, and improved some age-related phenotypes, such as tissue macrophage infiltration, renal glomerulosclerosis and skeletal muscle atrophy. A similar improvement in healthy life expectancy was observed in SIRT6 knockout progeria-like mice treated with NRTIs. In addition, the increase of LINE-1 reverse transcription transposition is related to the decrease of oocytes in fetal period, which will lead to more than two-thirds of oocytes dying before birth. Studies have shown that the treatment of pregnant female mice with nucleoside analogue AZT can improve oocyte loss,Improve the vitality of oocytes in embryos. This raises the possibility that reverse transcriptase inhibitors may prolong the reproductive life of women by targeting L1 element.

Although mouse studies show that NRTI is an effective therapeutic strategy for L1-driven age-related inflammation and pathology, long-term NRTI therapy has been proved to induce adverse side effects in human patients, such as hepatotoxicity, because it can also inhibit mitochondrial DNA polymerase γ. In addition, NRTIs can also inhibit telomerase, which is considered to contribute to the accelerated aging phenotype associated with HIV patients. Therefore, it is necessary to formulate more specific intervention measures to safely and effectively treat diseases caused by uncontrolled L1 activities. For example, promoting the degradation of cytoplasmic L1 DNA to reduce inflammation may be a promising direction of targeted therapy.

Prospect and conclusion

Since 1960s, it has been known that exogenous nucleic acids can stimulate immune response. However, this pathogen induction strategy also allows the detection of endogenous nucleic acids that are wrongly positioned or abnormal. In recent years, breakthroughs in biomedical research fields such as cancer, immunology, aging, DNA damage and chromatin regulation have accelerated the research progress on the molecular mechanism of endogenous cytoplasmic DNA formation and function. Although it is known that the cytoplasmic localization of endogenous DNA triggers the regulation of signal pathways related to many chronic diseases, there are still many unknown information to be discovered. The author puts forward two main questions in this paper: (1) What is the mechanism of the formation and function of endogenous cytoplasmic DNA? (2) How does the interaction between endogenous cytoplasmic DNA pathways maintain normal physiological functions and drive the occurrence and development of diseases? Further understanding of the similarities, differences and interactions between heterogeneous DNA and related pathways will provide therapeutic opportunities for the treatment of human diseases.

Common Mechanism of Cytoplasmic DNA Formation and Function

There may be a common mechanism between the formation and function of heteroplasmic DNA, and a summary of these common mechanisms can produce a new insight. Firstly, by comparing the formation and signal transduction mechanism of endogenous cytoplasmic DNA, we can deeply understand the role of cytoplasmic DNA in physiology and disease, and reveal many similarities. For example, the loss of nuclear membrane integrity in aging cells and fibrotic diseases, such as HGPS, are consistent with the loss of nuclear membrane integrity in MN. These similarities include abnormal nuclear membrane function, changes in nuclear fiber layer structure, accumulation of DNA damage and activation of downstream cGAS. The loss of nuclear membrane integrity is also a potential mechanism of cytoplasmic localization of retrotransposons, although the cytoplasmic reverse transcription of L1 may also be one of the mechanisms. Second, although the relevant mechanism is not clear, CCF and mitochondrial DNA are considered to be partially localized in endosomes, and then they are induced, degraded or possibly secreted by cells. The degradation of dnase, such as the treatment of all forms of endogenous cytoplasmic DNA by lysosomal DNase2 or cytoplasmic TREX, can be used as a negative feedback pathway to inhibit the activation of DNA sensors. CCF and MN are also thought to be degradable by autophagy. Recent studies have shown that cGAS itself can be used as an autophagy ligand for MN degradation, which indicates that autophagy degradation may be the common fate of cytoplasmic DNA related to cGAS. Various forms of cytoplasmic DNA may be secreted and used as involuntary signals of cells in physiology and diseases, which is considered as a biomarker of aseptic inflammation.Thirdly, different cytoplasmic DNAs have similar signal pathways, most notably cGAS-STING pathway, although mitochondrial DNA, MN and other DNA fragments related to DNA damage are also thought to activate AIM2 and NLRP3 inflammatory body pathways. It will be interesting to verify whether additional DNA sensors are also shared between cytoplasmic DNA, and the functional mechanism of these sharing is consistent with the evolutionary conservative strategy of monitoring foreign DNA as a danger signal. Interestingly, many species of bats have evolved to naturally tolerate cytoplasmic DNA by reducing their perception of it. Fourthly, many kinds of cytoplasmic DNA observed in aging cells correspond to the role of foreign DNA as an activator of cellular antiviral mechanism, which strengthens the connection between cell aging and antiviral programs. Specifically, cell senescence can be induced by virus infection, and aging cells can activate antiviral pathways, and the replication of many viruses may be damaged by SASP of aging cells. Notably, in COVID-19 animal model, senolytic therapy eliminated virus-induced aging cells and reduced inflammation and mortality, which indicated that aging cells were potential therapeutic targets for virus infection. At the molecular level, the key regulatory factors of aging cell phenotype are also the core of virus defense mechanism, including tumor suppressor pRB and p53, histone chaperone HIRA, PML nucleosome, and cGAS, STING and ISGs.It is found that the additional shared and conservative "seno-viral" mechanism may provide information for the therapeutic strategy of targeting multiple cytoplasmic DNA at the same time, such as regulating SASP in aging cells, which may be driven or enhanced by CCF, mitochondrial DNA and retrotransposon.

Different mechanisms of formation and function of cytoplasmic DNA

Although there are basic similarities between endogenous cytoplasmic DNA, detailed research reveals their mechanism differences and many unresolved problems (Figure 5). As for the formation mechanism, the time characteristics of cytoplasmic localization of CCF, mitochondrial DNA and retrotransposon and the dynamic changes of cytoplasmic DNA induction in time are still unclear. For example, in aging cells, the formation of CCF occurs after cell cycle arrest, which is consistent with the independent formation mechanism of cell cycle. However, the direct role of MN and mitochondrial DNA in this process is still unclear. Aging cells also show retrotransposon activation, however, this activation only occurs in the late senescence, which is different from CCF formation in the late senescence days. Because these processes may occur in the same cell, which are related to similar formation mechanisms (such as nuclear membrane dysfunction and DNA damage) and activate cGAS, it will be very interesting to analyze this time relationship. The authors speculate that the formation of CCF in aging cells degrades unrepaired DNA, changes the epigenome structure in a gradual way, and finally suppresses retrotransposons. The temporal evolution of senescence cell phenotype has been observed in the process of "deep senescence" before.

