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　　Reporter Dong Hanbo reported that on October 10th, Li Lecheng, deputy secretary of the provincial party committee and governor, came to Benxi City to observe the situation of mine geological disaster restoration and vegetation reconstruction, and made a special investigation on the greening of abandoned mines. He stressed that it is necessary to fully implement the spirit of the 20th Party Congress, further promote the study and implementation of the important speech delivered by the Supreme Leader General Secretary at the symposium on promoting the comprehensive revitalization of Northeast China in the new era, implement the work requirements of the provincial party committee, scientifically restore abandoned mines, restore ecosystem functions, and unswervingly follow the road of high-quality development with green and low carbon.

　　This year is the first year of a three-year breakthrough in the greening of abandoned mines in our province. It is planned to control an area of 126,000 mu of abandoned mines, including 82,000 mu of green areas. At present, the treatment of abandoned mines has entered the stage of greening in autumn, and the whole province has anchored the goal and task of tackling greening for three years, setting off a new upsurge of afforestation.

　　Walking into the site of the abandoned mine greening project in Gaoguan Town, Benxi Manchu Autonomous County, a piece of green came into view. Robinia pseudoacacia and oak trees planted along the highway and on the slope grew well, and the dilapidated scene of bare rock mass and gravel everywhere had disappeared. "Where does the project fund come from", "Are there any problems left over from mine closure" and "When will the saplings be planted" … … Li Lecheng went deep into the project site to learn more about the treatment of abandoned mines, and worked with the project leader to calculate the cost and discuss the planning. Li Le Cheng said that there are many abandoned mines left over from history, which not only affect the ecological environment, but also bring geological hazards such as landslides. It is necessary to carry out scientific and standardized restoration and treatment of abandoned mines left over from history, adopt a multi-pronged and systematic treatment, make overall plans to do a good job in geological environment management, eliminate hidden dangers of geological disasters, reduce environmental pollution of ores, beautify the ecological environment of mines, and go all out to restore the ecological functions of mining areas.

　　At the site of Niuxintai treatment project in Mingshan District, Benxi City, rows of newly planted saplings have added vitality to the brown mine. Since the beginning of this year, the local government has increased investment, sowed grass seeds, paved lawns and planted trees, and put on "green clothes" for mines. On the beach and beside the ditch, Li Lecheng carefully inspected the growth of sand and saplings in the river and listened to the introduction of greening work. He said that the ecology should not only be repaired, but also maintained. It is necessary to adhere to the problem orientation, continue to do a good job in quality supervision, plant local suitable tree species, improve the greening effect, strengthen the financial guarantee, ensure the effectiveness of ecological governance, and build a model project.

　　During the investigation, Li Lecheng affirmed the achievements made by Benxi in promoting the greening of abandoned mines. He emphasized that mine ecological restoration and management is an important content of ecological civilization construction and a concrete action to implement the supreme leader’s ecological civilization thought. All localities and relevant departments should take mine ecological restoration and management as a public welfare undertaking that better benefits the masses, and turn the deployment arrangement of the provincial party Committee into the action consciousness of green development. Scientific planning, precise policy, compact responsibility, speed up and improve efficiency, organize and implement greening work in a list, project and engineering manner, comprehensively promote the ecological restoration and management of mines in the province, and accelerate the formation of a new pattern of green and high-quality development of mining industry.

　　[car home Information] According to the enterprise investigation, Huawei Technologies Co., Ltd. applied for registration of the trademarks of "Zunjie" and "Qingjie", which are internationally classified as transportation tools and scientific instruments, and the current trademark status is pending substantive examination.

　　Prior to this, Huawei had applied for a series of related trademarks, including Wen Jie, Zhi Jie, Yong Jie, Hui Jie, Zhu Jie, Ao Jie, Zhi Jie and Yi Jie.

　　Earlier, Yu Chengdong, managing director of Huawei and chairman of BU, a smart car solution, said that apart from the intellectual and intellectual circles, there will be two circles in the future. In this regard, Yu Chengdong said that Huawei has issued an invitation for equity opening to Cyrus, Chery, Jianghuai and BAIC, and hopes that China FAW Group will join.

　　At present, Huawei has three cooperation modes in automobile business, one is parts mode, the other is Huawei HI mode, the other is intelligent car selection mode, and the third is the deepest cooperation mode. Among them, HarmonyOS Zhixing is a brand-new upgrade of intelligent car selection business, and cooperates with China automobile industry partners to create an innovative eco-car model. (Compile/car home Li Na)

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.

