In the economic field, debt economy is a common and complicated economic model. Simply put, debt economy is to obtain funds by borrowing and issuing bonds to promote economic development. This economic model is very common in the modern economic system, and many countries, enterprises and even individuals will use this method to meet their own capital needs.

At the national level, the government may issue treasury bonds to raise funds for infrastructure construction and social welfare. For example, some countries will build highways, railways and other transportation facilities on a large scale, and these projects need a lot of capital investment. The government will attract investors to buy them by issuing government bonds, thus obtaining funds to support the development of the projects. For enterprises, in order to expand production scale and carry out technological innovation, they will also borrow money from banks or issue corporate bonds. Like some emerging science and technology enterprises, in the process of developing new products, they need a lot of money for scientific research investment and equipment purchase, so they will choose debt financing to solve the funding problem.

Triangular debt is a special and thorny phenomenon in debt economy. Triangular debt refers to the debt chain formed by mutual arrears of payment between enterprises. In this case, enterprise A owes money to enterprise B, enterprise B owes money to enterprise C, and enterprise C may owe money to enterprise A, forming a complex debt cycle.

The influence of triangular debt is various. For enterprises, it will seriously affect the capital turnover of enterprises. When an enterprise’s payment is in arrears by other enterprises, its own funds cannot be withdrawn in time, which leads to the enterprise’s failure to pay the payment of raw material suppliers and the wages of employees on time, thus affecting the normal production and operation of the enterprise. In the long run, it may also lead to the reduction of the production scale of enterprises and even face the risk of bankruptcy.

From the macro-economic perspective, triangular debt will affect the operational efficiency of the whole economy. A large number of enterprises fall into the dilemma of triangular debt, which will make the capital flow in the market not smooth and hinder the rational allocation of resources. Debt disputes between enterprises may also trigger a series of legal proceedings and increase the transaction cost of society.

In order to understand the debt economy and triangular debt more intuitively, the following table is used for comparison:

In short, debt economy and triangular debt are both important issues that need to be paid attention to in economic operation. Correctly understanding and handling them is of great significance for maintaining economic stability and healthy development.

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foreword　 　

At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT). Chimeric antigen receptor (CAR) and engineered T cell receptor (TCR) are the main adoptive T cell immunotherapy in recent years. TCR engineering T cells express tumor antigen-specific receptors, and their α chains and β chains are produced by high-quality and high-affinity antigen-specific T cell clones.

TCR molecule belongs to a superfamily of immunoglobulin, which consists of two covalently bound polymorphic subunits, each of which is antigen-specific, and they are related to at least four different types of signal transduction chains. In order to activate T cells, there must be interaction between TCR and MHC.

The interaction between TCRs and pMHC(peptide-MHC) determines the fate of immature thymocytes, which is very important for the survival of naive T cells. Therefore, TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells. TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize tumor-specific antigens on the surface. This makes TCR-T cells more effective in tumor treatment.

At present, some new technologies and tools are being applied to TCR-T, which is helpful to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.

　 Comparison between CAR-T and TCR-T

In ACT therapy, TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CAR contains single chain antibody targeting tumor antigen, transmembrane domain and intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and CAR can bind untreated tumor surface antigens without MHC treatment.

The first generation of CAR-T cells showed limited expansion and relatively short persistence, and the "second generation" CAR-T added costimulatory receptors CD28, 4-1BB/CD137 and OX40. These costimulatory receptors are added to the CD3ζ domain of CAR-T cells, thus promoting a more powerful and lasting T cell response. The third generation CARs combines two co-stimulatory signals (CD28 and 4-1BB) at the same time, which has better amplification and longer persistence than the second generation CARs.

On the contrary, TCR is an α/β heterodimer that binds to MHC antigen complex. Compared with TCR, CARs has some disadvantages in identifying tumor antigens, such as extratumoral toxicity. Compared with CARs, TCRs has some structural advantages in T cell-based therapy, such as more subunits (10: 1) in its receptor structure, more tyrosine-based activation motifs (ITAMs) in immune receptors (10: 3), less dependence on antigens (1: 100), and more costimulatory receptors (CD3, CD4, CD28, etc.). TCR with a low MHC affinity range (104-106M-1) can effectively activate T cells, whereas CARs needs a higher affinity range (106-109M-1).

Therefore, CAR-mediated cytotoxicity depends on higher density of cell surface antigens. In addition, T-cell/antigen interaction IS initiated in the structure of immune synapse (IS), in which TCR presents an annular region with peripheral LFA-1 adhesion, while CAR presents a diffuse LFA-1 distribution without annular region. Therefore, TCR-IS is slower but lasts longer than CAR-IS. At the same time, CAR-T cells show faster killing function and migrate to the next tumor target (serial killing), which is in sharp contrast to TCR-T cells’ prolonged signal transduction and killing time.

Recombination TCRs 　

TCR is one of the most complex receptors in human body. It contains six different receptor subunits, which have a very wide range of functions in T cells. The change of TCR of tumor infiltrating lymphocytes (TILs) significantly affects tumor-specific T cells. Among them, the change of TCR is helpful to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.