The regionalization of cytoplasmic DNA in cytoplasmic chamber is not clear. Electron microscope showed that the aging cell CCF induced by oncogene could be located in autophagosomes with double membranes, and fluorescence microscope showed that CCF was co-located with lysosomes and activated by giant phagocytosis. However, it is not completely clear whether CCF is always consistent with the formation of autophagy bodies, or whether autophagy degradation is the only fate of CCF. Similarly, mitochondrial DNA is known to locate in endosomes and activate DNA receptors and pro-inflammatory mediators TLR9. Because the endosome is topologically adjacent to the outside of the cell, the location of DNA endosome is usually considered to depend on the endocytosis of extracellular DNA. This raises the question of how cytoplasmic mitochondrial DNA enters the endosome. The localization of CCF in autophagosome shows that the transport between autophagosome and other endocytosis compartments is another potential localization mechanism. Consistent with this hypothesis, antimicrobial peptide LL37 has been proved to promote the transport of aggregated DNA structures to early endosomes, promote the activation of TLR9 and the production of interferon. Further study on cytoplasmic DNA transport in cytoplasm can provide information for therapeutic strategies to degrade cytoplasmic DNA or prevent its secretion. Both of these methods have therapeutic potential for autoimmune diseases.

Although most of the research focuses on cGAS as the main sensor of cytoplasmic DNA, the regulation of cGAS seems to be upstream and downstream related. For example, although the activation of MN-dependent cGAS interferon gene has been well studied in cancer cells, the activation of cGAS in aging cells is usually related to NF-κb-dependent cytokine response, which is considered to be partially dependent on the activation of p38-MAPK in aging cells. In addition, there are some other potential factors that will affect the cGAS pathway. Recently, the research on cGAS’ induction of DNA has gradually revealed a complex regulatory network, including phosphorylation inhibition, nucleosome and chromatin structure binding inhibition, manganese activation, DNA damage-induced aging coactivator activation, and TFAM activation in mitochondrial DNA perception. At least in some cases, the localization of endogenous cGAS is considered to be in the nucleus and combined with nucleosome in an inactive state, but the exact mechanism of cGAS activation (such as MN disruption) is still unclear. Recently, there is evidence that cytoplasmic transport of nuclear cGAS is necessary for cytoplasmic DNA perception, at least in the context of exogenous DNA transfection and vaccinia virus infection. However, compared with being recruited from cytoplasm, the signal transduction function of cGAS transported from the main nucleus to MN and CCF needs to be further explored. Given that protein -DNA complex plays a central role in DNA function, it is not surprising that the cytoplasmic localization of DNA is regulated by specific environment and cytoplasmic protein components. of course，It is reported that cGAS can sense all major cytoplasmic DNA, but targeting other DNA sensors to detect cytoplasmic DNA, specific protein of cytoplasmic DNA source and specific protein of cytoplasmic subcellular can also play an important role in function and therapeutic targeting. In fact, the protein omics characteristics of CCF have identified these targets. Although the enrichment of heterochromatin-related histone markers indicates that CCF is produced by heterochromatin, the genomic region or specific site that produces CCF is not clear. Single cell genome sequencing has greatly improved the understanding of the mechanism of MN formation and chromosome breakage, which shows that similar methods can answer this outstanding question in CCF biology, and determining the DNA sequence of CCF can provide information for the targeting and formation mechanism of treatment.

Finally, although cGAS-STING pathway inhibitors are promising strategies for treating chronic inflammation and some cancers, the use of these drugs must take into account the diversity of endogenous cytoplasmic DNA functions. For example, the cGAS-STING signal that inhibits chronic inflammation downstream of CCF activation may be beneficial with age, but this strategy may also damage the signal transduction of intracellular immune monitoring and tumor inhibition initiated by MN. However, CCF and MN are difficult to distinguish under the microscope at present, and are often confused (Table 1). Therefore, the treatment methods must consider the specific endogenous cytoplasmic DNA, including the formation mechanism, localization and dynamics, as well as the interaction between different cytoplasmic DNA in the presence of multiple types, such as aging cells.

Fig. 5 types of cytoplasmic DNA and their perception of aging and diseases

Endogenous cytoplasmic DNA is produced by different mechanisms, but it is sensed and processed by similar cellular pathways. These mechanisms ensure chromatin homeostasis and DNA repair, as well as the catabolism of cytoplasmic DNA, and prevent the overactivation of innate immune signals. The loss of these homeostatic processes is considered to be one of the causes of inflammation and chronic diseases.

Conclusion

Whether exogenous or endogenous, DNA in cytoplasm can be used as a powerful stimulus signal to activate innate immune response. Although this field has long been concerned about the pathogenic activation of these pathways, recent work has found that endogenous cytoplasmic DNA is the main trigger of chronic diseases, especially cancer. These chronic diseases (including cardiovascular diseases, neurodegenerative diseases, sarcopenia, etc.) have common typical characteristics-patients are all elderly people. Chronic inflammation is partly caused by cytoplasmic DNA, which is related to many mechanisms and pathological changes reported in aging biology, which indicates that cytoplasmic DNA is one of the potential therapeutic targets to prolong human healthy life. Although preclinical studies on cytoplasmic DNA show that it is expected to be a target for the treatment of human health and aging-related diseases, there are still many challenges in its clinical application. Understanding the mechanism of cytoplasmic DNA formation and signal transduction, especially the subtype-specific mechanism of cytoplasmic DNA formation and sensing, will help to realize the treatment of clinical diseases, especially chronic diseases.

Original title: Cytoplasmic DNA and Aging and Diseases

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　　CCTV News:On June 11th, China’s first UHV project to send electricity outside the wind power photovoltaic base in desert, Gobi and desert areas — — Construction of 800 kV HVDC transmission project from Ningxia to Hunan started.

　　The total investment scale of Ningdian’s project in Hunan is about 100 billion yuan, starting from Zhongwei in Ningxia and passing through Gansu, Shaanxi, Chongqing, Hubei, Hunan and other five provinces (regions) and one city, with a total length of 1,634 kilometers. The project mainly transports green electricity and clean electricity produced by using clean energy such as solar energy and wind energy in desert, Gobi and desert areas, and has become an innovative project in Ningxia to achieve the goal of "double carbon" and a demonstration project to build a new power system and realize the optimal allocation of new energy in a large scale.

　　It is understood that the total installed capacity of supporting power supply for Ningdian’s project in Hunan is 17.64 million kilowatts, which will promote the transmission capacity of Ningxia power grid from 14 million kilowatts to 22 million kilowatts, and the installed capacity of new energy will exceed 50 million kilowatts, which will greatly promote the local consumption of new energy in Ningxia and optimize the allocation of new energy on a large scale, and fundamentally solve the problem of grid-connected consumption of new energy in central and southern Ningxia. After the project is put into production, it will increase Hunan by 36 billion kwh every year — 40 billion kwh of electricity consumption.

　　Ecological management of "planting green and protecting wires" makes the electric tower stronger

　　Ningdian’s project into Hunan is the first large power channel in China, which mainly focuses on developing desert photovoltaics and transporting new energy. What difficulties did the owner encounter in the pre-planning and current construction process? How is it solved?