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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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Winter is the season of high incidence of respiratory infectious diseases.

Among them, the flu is "coming"

Increased risk of concentrated disease caused by influenza virus

The annual flu season is usually based on

A certain influenza virus is dominant.

"There will be no second stream after the first stream is over."

Executive Deputy Director of National Respiratory Medicine Center

Cao Bin, Vice President of China-Japan Friendship Hospital.

Analysis of the current flu season presents two characteristics.

First, the influenza type is mainly H3N2 influenza A.

Second, the peak of influenza infection is one month ahead of schedule.

The flu season in the north

Often from October to March of the following year.

The peak of influenza infection should be in the middle and late January to early February.

But this flu season

The peak of infection was advanced to the beginning of December.

Source: @ CCTV. Look.

Experts also pointed out that

Judging from the epidemic law of influenza in the past

The peak of influenza infection often appears before the Spring Festival.

Let’s prepare healthy new year’s goods together

Reject the flu "trick" ↓

How to distinguish the flu from the common cold?

Influenza is an acute respiratory infectious disease caused by influenza virus, which can be divided into four types: A, B, C and D.

Among them, influenza A (H1N1 subtype and H3N2 subtype) and influenza B virus will cause seasonal epidemic every year, which is highly contagious.

The flu is not as simple as an "epidemic" cold. It comes more suddenly and has more serious symptoms. Take more precautions!

Who needs a flu shot?

Vaccination against influenza is one of the most effective measures to prevent influenza, which can significantly reduce the risk of infection and improve the symptoms after infection.

The Technical Guide for Influenza Vaccination in China (2023-2024) recommends that all people who are ≥ 6 months old and have no vaccination contraindications should be vaccinated with influenza vaccine. In addition to the "one old" (elderly people aged 60 and above) and "one young" (children aged 6-59 months), the following groups are also recommended for timely vaccination:

Can oseltamivir "cure everything"?

Oseltamivir is an effective drug to treat influenza, but it is not a "magic drug". It is wrong to put oseltamivir in your mouth whenever you catch a cold.

As a neuraminidase inhibitor, oseltamivir is only effective against viruses with neuraminidase. At present, only influenza virus has such enzyme on its surface, while other viruses such as rhinovirus, respiratory syncytial virus and Covid-19 do not have such protein microdots on their surfaces.

Therefore, the symptoms of respiratory diseases, it is best to seek medical advice in time to confirm what virus is infected, and must follow the doctor’s advice. If oseltamivir is used blindly, it will only increase the burden of liver and kidney function.

From: National Emergency Broadcasting (including pictures)

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Original title: "The peak of infection in this flu season is one month ahead of schedule! Do you know these things? 》

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Requirements:

1. Bachelor degree

2. Flexible and efficient, with good data analysis ability and negotiation ability.

3, honest, gentle personality, strong adaptability, communication and coordination skills and interpersonal insight.

4. Be familiar with the fast pace of the Internet industry.

Salary: 6000-8000 yuan/month

Purchasing Assistant /2 persons

Requirements:

1. College degree or above.

2. Skillfully use office software and ps software.

3. Have certain ability of data acquisition and analysis.

4. Strong sense of responsibility, strong adaptability, negotiation and communication skills and learning ability.

Salary: 5000-7000 yuan/month

New Media Marketing /20 people

Requirements:

1. Bachelor degree

2. Have certain experience in kol talent/red man docking, and work experience in mcn organization is preferred.

3. Good communication skills and adaptability.

4. Have a keen judgment on the development trend of emerging new media.

Salary: 6000-8000 yuan/month

E-commerce operation /15 people

Requirements:

1. College degree or above, major in marketing/e-commerce is preferred.

2. Skillfully use office software and ps software.

3. Have certain ability of data acquisition and analysis.

4. Strong sense of responsibility, strong adaptability, negotiation and communication skills and learning ability.

Salary: 5000-7000 yuan/month

2. Shanghai Dongyang Ink Manufacturing Co., Ltd.

Enterprise address: No.2450, Shengang Road, Songjiang Industrial Zone

Business manager /1 person

Requirements:

1, college degree or above, can receive fresh graduates.

2. Proficient in Japanese

Salary: 7000-8000 yuan/month

III. Shanghai Faxin Electromechanical Equipment Manufacturing Co., Ltd.

Enterprise Address: No.258 Xinzhuan Highway, Songjiang District

Sales Engineer /2 persons

Requirements:

1. Major in automotive engineering/automation/electrical engineering/mechatronics/mechanical manufacturing, college degree or above.

2. Strong communication and learning skills, strong achievement motivation, and like challenges.

3. Good conduct, enthusiasm and cheerfulness, hard-working, and have certain teamwork ability and pressure resistance.

Salary: 6000-10000 yuan/month

After-sales technical engineer /2 persons

Requirements:

1. Major in automotive engineering/automation/electrical engineering/mechatronics/mechanical manufacturing, college degree or above.

2. Have strong hands-on ability and service consciousness.

3, clear thinking, responsive, strong learning ability, good at analyzing and solving problems.

4. Good conduct, enthusiasm and cheerfulness, hard-working, and have certain teamwork ability and pressure resistance.

Salary: 6000-8000 yuan/month

Product Engineer /2 persons

Requirements:

1. Major in automotive engineering/automation/electrical engineering/mechatronics/mechanical manufacturing, bachelor degree or above.

2. Good language skills, high level of Chinese and English.

3, hard-working, strong team spirit and service consciousness.

Salary: 6000-10000 yuan/month

R&D Engineer /2 persons

Requirements:

1. Bachelor degree in automotive engineering/automation/electrical engineering/mechatronics/mechanical manufacturing and other related majors.

Salary: 6000-10000 yuan/

4. Shanghai Gaoshi Optoelectronics Co., Ltd.

Enterprise Address: No.718 Lianying Road, Chedun Town, Songjiang District

Mechanical Engineer /2 persons

Requirements:

1, mechanical major, college degree.

2. At least 2 years working experience in electromechanical/automation design.

3, familiar with the mechanical principle/hydraulic system and pneumatic system/machining process.

4. Proficient in computer-aided design and related design of non-standard equipment/fixtures.

5. Have certain project responsibility, management, organization and coordination ability.

Salary: 6000-8000 yuan/month

Mechanical and electrical engineer /2 persons

Requirements:

1. College degree, major in mechatronics is preferred.

2. Hold the certificate of electrician/welder/fitter.

3. Experience in field equipment maintenance.

4, master the performance and operation of production equipment, understand the equipment repair/maintenance process and standards.

5, strong execution and equipment operation skills, familiar with the maintenance of large equipment in manufacturing industry.

Salary: 7,000-10,000 yuan/month

Project Assistant /2 persons

Requirements:

1, mechanical major, college degree.

2. Have cad drawing skills.

3. Skilled in operating office software

Salary: 5000-6000 yuan/month

Purchasing Assistant /3 people

Requirements:

1. College degree, major in mechanical/physical/material is preferred.

2. Skilled in operating office software

Salary: 5000-6000 yuan/month

Sales Assistant /3 persons

Requirements:

1. College degree or above, major in marketing is preferred.

2. Having passed CET-4 is preferred

3. Skilled in operating office software

Salary: 5000-7000 yuan/month

Cad drawing process engineer /2 persons

Requirements:

1. Have more than 2 years working experience in related positions.

2, cheerful personality, strong learning ability and communication skills.

Salary: 5000-8000 yuan/month

Electrical Engineer /2 persons

Requirements:

1, mechanical and electrical integration major

2. Hold a low-voltage electrician certificate.

Salary: 6000-10000 yuan/month

V. Shanghai Guolong Biotechnology Group Co., Ltd.

Enterprise Address: No.1505 Shuhai Road, East Zone, Songjiang Industrial Park

Technical service engineer /1 person

Requirements:

1. Major in animal nutrition and feed science/breeding, bachelor degree or above.

2. At least 2 years working experience as an animal nutritionist (formulator).

3, familiar with feed formula and feed production process, understand the oil nutrition and feed nutrition, the above ability is not limited to professional and academic qualifications.

4. Good information/data collection and compilation skills.

5. Good communication skills, strategic thinking and problem-solving skills.

6. Strong ability to withstand pressure and solve problems on site.

7, skilled use of computer and other office equipment, familiar with office software.

8. Recognize the value and development potential of fatty acid nutrition in feed production.

9. Accept long-term business trip/regular on-site work.

Salary: 5000-7000 yuan/month

Fermentation Engineer /1 person

Requirements:

1. Major in bioengineering/fermentation engineering/biotechnology/microbiology, bachelor degree or above.

2. Rich experience in fermentation process control/process optimization.

3, familiar with the operation of fermentation related equipment, can independently design the experimental scheme, and can scientifically analyze and solve problems.