　　The total length of Ningdian project in Hunan is 1634 kilometers, and the Ningxia section is 261 kilometers. Among them, 68% of the lines pass through desert, Gobi and desert terrain, which means that some power towers need to be built in the "Shage Desert" area, and the sparse vegetation and complex terrain in the area, coupled with the invasion of sandstorms, will make the power towers fall down, threatening the safe and stable operation of transmission lines.

　　In order to solve this problem, the project owner used the previous experience of UHV operation and maintenance management for reference, and launched the "Green Line Protection" plan.

　　"New energy+energy storage" ensures the stability of power supply to the network.

　　In addition, the engineering construction team also explored the technology of "new energy+energy storage" to solve the technical problem of unstable new energy.

　　In order to master the law of new energy power generation, Ningxia electric power department has stepped up scientific and technological research, developed and established an early warning system, and used artificial intelligence to process and analyze massive data to monitor the operation of new energy power in real time.

　　At the same time, in order to ensure the stable transmission of new energy power, Ningxia electric power system continues to tackle key problems of "new energy+energy storage" technology, providing strong support for project construction.

　　Guangming Daily reporter Zhang Zheng Guangming Daily correspondent Zhang Ziqi Deng Bailu

　　Xie Wei, director of the Cultural Tourism Bureau of online celebrity, Suizhou City, Hubei Province, who was both "spitted" and happy by netizens because of her hair accessories and slightly fat figure, told reporters with joy: "In the first quarter of this year, the city received a total of 7.526 million tourists, achieving a tourism income of 4.67 billion yuan, exceeding the data of the same period in 2019 and setting a record high."

　　Contrary to the image of the video, he is meticulous at work. Recently, when he spot-checked a problem at a scenic spot, he seriously told the staff of the local cultural tourism system: "If the traffic goes up and the word-of-mouth drops, we will only be bitten by the traffic!"

　　In the past two years, the directors of cultural tourism bureaus in various places have been "very busy": they have to "show their faces" in a high-profile way to promote cultural tourism, and they have to bear the pressure brought by the network — — Some people call it "the director trapped in traffic."

　　In the face of some controversy and traffic, Xie Wei is optimistic, "willing to appear in the camera ‘ Volume ’ The director of the cultural tourism bureau still hopes to do something. " After all, he did not forget to tell reporters to give more publicity to Suizhou.

　　Many readers are curious, why did they become online celebrity? What kind of confusion are you facing? Can you maintain the heat for a long time? To this end, Guangming Daily reporter conducted an in-depth interview with this group.

　　Tourists visit Hongcun Scenic Spot in yi county, Huangshan City, Anhui Province. Photo by Xu Jiadong/Bright Picture

　　Why did they become online celebrity?

　　No matter in appearance or expression, Xie Wei seems to have nothing to do with the standard of "online celebrity". In the video that made him out of the circle, Xie Wei wore Hanfu, which quickly attracted ridicule from netizens. "I knew from the beginning that I was very sloppy, but at that time, I felt that this would not affect the beauty of the Millennium Ginkgo Valley. I didn’t expect netizens to focus on me. " Xie Wei said.

　　Being online celebrity is not Xie Wei’s initial intention. In February 2022, Xie Wei was transferred from Suixian County to Suizhou City, Hubei Province as the director of the Culture and Tourism Bureau. During the epidemic prevention and control period, the local cultural tourism industry suffered heavy losses. Xie Wei took office for a month, which coincided with the peach blossom season in Suizhou. He confidently invited more than 20 people from the media to promote it. Unexpectedly, after the video was sent out, the response was flat and the publicity effect was not satisfactory.

　　Xie Wei called "meat pain" after calculating the account. "An activity, each big V needs hundreds to thousands of dollars in labor costs. If there are such activities every month, the annual budget will be several hundred thousand smaller. Comparing the effect, spending too much money is not a long-term solution. "

　　At that time, Liu Hong, director of the Cultural Tourism Bureau of Ganzi Prefecture, Sichuan Province, had become popular on the Internet with his martial arts costume and became one of the first directors of online celebrity, attracting a lot of attention.

　　This made Xie Wei see new possibilities. "I thought, why not follow the example of Director Liu Hong and try it yourself? It will save more money than inviting stars and big V." Xie Wei said.

　　Whether there is controversy or not, we have to admit that Xie Wei’s "explosion" has indeed saved a lot of money for Suizhou’s image promotion.

　　Tourists visit the drum culture exhibition at the Bell and Drum Tower Museum in Xi ‘an, Shaanxi. Xinhua news agency

　　Xie Wei, who took off the label of "online celebrity", is the most typical image of a civil servant in the public mind: wearing a dark coat with a white shirt, showing a calm temperament in his gestures. Before entering the cultural tourism system, he served as secretary of the township party Committee and participated in flood control and disaster relief work.

　　In his view, high-profile popularity is not contrary to his original intention. What the tourism industry needs is "marketing like a madman". Xie Wei said frankly, "online celebrity officials are just a statement. Actually ‘ Red ’ It’s a flash, and civil servants are our job. I can’t accept myself when everyone is writing ‘ Do not move ’ This will be sorry for the trust of the organization. "

　　Ouyang Min, an associate professor at the School of Journalism and Communication, Wuhan University, believes that the change from "low-key" in grass-roots work to "high-key" in cultural tourism marketing actually reflects the functional transformation of government departments from "managers" to "servers".

　　"For a long time, the image of officials has always been serious. In this upsurge, the directors took the initiative to ‘ Decapitation ’ In front of the camera, the expression of escaping and youthfulness subverts the public’s inherent cognition of civil servants. The interweaving of online celebrity and officials has produced a strong sense of comedy and conflict, which accords with the audience’s ‘ Curious ’ Psychology. " Ouyang Min believes that this is a development opportunity for the local cultural tourism industry.

　　What are the dilemmas in traffic?

　　The directors at the center of the topic found that traffic brought not only economic benefits, but also many controversies and rumors.

　　"I don’t know if you have seen the video circulating on the Internet? In their video, I was turned into a little girl in her twenties, wearing a sling and ogling everywhere. " When talking about this matter, Xie Wei frowned and looked very helpless.

　　In March of this year, some self-media AI-changed Xie Wei’s video and marked it with the words "Xie Director’s modern video footage" in an attempt to share a piece of the traffic tide, which also misled many netizens.

　　After the video was released, negative comments on the Internet flooded into Xie Wei. Someone asked him in the comment area: "Is it necessary to sell ugliness because of ugliness?"

　　Submerged in the voice of public opinion, Xie Wei said frankly that he once felt at a loss. He is afraid that he will be labeled as "grandstanding" and even more worried that the surging bad reviews will affect the image of Suizhou. "Because of this incident, many fans have withdrawn from my fan base, and the video click rate has also been affected." Xie Wei said.