4. Experience in fermentation of genetically engineered bacteria such as Escherichia coli/yeast is preferred.

5. Fresh graduates who have experience in fermentation-related topics/internships and are familiar with microbial fermentation processes can also do so.

6. Good execution and obedience, strong sense of responsibility and teamwork spirit.

Salary: 5000-7000 yuan/month

Key Account Manager /1 person

Requirements:

1. Major in animal nutrition, bachelor degree or above.

2, proficient in animal nutrition related knowledge

3. Strong communication and expression skills and pioneering spirit

Salary: 5000-7000 yuan/month

Product Manager /1 person

Requirements:

1, animal husbandry and veterinary/animal medicine and other related majors, bachelor degree or above.

2, strong research ability, can capture the market orientation and market demand.

3, have certain product planning ability, from scratch to product marketing methods to carry out the overall product planning, and implement the planning.

4. Good communication skills and coordination skills.

Salary: 5000-7000 yuan/month

6. Shanghai Haiying Sanitary Products Co., Ltd.

Enterprise address: Lane 199, Dajiang Road, Yongfeng Street, Songjiang District

Mechanical maintenance engineer /2 persons

Requirements:

1. College degree or above, major in mechanical engineering is preferred.

2. Have 5 years or above relevant working experience and can accept excellent fresh graduates.

3. I can read pictures, draw drawings and use solidworks/

Autocad and common office software

Salary: 7,000-10,000 yuan/month

Mechanical design engineer /2 persons

Requirements:

1. Major in industrial design/mechatronics/automation, college degree or above.

2. Have 5 years or above relevant working experience and can accept excellent fresh graduates.

3, master solidworks/autocad and other related design software.

4, master the research tools/instruments.

5. Have good learning ability and certain leadership.

Salary: 7,000-15,000 yuan/month

7. Shanghai Hanbo Water Treatment Engineering Co., Ltd.

Address: No.159 Shenguang Road, xinqiao town, Songjiang District.

Electrician and Electrical Engineer /1 person

Requirements:

1, mechanical and electrical integration major

2. Hold a valid electrician certificate, and a low-voltage electrician certificate is preferred.

3, familiar with industrial electrical wiring/wiring/electrical control cabinet /plc installation and debugging, familiar with safety specifications and operating specifications.

4. plc programming is preferred.

4. Be able to work independently according to the drawings, bear hardships and stand hard work, and be actively responsible.

Salary: 4,000-8,000 yuan/month

8. Shanghai Hong Sheng Culture Media Co., Ltd.

Enterprise address: No.655, Gaoji Road, Sijing Town, Songjiang District

Online shop customer service /1 person

Requirements:

1, the typing speed is faster

2, have good communication skills and ability to work under pressure.

Salary: 5000-6000 yuan/month

Operation Assistant /4 persons

Requirements:

1. Be kind and have good communication skills.

2. Strong ability to accept new things

Salary: 5000-8000 yuan/month

Shanghai Huamei Elevator Decoration Co., Ltd.

Enterprise Address: No.6588 Yexin Highway, Maogang Town, Songjiang District

Finance Assistant /1 person

Requirements:

1, finance/accounting/economics and other related majors, college degree or above.

2, have more than 1 year working experience in accounting, familiar with the golden tax system.

3. Have a good accounting professional foundation.

4, careful, have the ability to work and study independently, as well as strong communication skills, understanding and analytical skills.

5. Have good professional ethics, teamwork spirit and sense of responsibility.

Salary: 3000-4000 yuan/month

Sales staff /5 people

Requirements:

1. Be able to work independently in sales, have certain knowledge of sales theory and master certain negotiation skills.

2. Have certain interpersonal and communication skills, as well as strong adaptability and learning ability.

3, have strong ability to withstand pressure, can adapt to travel or resident in other provinces and cities.

Salary: salary is negotiable.

X. Shanghai Huaming Intelligent Terminal Equipment Co., Ltd.

Enterprise Address: North of Shihui Road, Rongbei Industrial Zone, Songjiang District

Hardware Support Engineer /3 persons

Requirements:

1. Major in electronic engineering, bachelor degree.

2. Understand the system structure of 51 series mcu/arm7 processor.

3. Hardware schematic diagram and pcb schematic diagram can be analyzed independently or under the guidance of others.

4. You can debug the hardware independently or under the guidance of others.

5. The module interface and system configuration scheme can be written independently or under the guidance of others.

6, master office software.

7, understand the automatic fare collection equipment electrical design/electromechanical module control circuit design/firmware development.

Salary: 7000-8000 yuan/month

C++ Development Engineer /3 persons

Requirements:

1. Experience in linux system development, and experience in linux driver development is preferred.

2. Experience in network communication, process control and task scheduling software development.

3, familiar with embedded C language development

4. Proficient in c/c++ software programming/familiar with data structures and algorithms.

6. Familiar with qt development, with relevant foundation is preferred.

Salary: 7000-8000 yuan/month

Test Engineer /3 people

Requirements:

1. Major in computer/software, college degree or above.

2. Be familiar with the installation/tuning of common databases and the writing of sql statements.

3. Have a certain understanding of linux operating system and can use basic operating commands.

4. Have experience in software testing and be familiar with white box/black box functional testing methods.

5. Have experience in performance testing and understand the use of performance testing tools.

6. Have a good understanding of version baseline planning/defect management and be familiar with code management tools such as git/svn.

7. Familiar with software project support process, able to communicate well with R&D/project implementers, and be able to systematically explain and train software product functions.

8. Familiar with relevant processes of fmeca, and being able to write such documents independently is preferred.

Salary: 7000-8000 yuan/month

Xi. Shanghai Jiaheng Daily Chemicals Co., Ltd.

Enterprise address: No.1069, Taogan Road, sheshan town, Songjiang District.

Mechanical Engineer /1 person

Requirements:

1, mechanical and other related majors, bachelor degree.

2, familiar with cad/solidworks software operation.

Salary: 6000-10000 yuan/month

Packaging reserve cadre /1 person

Requirements:

1. Major in packaging engineering/packaging design, bachelor degree or above.

2, cheerful personality, good English

Salary: 6000-10000 yuan/month

Microbiologist /2 people

Requirements:

1, chemistry and other related majors, bachelor degree or above.

2, like to do testing, hard-working.

Salary: 6000-10000 yuan/month

Physical and chemical experimenter /2 people

Requirements:

1, chemistry and other related majors, bachelor degree or above.

2, like to do testing, hard-working.

Salary: 6000-10000 yuan/month

R&D reserve cadres /2 persons

Requirements:

1. Major in Fine Chemical Engineering/Chemical Technology and Engineering, bachelor degree or above.

2, cheerful personality, good at communication and strong learning ability.

Salary: 6000-10000 yuan/month

Shanghai Jiaqiang Automation Technology Co., Ltd.

Enterprise address: No.8 Dongbao Road, Songjiang District

Mechanical Engineer /2 persons

Requirements:

1. Major in mechanical engineering and automation, bachelor degree or above.

2. Experience in precision product structure design, and experience in medical/instrument/optical equipment development is preferred.

3. Skillfully use solidworks for product design.

4, can use a software for statics check/motion simulation, familiar with motor selection/load inertia check.

Salary: 6000-12000 yuan/month

Secretary to the General Manager /1 person

Requirements:

1. Bachelor degree or above, major in secretarial science is preferred.

2. Excellent English, good oral communication skills and written letter writing skills are preferred.

3, have good data analysis ability, skilled use of all kinds of office software.

4. Good communication skills and language skills.

5. Have a strong sense of responsibility, confidentiality and teamwork spirit.

6, meticulous work, high stability, strong enthusiasm, strong pressure resistance and good time management ability.

Salary: 6000-8000 yuan/month

Product sales engineer /2 persons

Requirements:

1. Bachelor degree or above, major in machinery/automation/optoelectronics is preferred.

2. Excellent English is preferred.

3, love the sales industry, articulate, hard-working, positive, strong communication skills and teamwork spirit.

Salary: 6000-10000 yuan/month

Product application engineer /2 persons

Requirements:

1. College degree or above, major in CNC/automation/mechatronics is preferred.

2. More than 1 year experience in electrical or machine tool debugging is preferred.

3, maintenance electrician above intermediate level is preferred.

4, master the principle of electrical control, skilled use of autocad/eplan and other software is preferred.

5, have strong hands-on ability and problem analysis ability, timely feedback on-site problems and analysis process.

6. Active thinking, good communication skills, teamwork spirit and initiative.

7, hard-working, practical and willing to work, obey the company’s work arrangements, accept business trips.