　　In Bainiu Village, Changhua Town, Lin ‘an District, Hangzhou, Zhejiang Province, Luo Xingyue (first from right), an investment operator of the village scenic spot, introduced the natural scenery of Bainiu Village to tourists. Xinhua news agency

　　While Xie Wei is facing confusion, directors in other places have also begun to examine the "double-edged sword" of traffic.

　　In March last year, director of the Cultural and Tourism Bureau of daofu county, Sichuan Province, Jiang Zeduoji quickly "went out of the circle" with a sci-fi propaganda film and fluent English, becoming another well-known director of online celebrity after Liu Hong.

　　Up to now, his videos have almost "zero bad reviews", but he is still worried about his high exposure. "My friend said I was ‘ Seek your own way out ’ Exposed to the spotlight, all the subtle movements will be artificially amplified. If the traffic is too large, there may be gossip. " Denzawa Dorje said frankly.

　　In this regard, Ouyang Min believes that it is not unexpected that the traffic will bite back under the strong secondary creation of short videos, and the directors should be prepared.

　　Chen Bo, a professor at the National Institute of Cultural Development of Wuhan University, pointed out: "Director Xie ‘ Ugly out of the circle ’ It has indeed enhanced the visibility of the city. From the results, this is a relatively successful marketing. But this is not a good medicine for developing tourism. After the track of the director is saturated, what do the directors in other places rely on to get traffic? "

　　Chen Bo believes that in order to avoid the traffic itself, directors should clearly realize that publicity is only a means, not an end. Compared with "packaging is new", the cultural tourism industry should take the route of "content is king" and retain tourists with high-quality cultural tourism experience, otherwise it will be short-lived and will not last long.

　　How to seek "allowance" in "flow"

　　As more and more directors join the "online celebrity" tide, sharp-eyed netizens find "clues", and the short videos of cultural tours gradually appear homogenization phenomenon — — The directors are scrambling to adopt similar practices such as "cross-dressing show" and "showing beautiful scenery", which makes the public feel aesthetic fatigue.

　　"Imitation is the least controversial and the least investment." A director of online celebrity Cultural Tourism Bureau with a large number of fans bluntly said that because there is no professional operation team, creativity is easy to dry up and operation is difficult. In order to keep the account updated, we have to follow suit.

　　Tourists visit Nalati tourist scenic spot in Xinjiang. Xinhua news agency

　　Not long ago, the barbecue in Zibo was "out of the circle", which also provided a new inspiration for Director online celebrity — — You can’t just "roll in" endlessly in the video, but you should pay more attention to the travel experience.

　　Mitsuzawa Dorje once held a special meeting to re-examine Zibo’s out-of-circle password, and finally came to the conclusion that — — A city should have a core of fireworks.

　　"Barbecue seems to be a carrier of the taste of street life, but the affinity and interactivity reflected in this process are the core competitiveness." Yasuzawa Dorje believes that the development of cultural tourism should not only have the "face" of video promotion, but also have the "lizi" of tourism experience.

　　Some directors of cultural tourism said in interviews that the root cause of the fire in Zibo was to identify the uniqueness of the city. We should not simply imitate it, but give full play to local strengths according to local conditions and create a unique and grounded cultural tourism environment.

　　"I have been busy attracting investment recently." Online celebrity’s influence is being "realized". "Recently, four companies came to me by name to talk about investment and investment in homestay projects and amusement facilities."

　　In Dafang County, Guizhou Province, Wu Jiaojiao, deputy director of the online celebrity Municipal Bureau of Culture and Broadcasting, experienced the network dividend — — Online data is converted into offline income. A few years ago, they encountered the problem of "pain point". Some fans bluntly told her that the tourism format of young consumer groups was still in a blank, and there was "something to watch" but not "play" for young people. How to solve it once became a difficult problem.

　　This year, the local reference big data "suits the right medicine": a variety of new tourism formats have been launched — — Yi people’s immersive script tour, dressing tour, terrace light show, theme performance in the 1980 s and other ingenious activities. "On May 1 this year, the number of young tourists who come generously has also increased. The daily average number of marchers is as high as tens of thousands. Among them, among the leisure tourism consumer groups, young users and parent-child groups after the 90 s accounted for nearly 90%. " Wu Hao said.

　　Wu Jiaojiao (first from right), deputy director of the Bureau of Culture and Broadcasting in Dafang County, Guizhou Province, is at work. Bright picture

　　Recently, many directors of online celebrity Cultural Tourism Bureau have been thinking — — How to realize the transformation from "online celebrity" to "long red" and from "flow" to "reserve"?

　　Combining with relevant research, Ouyang Min gave suggestions to the directors: "As a tourist destination known for its natural scenery, it is suggested to build a selling point to relieve urban pressure, embrace nature, purify the soul and strengthen emotional experience. Tourist destinations with profound cultural heritage can focus on the development of folk resources, such as traditional crafts, folklore, historical allusions, etc., and explore deeper cultural connotations. "

　　A director of the online celebrity Cultural Tourism Bureau said that in the face of the cultural tourism fever in various places, it is also necessary to be wary of rushing into the project.

　　In this regard, Chen Bo, an expert who has been paying attention to cultural studies for a long time, reminded that the local cultural tourism departments should also do a good job in evaluating the online traffic conversion ability on the premise of clearly publicizing and positioning. "After all, online traffic cannot be directly realized. The cultural tourism department should measure the return on investment of the offline tourism industry and adjust the cultural tourism development strategy in real time according to the evaluation results." Chen Bo said.

　　The national consumer price index CPI in October released by the National Bureau of Statistics today rose by 0.5% year-on-year and decreased by 0.3% quarter-on-quarter. Food prices are still the core factor affecting the downward trend of prices. PPI, the ex-factory price index of industrial producers, remained stable year-on-year and quarter-on-quarter.

　　From a year-on-year perspective, CPI rose by 0.5%, and the growth rate dropped by 1.2 percentage points from last month. Mainly due to the high comparison base in the same period last year, the reduction of hikes and the impact of pork prices from rising to falling.

　　Specifically, pork prices fell for the first time after rising for 19 consecutive months, down 2.8% year-on-year; However, the year-on-year prices of eggs, chicken and duck are in the negative growth range, and the decline has expanded. The prices of eggs, chicken and duck decreased by 18.3%, 13.2% and 6.5%, respectively, with a decrease of 0.6, 4.1 and 1.8 percentage points.

　　In addition, the year-on-year increase in the prices of fresh vegetables, beef and mutton also declined, which made food prices the core reason for the decline in CPI. Non-food prices remained basically stable, but the prices of gasoline and diesel dropped significantly, with gasoline and diesel prices dropping by 17.4% and 19.1% respectively.

　　Alvin Wong, Dean of Founder Mid-term Futures Research Institute: Overall, the decline in food prices is a major reason for the decline in CPI; In terms of non-food, some energy prices also fell in October with the changes in the international market. Therefore, CPI continued to be in a downward trend in October.