Salary: 6000-7000 yuan/month

Plc electrical engineer /1 person

Requirements:

1. Bachelor degree or above, major in CNC/automation/mechatronics is preferred.

2. Experience in laser cutting/welding/robot application is preferred.

3, master the principle of electrical control, skilled use of autocad/eplan and other software is preferred.

4, master at least two kinds of servo driver debugging methods and problem diagnosis ideas.

5, master plc programming and debugging.

6, have strong hands-on ability and problem analysis ability, timely feedback on-site problems and analysis process.

7. Active thinking, good communication skills, teamwork spirit and enterprising spirit.

8, hard-working, practical and willing to work, obey the company’s work arrangements, accept business trips.

Salary: 6000-8000 yuan/month

Linux software development engineer /1 person

Requirements:

1, computer/electronic information and other related majors, bachelor degree or above, can accept fresh graduates and interns.

2. Proficient in c/c++ development under linux environment and familiar with multi-thread/multi-process/network communication.

3. Familiar with common scripting languages such as python/shell/makefile.

4. Proficient in c/c++, deeply understand and implement the language characteristics of c/c++, and can accurately obtain debugging information.

5. Have strong learning ability, execution ability, ability to analyze and solve problems, be good at thinking and be diligent in studying.

6. Good communication skills and teamwork spirit.

Salary: 6000-8000 yuan/month

Xiii. Shanghai Jiaoke Zhongchuang Space Management Co., Ltd.

Enterprise Address: No.351 Sizhuan Road, Songjiang District

Marketing Specialist /1 person

Requirements:

1. Major in marketing, college degree or above.

2, have more than 1 year working experience in the same position.

3. Understand the marketing service platform of Weimeng, and be able to integrate different resources to carry out marketing work.

4. Outgoing personality, strong observation/analysis/planning/organization/coordination/communication and negotiation ability and strong market development ability.

Salary: 6000-8000 yuan/month

Investment Promotion Specialist /5 persons

Requirements:

1. College degree or above.

2. Familiar with business development/business reception/business lease negotiation and other work processes is preferred.

3. Excellent customer service awareness, strong business development ability and interpersonal communication skills.

4. Obey the arrangement of superiors, have strong execution, and be good at thinking, summarizing and communicating.

5, love sales, self-confidence, perseverance, clear goals, hard work.

Salary: 5000-10000 yuan/month

Xiv. Shanghai hot wheels Transmission Technology Co., Ltd.

Enterprise address: No.406, 3rd floor, Petrochemical Shopping Mall, Jinshan District.

Sales Assistant /3 persons

Requirements:

1, technical secondary school degree or above, can recruit fresh graduates.

2. Skilled in operating office software such as excel/word.

3. Have a strong sense of customer service, and good communication skills and adaptability.

Salary: 4,000-6,000 yuan/month

Channel sales /3 people

Requirements:

1, technical secondary school degree or above, can recruit fresh graduates.

2, hard-working, strong sense of responsibility, communication skills and teamwork spirit.

Salary: 4,000-7,000 yuan/month

Shanghai Fuhong Hanlin Biotechnology Co., Ltd.

Enterprise address: No.1999, Zhangheng Road, Pilot Free Trade Zone

Biochemical Analyst (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1. Major in biology/pharmacy, bachelor degree or above.

2, familiar with the use of cell culture/microplate/cell counter/microscope and other instruments.

3, master the basic computer skills.

4. Have a certain English foundation.

5, hard-working, earnest and practical, with good teamwork spirit.

Salary: salary is negotiable.

Raw materials analyst (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1. Major in medicine/analysis, bachelor degree or above.

2. Understand gmp specifications or have relevant experience in pharmaceutical enterprises.

3. Master the operation skills of detecting basic raw materials such as infrared/ultraviolet/titration test, and gas detection is preferred.

4, understand or master the related operation of raw materials testing and instrument operation, and can independently analyze and solve problems.

5. Have a good team spirit.

Salary: salary is negotiable.

Physical and Chemical Instrument Analyst (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1, pharmacy or related major, bachelor degree or above.

2. Internship/working experience in gmp pharmaceutical factory or similar experience is preferred.

3. CET4 or above.

4, master the basic knowledge of analysis and drug testing, understand the instrument or physical and chemical analysis operation.

5, understand the analysis method verification requirements, can independently verify.