　　PPI, another price index, dropped by 2.1% year-on-year, the same as last month, and industrial production prices remained stable as a whole.

　　Liu Xinwei, senior researcher of Zhuo Chuang Information: Overall, the infrastructure real estate data is better than expected; The price of black products rose month-on-month. With the increase in heating demand in the north, coal prices maintained an upward trend in October, achieving positive growth year-on-year; In terms of crude oil prices, the decline accelerated in late October, or touched the floor price again.

Housing prices in first-tier cities skyrocketed at the beginning of the year.

The property market in early 2016 is very similar to the stock market in early 2015. Everyone talks about stocks and everyone talks about houses. Housing prices in first-tier cities have gone up like a runaway, and Shanghai has even seen a price jump of 700,000 a day. At the same time, the scene of buying a house is no less than the double eleven.

In Shanghai, Lujin Shanghai School attracted nearly 100 buyers to queue up overnight in the middle of the night before the opening, and even friends in the team came wrapped in quilts, which surprised many people in the industry.

In Hangzhou, the second phase of Yangliu County in Greentown opened, and even 1000 people grabbed the source of 388 suites.

In Guangzhou, Vanke Mountain View City, which was just the opening time before, couldn’t wait to push it after the holiday, and it was robbed half an hour after the opening.

In addition to the bursting of real estate, the real estate trading center is also overcrowded, and Shanghai Baoshan Trading Center has to implement current-limiting measures.

On the one hand, the real estate in first-tier cities is an ideal haven, and safe-haven investment has become the most direct factor to promote this round of skyrocketing. On the other hand, at the beginning of this year, the central bank lowered the down payment ratio, and social funds also participated. The loose credit policy provided financial solutions for buyers, and financial services similar to "down payment loans" also boosted the rise of housing prices to some extent.

De-leverage the property market and strictly control the "down payment loan"

The so-called down payment loan refers to the fact that when the down payment funds of buyers are insufficient, real estate agents or financial institutions can provide them with subsidy funds for borrowing, which can be used by buyers to enlarge the leverage of buying houses. In some areas where house prices are rising rapidly, the existence of down payment loan has reduced the actual down payment of some buyers to 10%, which is equivalent to 10 times the leverage, and the leverage ratio is much higher than the "off-site fund-raising" at the peak of the stock market last year.

With the skyrocketing housing prices in first-tier cities, "down payment loans" began to surface, attracting the attention of the regulatory authorities. Shenzhen was the first to take the shot. In March this year, Shenzhen Financial Office issued a letter to prevent financial risks in the real estate industry, requiring Internet finance associations and small loan associations to investigate the situation of leveraged lending by enterprises under their jurisdiction and sort out the product model and the amount involved. At the same time, Guangzhou also began to investigate P2P and small loan companies to issue down payment loans.

A regulatory storm against leveraged funds represented by "down payment loans" is coming. If house prices continue to rise, using leverage may make a lot of money; Once house prices fall, there may be "trampling". If the high leverage of housing market is allowed to continue, it will be a financial disaster.

Real estate in first-tier cities is overheated, and the government urgently regulates it.

On March 25th, the Shanghai Municipal Government promulgated "Several Opinions on Promoting the Stable and Healthy Development of the Real Estate Market" to strictly control the property market, among which the most stringent provisions include: "Non-registered households in this city must pay social security for five years or more; For households with a set of housing, the down payment ratio for purchasing improved ordinary self-occupied housing has increased to 50%, and the down payment ratio for purchasing non-ordinary housing has increased to 70%. "

This regulation policy is called the strictest regulation in Shanghai. Coincidentally, Shenzhen has also introduced a regulation policy: non-deep households buy houses in Shenzhen, and the social security payment period is increased from the previous year to three years; The first suite paid off the mortgage, and when buying the second suite, the down payment was increased from 30% to 40%.

Under the strict control policy, the transaction volume of housing prices in Shanghai and Shenzhen dropped sharply, followed by the sale of some properties at reduced prices. Different from Shanghai and Shenzhen, due to the crowding-out effect of regulation, the property market in second-tier cities, such as Suzhou and Nanjing, began to boom, and the transaction volume and transaction price rose.

The expiration of some real estate land use years in Wenzhou has aroused the concern of the whole people.

In April this year, some citizens in Wenzhou were unable to conduct normal transactions when buying and selling second-hand houses. The reason was that the land had expired, and they had to pay hundreds of thousands of yuan of land transfer fees to re-apply for land certificates. They spent millions of yuan to buy houses, and they had to pay a lot of money after the expiration. After our house expires, we have to spend a lot of money to renew it, which has aroused heated discussion and concern from all walks of life.

The property right of the house we live in is divided into two parts, one is the house ownership, which is permanent, and the other is the land ownership. The right to use residential land is generally 70 years, which is also a controversial place.

What should I do if the property right expires after 70 years? According to the relevant provisions in the Property Law, the house is "automatically renewed" when it expires, but it has never been said that this is automatically free.

On the morning of December 23rd, Wang Guanghua, Vice Minister of the Ministry of Land and Resources, said that there was no need to apply for renewal, charge no fees, and handle the transaction and registration procedures normally, which was a clear solution. However, Wang Guanghua also mentioned that this is a transitional approach, and the formal approach has to wait for the introduction of relevant legal arrangements.

There are frequent land kings in first-and second-tier cities, and the price of "flour" is higher than that of "bread"

In May this year, the land market in Shanghai ushered in the first land transfer after the regulation of "Shanghai Nine Articles". The three plots of land in Fengxian and Songjiang all had a premium of more than 100%. The floor price of the two plots in Songjiang was close to 40,000/square meter, and the guaranteed price was 60,000/square meter, which was higher than the regional house price. A week later, the Zhou Pu plot was auctioned, with a floor price of 54,500/m2 and a guaranteed price of 79,000/m2. Similarly, in Nanjing, Hangzhou, Xiamen and Hefei, there have been cases of high premium land acquisition.

Developers seem to be crazy about taking land, the main reason is that they are worried about the future land supply. Take Shanghai as an example, Shanghai has locked up 3,226 square kilometers of construction land, and by 2013, 3,070 square kilometers have been used, leaving less than 156 square kilometers (including business and industry) in the future. Therefore, the scarcity of land in Shanghai has reached an unimaginable level. Coupled with the downturn of the real economy, the real estate market has become a safe haven for wealth.

Shanghai exploded rumors of the new mortgage policy, and divorced people crowded into the Civil Affairs Bureau.

At the end of August, a crazy divorce tide was staged in Shanghai. Divorced people crowded the civil affairs bureaus, and some civil affairs bureaus had no choice but to start limiting the number. Shanghai people’s desperate divorce stems from a rumor that "after September, buyers who have been divorced for less than one year will be treated according to their family situation before divorce." As a result, families who were afraid that they could not buy a house after the New Deal began to queue up for divorce. Although, it was later proved that this was a rumor fabricated by a real estate salesman. However, divorce to buy a house has always existed. Marriage is to protect the family, but now it has become a tool for profit-seeking. Is this the irony of the marriage system or a silent accusation against the real estate system?

Real estate in first-and second-tier cities is out of control, and many cities have introduced purchase restriction policies.

In September this year, the property market went crazy again. Nanjing sold 1,500 sets of houses, and Hefei property buyers rushed for houses in the rain. The price of a building more than 20 kilometers away from the main city of Hangzhou jumped directly from 6,000 yuan to 9,500-11,500 yuan. In Shenzhen, a 6-square-meter pigeon cage with a price of 150,000 yuan per square meter broke out, and the people of the whole country were like witchcraft.

With the booming property market, the purchase restriction policy was immediately introduced. Around the National Day Golden Week, the purchase restriction orders of nearly 20 cities were intensively introduced, and the real estate market in many places was sorrowful. The turnover of new houses in hot cities such as Beijing, Hangzhou and Nanjing declined in a cliff-like manner. At the same time, due to the influence of the New Deal and the adjustment of the down payment ratio, many property buyers have to cancel their contracts because they can’t afford to buy a house.

On the other hand, due to the property market restriction, some funds began to switch to A shares or overseas insurance, which objectively created the structural market of A shares after the National Day and the enthusiasm of mainland investors for Hong Kong insurance.

China CDSWill the real estate bubble be good when it strikes?

On September 23rd, China Association of Inter-bank Market Dealers "Business Rules for Pilot Credit Risk Mitigation Tools in Inter-bank Market" (hereinafter referred to as business rules) and related supporting documents, based on the original two products, launched two new products, including credit default swaps (CDS).

In the movie "Big Short", the protagonist from Wall Street saw the bubble of real estate subprime loans and made huge profits by shorting CDS. Therefore, CDS is also considered to be an important driver of the 2008 financial crisis.

Whether the China version of CDS can help squeeze out the real estate bubble remains to be seen.

Li Ka-shing sells mainland property and withdraws from China.

In October this year, Changjiang Industrial Real Estate Co., Ltd., a subsidiary of Li Ka-shing, announced that it would sell the "Century Hui" complex in Lujiazui, Shanghai for 20 billion yuan. This transaction will bring Cheung Kong Real Estate 5.43 billion yuan, which is also the largest property sold in mainland China by Li Ka-shing so far.

At the same time, Li Ka-shing focused its investment on Europe — — Britain, in particular, has invested in power, natural gas, transportation, retail and other fields, and focused on infrastructure. Britain has become Li Ka-shing’s biggest profit source.

The main reason for Li Ka-shing’s selling of mainland real estate is that there are too many bubbles in mainland real estate, and the risks outweigh the opportunities. Early action can make the company in an invincible position.

The Central Economic Work Conference decided that "the house is for living, not for speculation"

In December, the Central Economic Work Conference was held in Beijing, which mentioned that "houses are used for living, not for speculation", which not only curbed the real estate bubble, but also prevented ups and downs; Cities with high pressure of rising housing prices should reasonably increase land supply, and megacities should speed up the relief of some urban functions and promote the development of surrounding small and medium-sized cities; It is necessary to speed up the legislation of the housing leasing market and accelerate the development of institutionalized and large-scale leasing enterprises.

According to the content of real estate in the meeting, it can be inferred that the era of getting rich by real estate speculation has passed and real estate will return to the residential property; The functions of first-tier cities such as Shanghai and Shenzhen will be evacuated, and there will be more opportunities in surrounding small cities; The focus of the real estate industry will gradually shift from the buying and selling market to the leasing market, which may be the next opportunity for the real estate industry.

　　At 8 o’clock every day, CCTV will sort out the big and small things that happened around us within 24 hours.

　　[concern]

　　The relevant state departments decided to file an investigation into the alleged damage to the legitimate rights and interests of Chinese users by FedEx.

　　Recently, FedEx did not deliver the express mail according to the name and address in China, which seriously damaged the legitimate rights and interests of users and violated the relevant laws and regulations of China’s express delivery industry. The relevant state departments decided to file an investigation.

　　Great joy! Mother-daughter traffickers were sentenced to death, and buyers were also jailed.

　　On May 31st, the Intermediate People’s Court of Yangquan City, Shanxi Province publicly pronounced the case of 12 people abducting and selling abducted children across provinces. The defendants Wang Xi ‘e and Liu Liping were sentenced to death for crime of trafficking in children.

　　It was found through trial that since 2015, Shanxi defendants Wang Xi ‘e, Liu Liping and some family members have bought a large number of babies through various channels in order to seek illegal interests, and sent them to Shandong for sale through Shandong defendants Wang Chuanbin, Li Xiushan and Xu Qingquan. Shandong defendants Xu Qingquan, Yan Shaofu and Chen Guangzhou knew that they were trafficked children, but they still bought them themselves or helped their relatives buy them for adoption.

　　According to the number of abducted children in this case, combined with the nature, circumstances, degree of social harm and guilty attitude of each defendant, Yangquan Intermediate People’s Court sentenced the defendants Wang Xi ‘e and Liu Liping to death, deprived them of political rights for life and confiscated all their personal property. Sentenced the defendant Wang Chuanbin to life imprisonment, deprived of political rights for life, and confiscated all personal property; The remaining defendants were sentenced to fixed-term imprisonment ranging from 15 years to 6 months, and property or fines were also confiscated.

　　[domestic]

　　The exhibition center of Beijing Winter Olympics and Paralympic Winter Games is open to primary and secondary school students for the first time.

　　On June 1st, more than 200 students from Beijing sang songs such as "We are successors of communism" and My People，My Country in front of the exhibition center of Beijing Winter Olympics and Paralympic Winter Games, and the door of the exhibition hall slowly opened with their loud songs. Under the guidance of the commentator, the children learn about the progress of the preparations for the Beijing Winter Olympics, learn Olympic culture and knowledge, and be familiar with the Winter Olympics and Paralympic Games.

　　For the first time, BOCOG opened the exhibition center of Beijing Winter Olympics and Paralympic Winter Games to primary and secondary school students. From June 1st, primary and middle school students in China can visit the exhibition center in an organized way through the education administrative department.

　　Investigation on 108 Black and Evil "Umbrella" Cases in Zhaotong, Yunnan Province

　　According to the website of the Yunnan Provincial Commission for Discipline Inspection and Supervision, up to now, Zhaotong City, Yunnan Province has filed an investigation on 108 people suspected of being involved in black, evil and corruption and acting as "protective umbrellas" for evil forces. 53 people have been dealt with, including 27 people who have been punished by party discipline and government affairs, and 26 people who have been dealt with by organization and accountability; Fifteen people were detained, and four people were transferred to judicial organs for review and prosecution according to law.

　　Forbes China list of scientific and technological women: Tu Youyou and other 50 people were selected.