6. Aggressive, upright and rigorous, with strong sense of responsibility, pressure resistance, communication skills and teamwork spirit.

Salary: salary is negotiable.

Microbiological Analyst (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1. Major in biology/pharmacy/analytical chemistry, bachelor degree or above.

2. Have basic experience in microbial aseptic operation.

3. Understand the gmp standard of drugs or have relevant experience in pharmaceutical enterprises.

4, understand or master the related operation of raw materials testing and instruments, and can independently analyze and solve problems.

5. Good teamwork and communication skills.

Salary: salary is negotiable.

Production Support Engineer (Songjiang, Shanghai) /1 person

Requirements:

1. Major in biology/pharmacy/biochemistry/biotechnology, master degree or above.

2. More than 1 year relevant experience is preferred, and fresh graduates can be accepted.

3. Master the basic knowledge of biological/pharmaceutical principles, and have a certain understanding of the characteristics and research and development process of monoclonal antibody products is preferred.

4. Be able to participate in gmp production and small-scale laboratory experiments.

5. Have basic computer operation ability.

6. Have certain English reading and writing skills.

7. Strong communication and logic skills, able to deal with complicated technical compliance issues.

Salary: salary is negotiable.

Pilot preparation technician (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1, biochemistry/pharmaceutical engineering/biochemistry and other related majors, bachelor degree or above, can accept fresh graduates.

2. Master gmp-related professional knowledge and have aseptic operation concept and experience.

3. Have certain English reading and writing skills and be familiar with simple technical terms.

4, skilled use of office computer software

5. Have a good sense of responsibility, teamwork spirit and communication skills.

Salary: salary is negotiable.

Pilot Purification Technician (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1, biochemistry/pharmaceutical engineering/biochemistry and other related majors, bachelor degree or above, can accept fresh graduates.

2. Experience in chromatography/filtration/downstream purification/disposable product operation is preferred.

3, gmp related professional background.

4. Have certain English reading and writing skills and be familiar with simple technical terms.

5, skilled use of office computer software

6. Have a good sense of responsibility, teamwork spirit and communication skills.

Salary: salary is negotiable.

Pilot cell culture technician (Shanghai Xuhui, Songjiang) /1 person

Requirements:

1. Major in biochemistry/pharmaceutical engineering/biochemistry, bachelor degree or above.

2. Experience in cell culture operation is preferred.

3. Master gmp-related professional knowledge and have aseptic operation concept and experience.

4. Have certain English reading and writing skills and be familiar with simple technical terms.

5, skilled use of office computer software

6. Have a good sense of responsibility, teamwork spirit and communication skills.

Salary: salary is negotiable.

Preparation Technician (Shanghai Songjiang) /1 person

Requirements:

1. Major in biochemistry/pharmaceutical engineering/biochemistry, bachelor degree or above.

2. Have a certain knowledge and understanding of pharmaceutical production process and gmp production.

3. CET-4, with good English writing ability.

4. Strong logical thinking ability and communication and coordination ability.

5. Aggressive, with strong sense of responsibility and pressure resistance.

Salary: salary is negotiable.

Purification Technician (Shanghai Songjiang) /1 person

Requirements:

1. Major in biochemistry/pharmaceutical engineering/biochemistry, bachelor degree or above.

2. Have a certain knowledge and understanding of pharmaceutical production process and gmp production.

3. CET-4, with good English writing ability.

4. Strong logical thinking ability and communication and coordination ability.

5. Aggressive, with strong sense of responsibility and pressure resistance.

Salary: salary is negotiable.

Cell Culture Technician (Shanghai Songjiang) /1 person

Requirements:

1. Major in biochemistry/pharmaceutical engineering/biochemistry, bachelor degree or above.

2. Have a certain knowledge and understanding of pharmaceutical production process and gmp production.

3. CET-4, with good English writing ability.

4. Strong logical thinking ability and communication and coordination ability.

5. Aggressive, with strong sense of responsibility and pressure resistance.

Salary: salary is negotiable.

Correspondent: Song Renbao

Editor: Zhou Zhenghao

ShangguanNo. Author: Shanghai Songjiang

1905 movie network news On July 2nd, happy heroes’s latest big movie held the 12th birthday party of happy heroes League in Guangzhou. Not only did the big movie "Superman Energy FUN Summer" make its grand debut in South China, but also "old friends" Pleasant Goat and Big Big Big Wolf parachuted into the air to celebrate the birthday of happy heroes League, which has been with the audience for 12 years. The climax of the event was full of surprises, and many viewers expressed that they were "very moved and happy, thanks to happy heroes’s company all the way". It is reported that the film will be officially released nationwide on July 22.