　　Forbes published the "China list of scientific and technological women" for the first time, and 50 women including Tu Youyou, lifelong researcher and chief researcher of Institute of Traditional Chinese Medicine, Chinese Academy of Traditional Chinese Medicine; He Tingbo, president of Huawei Hisilicon; Ge Yue, vice president and managing director of Greater China of Apple; Du Hong, president of Sina /COO; and Liu Qing, president of Didi Chuxing, entered the list. Forbes China said that the list is a ranking-free evaluation of 50 outstanding women in science and technology. They are founders, executives, front-line R&D engineers or pioneers of technological innovation.

　　Haikou duty-free shop opened in the second phase, with a business area of 22,000 square meters.

　　The second phase of Haikou Duty Free Shop opened on June 1st. So far, Haikou’s only duty-free shop with a business area of 22,000 square meters has been fully opened. Haikou Duty Free Shop is located in Riyue Square of the city, with a second-phase operation area of 9,000 square meters. At present, the duty-free shops are selling nearly 200 internationally renowned brands of duty-free goods.

　　[international]

　　Gun case in the United States: one injured person died, and the number of victims rose to 12.

　　According to comprehensive reports, a large-scale shooting incident occurred in Virginia, USA. As one injured person died on the way to hospital, the number of victims in this incident rose to 12, and many others were injured. In addition, the gunman also died after exchanging fire with the police.

　　The identity of the seven victims of the Hungarian shipwreck was confirmed. The captain denied the violation.

　　A tourist boat collided with a cruise ship in the Danube waters of Budapest, Hungary, killing seven Koreans on board. Recently, the South Korean Foreign Ministry said that the identity of the victims has been confirmed. In addition, the captain of the cruise ship was arrested, but he denied breaking any regulations or breaking the law.

　　The new zip line project of Eiffel Tower is hard for tourists to experience.

　　According to British media reports, a zip line with a height of 377 feet (about 115 meters) and a length of 2,600 feet (about 792 meters) has been built on the Eiffel Tower, a landmark building in Paris, France, for visitors to experience the thrill of crossing the sky quickly. It is understood that the project is "one ticket is hard to find": those who want to participate need to register on the homepage of brand social media, and the lucky ones are randomly selected.

　　Society

　　Tricycle stole 1 ton of stone lion. Thieves and cultural relics dealers were all detained.

　　A few days ago, a quadrangle in Dongcheng District of Beijing was stolen, and a stone drum and a stone lion weighing nearly a meal were stolen at the door. After investigation, five men stole the stone drum lion with an electric tricycle and sold it to Liu, a cultural relic dealer. On June 1, Dongcheng police reported that the stolen stone drum was identified as a cultural relic. At present, five men who stole cultural relics were criminally detained according to law on suspicion of stealing cultural relics and collecting stolen goods.

　　Guangdong police cracked a huge case of false invoicing, involving more than 5.3 billion yuan.

　　According to the Guangdong Provincial Public Security Bureau, police in Shenzhen, Guangdong Province recently busted a criminal gang that falsely invoiced ordinary VAT invoices, arrested seven people involved and found out more than 900 units that falsely invoiced, involving more than 5.3 billion yuan.

　　Nanning police quickly handle a hostage-taking case. Police stormed and subdued the suspect.

　　Xixiangtang Branch of Nanning Public Security Bureau of Guangxi reported on the 1st that on May 31st, the bureau, together with the special police detachment of Nanning Public Security Bureau and other units, quickly handled a sudden case of hostage-taking, arrested the suspect Zhou on the spot, and the detained person Wei was safely rescued. After preliminary investigation, the case was triggered by a family dispute. The public security organs are currently further investigating the case.

　　Hunan: Arrested 46 telecom fraud suspects, involving millions of yuan.

　　Recently, the People’s Procuratorate of Furong District of Changsha City approved the arrest of 46 suspects, including Yang Moumou, on suspicion of fraud. At present, this case is under further investigation. Since February 2019, in the name of the company, Yang Moumou and others have organized employees to falsely register female accounts through social software and add netizens. After gaining the trust of the victim, the criminal suspect induced the victim to register and recharge the "five-point lottery" on the Star Road Entertainment website. The criminal suspect defrauded others of money by manipulating the results of the "five-point lottery" in the background, involving millions of yuan.

　　[Sports]

　　Ma Long/Wang Chuqin won the runner-up in the men’s doubles final of 2019 China Table Tennis Open.

　　On June 1st, in the men’s doubles final of the ITTF World Tour 2019 China Table Tennis Open in Shenzhen, China team Malone/Wang Chuqin lost to German team Boer/Francesca 0-3 and won the runner-up.

　　[face]

　　[Zhan Guangwei] The teacher "Frozen Man" has been sticking to the podium for more than 20 years.

　　More than 20 years ago, Zhan Guangwei, who first came to the podium, was diagnosed with "progressive muscular dystrophy", commonly known as "frozen person". With the continuous deterioration of the disease, from being able to walk by yourself, to needing help, and then to sitting in a wheelchair … … Nowadays, he even has a hard time getting textbooks and teaching AIDS. However, this teacher still sticks to the front line of education and continues to "radiate heat" in the classroom.

　　See you at 8 o’clock tomorrow!

　　Editor: Zhu Xinyu

　　"The monthly container production capacity has increased to 500,000 TEUs, and the shortage of empty containers in major ports in China has dropped to 1.3% in May, which has gradually eased." On June 24th, at the press conference held by the State Council Office, foreign trade logistics became one of the hot spots. In fact, tight logistics and rising freight rates have always been difficult problems faced by foreign trade enterprises in the near future, and they are also the focus of the work of relevant departments.

　　The reporter of the Economic Information Daily noticed that in just two days, at the the State Council executive meeting, the press conference of the State Council Office and the press conference of the Ministry of Commerce, a number of authoritative departments voiced their voices one after another, focusing on strengthening cross-border logistics cooperation, increasing transport capacity guarantee, freight rate supervision, strengthening supply and price stability, and stabilizing exchange rate, and brewing more support policies to help foreign trade enterprises develop and promote the stability and quality of China’s foreign trade.

　　All parties actively respond to ease the pressure on foreign trade enterprises.

　　"The capacity of 23 million TEUs is now put into shipping except for about 1% of the ships under repair, and even some non-container ships come to carry containers." At the press conference of the State Council Office on the 24th, Zhao Chongjiu, Vice Minister of the Ministry of Transport, introduced it.

　　On the same day, Gao Feng, spokesman of the Ministry of Commerce, said that Guangdong Province is taking effective measures to co-ordinate the prevention and control of epidemic situation and smooth the international logistics work, and do its utmost to solve the problem of ships pressing on Hong Kong. From 0: 00 on the 24th, the overall operation of Shenzhen Yantian Port was fully restored.

　　The reporter saw at the scene of Yantian Port that there are berths in 20 berths in the central and western port areas, and all the operating shore cranes have been fully opened.

　　These are just the epitome of all parties helping import and export enterprises to solve problems. Since last year, the shortage of international logistics has become a headache for foreign trade enterprises. "Some customers with relatively weak strength can’t bear the cost pressure caused by this, and the goods can’t be shipped out and piled up in the warehouse, which increases the inventory and turnover cycle." Chloe Wang, vice chairman of the board of directors of Shengwei International Holdings (China) Co., Ltd., told the Economic Information Daily.

　　"This year’s sales have increased a lot compared with the same period of last year, but the profit side is not very optimistic." A person in charge of a foreign trade enterprise in Ningbo said frankly that the increase in freight and raw material prices squeezed the profit margin.

　　Gao Shiwang, director of the Industry Development Department of the China Chamber of Commerce for Import and Export of Mechanical and Electrical Products, told the Economic Information Daily that these factors have a great impact on foreign trade enterprises, especially some industries where raw materials account for a high proportion of costs, such as household appliances, low-voltage electrical appliances, machinery and tools. The transportation problem increases the inventory cost, and demurrage, container pressing and overnight expenses add up to be a big burden.

　　Solving these problems requires many efforts. In terms of customs clearance convenience, the General Administration of Customs has recently jointly launched 18 policy measures with the National Development and Reform Commission, the Ministry of Finance, the Ministry of Commerce, the Ministry of Transport, the General Administration of Market Supervision and other departments, focusing on optimizing processes, reducing costs, reducing time and improving efficiency, etc., and making efforts to solve the blocking points, pain points and difficult problems that the current market players are concerned about.

　　Some measures have achieved initial results. The reporter learned at Nanjing Customs that the customs introduced Yangshan — The new supervision mode of "joint loading and unloading, treating as one port" in Taicang Port realizes one-time declaration, one-time inspection and one-time release of container goods, effectively improving customs clearance efficiency.

　　In beibu gulf port, through scientific and reasonable organization of production and overall coordination of production resources in the three ports, the shortage of shipping space on ocean routes has been effectively alleviated. From January to May, the container throughput of this port increased by 29.5% year-on-year.

　　Li Jinhua, Marketing Manager of China Qinzhou Ocean Shipping Agency Co., Ltd., said that customers have been giving full play to the developed domestic transportation system and flexibly choosing delivery points. "Customers in the southwest area may have taken Qinzhou Port more, and now they will take Guangzhou Port or Shanghai Port, which is equivalent to an internal resource optimization and allocation."

　　Multi-sector intensive deployment, stable foreign trade, and policy strengthening

　　It is worth noting that stabilizing foreign trade will usher in more favorable policies. The executive meeting in the State Council on 23rd decided to take measures to accelerate the development of new foreign trade formats and new models, promote the upgrading of foreign trade and foster new competitive advantages. The meeting proposed to strengthen international cooperation in the fields of intellectual property protection and transnational logistics.

　　Multiple deployments are also carried out at the ministerial level. On the 24th, Gao Feng said that the Ministry of Commerce, together with the People’s Bank of China and the State Administration of Foreign Exchange, promoted financial institutions to continuously optimize exchange rate hedging products and services, and actively promoted the Foreign Trade and Economic Cooperation Enterprise Exchange Rate Hedging Business Manual to provide targeted guidance for enterprises to hedge. He also made it clear that he will continue to pay attention to the exchange rate fluctuations and help foreign trade enterprises actively respond.

　　Earlier, in response to a reporter’s question from the Economic Information Daily, Gao Feng said that recently, the Ministry of Commerce, together with relevant departments, conducted in-depth research on 7,500 foreign trade enterprises through the foreign trade and foreign investment platform, and took measures together with relevant departments and local institutions, such as promoting import diversification and building stable trade channels for bulk commodities. In the next step, we will further optimize and improve the trade policy toolbox to help foreign trade enterprises reduce costs and expand the market.

　　The Ministry of Transport has made it clear that it will work with the Ministry of Commerce and other departments to continue to implement relevant measures to stabilize foreign trade, guide international liner companies to continuously increase the supply of Chinese mainland’s export routes, improve the container turnover efficiency, and guide local transportation departments to ensure the stability and smoothness of the international logistics supply chain while doing a good job in epidemic prevention and control. In terms of price, it will cooperate with the market supervision department to strengthen the supervision of maritime port charges and investigate and deal with illegal charges according to law.

　　The General Administration of Customs has previously stated that the next step will be to fill the "short board" in terms of port collaborative governance, deep cooperation between enterprises and enterprises, and cross-departmental data sharing.

　　Business associations are also actively taking measures. Gao Shiwang said that with the support of the Ministry of Commerce, various import and export chambers of commerce have strengthened communication and cooperation with shipowners’ associations and China Shipping Remote Control, and are seeking more effective solutions for foreign trade enterprises.

　　Seize the opportunity of development and accelerate the transformation and upgrading

　　Regarding the situation faced by China’s foreign trade, Pang Chaoran, an associate researcher at the Research Institute of the Ministry of Commerce, believes that the recent recovery of external demand and the return of orders have driven China’s export growth, while short-term unfavorable factors such as exchange rate, inflation, shipping, chip supply and rising labor costs have increased the cost of export enterprises. "But these disturbing factors are exogenous, phased and temporary in general." He told reporters.

　　Liu Xingguo, a researcher from the Research Department of china enterprise confederation, said in an interview with the Economic Information Daily that at present, China’s foreign trade enterprises not only have to deal with many challenges, but also face greater opportunities, with both favorable and unfavorable factors.

　　In Pang Chaoran’s view, relevant departments and foreign trade enterprises should seize the opportunity to accelerate the process of moving towards the high-end link of the industrial chain and continuously enhance their foreign trade competitiveness in the process of continuous transformation and upgrading of domestic production capacity.

　　Pang Chaoran suggested that from the policy point of view, all departments should still pay close attention to the changes in the situation, find out the emerging and trend problems in time, make pre-judgment and early warning, and provide stable policy support for the sustained and healthy development of foreign trade enterprises; Enterprises should accelerate transformation and upgrading, constantly improve the international competitiveness and bargaining power of products, promote short orders to become long orders, and prevent price changes from affecting profits.

　　Liu Xingguo believes that while government departments take appropriate measures, enterprises should also take the initiative to seize the opportunity to accelerate development: First, strengthen cost management and maximize the pressure of cost increase; Second, scientifically and cautiously use innovative tools in international financial markets to partially eliminate the impact of RMB exchange rate fluctuations; The third is to speed up innovation and development, transformation and upgrading, and enhance the bargaining power of foreign trade enterprises in international trade with high-quality products.

　　In fact, foreign trade enterprises are already taking active actions. Chloe Wang said that overall, the export market is expanding this year, and the company is further expanding its production capacity and intensifying supply chain integration. "In order to cope with the uncertainty in the future, the company will improve product competitiveness and expand more international markets as an important task in the second half of the year."