Pleasant Goat and Big Big Wolf Dance Happy. The cosmic support club can break the wall and send blessings.

The 12th birthday party of the happy heroes League held this time can be described as climax after climax. In the interactive session after the screening, the director made a joint appearance with five birthday protagonists of the happy heroes League, sharing the production process, and evoking a "memory killing". Among them, Careless. S’s dubbing actors and grotesque dubbing actors came to the scene and interacted with the audience by dubbing the characters in the film, which caused constant screaming at the scene. During the activity, Pleasant Goat and Big Big Wolf parachuted in as surprise guests. In order to send special birthday wishes to the happy heroes League, they danced with the children on the scene along with the theme song "Happy Fly Forward", which pushed the atmosphere to a climax.

In addition, the live broadcast of the special blessing is also eye-catching. Not only Pleasant Goat, Lazy Goat, Big Wolf, Mikey and Le Di, but also a group of members of "happy heroes Cosmic Support Association" brought super blessings to break the dimensional wall, which doubled the blessings and happiness for the 12-year-old happy heroes League. The happy atmosphere infected everyone at the scene.

　

Zu Qing and Gao Shengsheng changed their voices for one second, and the Superman League did not change its mind for twelve years.

It is worth mentioning that "Careless. S" Zuqing and "Grotesque" Gao Quansheng also staged a dubbing film clip "Highlighting Moment", which made the birthday party "live" and won cheers from friends of all sizes. Since then, the two of them have shown their "stunts" on the spot. Zu Qing changed freely from Pleasant Goat to Careless. S, and Gao Quansheng also changed the voice of Slow Goat into a big freak, and jointly sent blessings to the 12th anniversary of the happy heroes League. The audience present were all shocked and applauded, and some people even expressed their heartfelt feelings that "as expected, seiyuu are monsters".

In addition to the happy atmosphere created at the birthday party, the audience also responded enthusiastically to the big movie they watched. Many of the audience who participated in the birthday party were "old friends" of the happy heroes League, and they had a deep bond with happy heroes. Many people felt after watching the movie that "five little Superman have been with us for 12 years unconsciously" and "my childhood has always been there, and happy heroes has guarded my dreams". The children at the scene were immersed in happy heroes’s world while watching the movie, and after watching the movie, they scrambled to share the interesting scenes in the movie, lining up five Superman, hoping to have their super powers. The accompanying parents also said that "this film is very worth taking children to watch. The five Superman represent different excellent characters, and the unity shown by the super people is very educational." The positive significance of "being a superman without superpowers" shown in the film can bring infinite energy to the audience in the face of difficulties.

What xiaobian wants to introduce to you today is. As for its advantages, please read on.

Let’s look at the appearance of Fengyun T9 first. Fengyun T9′ s front face is fierce and looks more dynamic. Coupled with the headlights, the visual effect is not bad. The car is equipped with LED daytime running lights, automatic opening and closing, adaptive far and near light, delayed closing and so on. Coming to the side of the car body, the size of the car body is 4795 mm * 1930 mm * 1741 mm. The car adopts stable and atmospheric lines, which gives people a very fashionable and dynamic feeling. With large-sized thick-walled tires, the overall visual effect is very comfortable. In the rear part, the rear looks dignified, and the taillights are very round and neat.

Sitting in the car, the interior looks very clean and refreshing, which meets the aesthetic standards of young people. The steering wheel of this car is very personalized in shape, made of genuine leather, and feels good. Take a look at the central control, the car is equipped with a touch-sensitive LCD central control screen, which makes the interior design quite layered, and the details are still in place. The dashboard and the seat are equally eye-catching. The dashboard of the car presents a tough design style and looks very sharp. The car uses leather seats, equipped with auxiliary seat electric adjustment, seat with memory electric adjustment, seat proportion down and other functions, with exquisite materials and comfortable ride.

In terms of functional configuration, Fengyun T9 is equipped with car networking, driving mode selection, remote control key, Bluetooth key, rear wiper, interior atmosphere light and other configurations.

OK！ Next, let’s sum up. The car introduced today is not only eye-catching in space, but also has reached the mainstream level in various configurations, and there is nothing to be picky about driving experience and space experience.