TCR engineering of TIL is one of the best treatment methods for tumors. TCR consists of α chain and β chain bound to peptide -MHC ligand, signal subunits (,γ and δ) of CD3 complex and CD3ζ homodimer. Except CD3ζ, all subunits have extracellular immunoglobulin (Ig) domain. Based on these structures, new technologies using engineering TCR include ImmTAC, TRuCs and TAC.

Immune mobilization monoclonal t cell receptor (ImmTAC)

ImmTACs is designed using engineered, soluble and affinity-enhanced monoclonal TCRs(mTCRs). ImmTACs is basically a fusion protein, which combines the engineering TCR targeting system and single chain antibody fragment (scFv) effector function. In the construction of ImmTACs, TCR can recognize peptides from intracellular targets presented by human leukocyte antigen (HLA).

ImmTAC specifically targets HLA- peptide complexes on the surface of tumor cells, and promotes T cell-mediated effector function through the interaction between scFv antibody fragments and CD3. ImmTAC also activates CD8+T cells in a dose-dependent manner, and can effectively redirect and activate CD8+ and CD4+ cells. ImmTAC shows multifunctional reaction by secreting various cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β and IFN-γ inducible protein 10.

In addition, selecting the appropriate target antigen is the key to ImmTACs, and mass spectrometry and MHC polymer technology are helpful to identify the appropriate antigen. It is worth noting that TCR engineered T cells also show unexpected targeted toxicity. Generally speaking, ImmTACs has been proved to enhance the anti-tumor response of TCR-T cells, but its safety needs further study.

T cell receptor fusion structure

T cell receptor fusion structure (TRuCs), an antibody binding domain fused with T cell receptor subunits, is designed to effectively recognize tumor surface antigens. TRuCs is composed of specific antibodies targeting tumor-associated antigens fused to the extracellular N- terminal of five TCR subunits (TCRα, TCRβ, CD3, CD3γ and CD3δ), which provides new targeting specificity and HLA-independent target cell clearance for engineered T cells and can be activated by corresponding target cells.

Compared with the second generation of CAR-T cells, this method shows better anti-tumor effect. In addition, TRuCs dominates all the signal mechanisms of TCR complex, while CARs only uses the limited signal of the isolated intracellular segment of CD3ζ.

T cell antigen coupling agent (TAC)

T cell antigen coupling agent is another engineered TCR cell, which can induce more effective anti-tumor response and reduce toxicity in an MHC-independent way. TAC chimeric protein can form TCR/CD3 complex and get more T cell responses by binding to CD3 domain.

The activity of TAC receptor is closely related to the selection of CD3 binding domain. For example, a single chain antibody from OKT3(muromonab-CD3) has lower cytokine production and cytotoxicity compared with UCHT1, which may lead to substantially different functional results. Compared with the second generation of CARs, T cells engineered with TAC gene are not only beneficial to the greater infiltration in solid tumors after adoption, but also reduce the expansion and extratumoral toxicity of T cells in healthy tissues expressing antigens.

Workflow of TCR-T cell therapy 　

In order to isolate therapeutic TCR, antigen-specific T cells must be isolated from the blood of patients or healthy blood donors and amplified in vitro with specific peptide antigens and cytokines (such as IL-2 and IL-15). This process needs to determine the specific tumor-related peptide targets that can be safely targeted to patients in advance. After selecting the target antigen, different methods can be used to screen TCR with the required high affinity and tumor specificity. Pre-clinical safety testing is also necessary to ensure the minimum off-target effect and cross-reactivity of isolated high affinity TCR. Viral vectors are usually used to genetically modify autologous patient T cells to express the proven therapeutic TCR, and then transfuse it back into patients.

Determine the target antigen

Melanoma antigen 1(MART-1) recognized by T cells is the first tumor-related antigen targeted in TCR-T clinical trials. After this breakthrough, TCR-T therapies for various tumor antigens have been developed, including TCR-T therapies for MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1 and viral peptides derived from HPV and EBV. Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and it has achieved success in the treatment of synovial sarcoma, with an objective effective rate of 67%.

The ideal TCR-T target antigen shows the following characteristics: (1) the ability to induce immune response; (2) It is related to driving tumor phenotype (such as oncogene) to reduce the risk of antigen loss and tumor immune escape; And (3) expression on tumor stem cells to promote permanent tumor eradication.

Identification method of tumor-associated antigen

High-resolution mass spectrometry (MS) has been proved to be the most powerful Qualcomm method to promote the direct identification of HLA-I binding peptides from tumor cells. In this method, HLA-I/ peptide complexes are separated from tumor tissues or cell lines by immunoprecipitation (IP), and then the binding peptide antigens are separated from HLA-I molecules and antibodies for IP by fully washing and applying acidic elution buffer. This strategy allows each tumor sample to identify thousands of validated peptide targets, and has been used to identify HLA-I ligands of glioblastoma (GB), melanoma, renal cell carcinoma (RCC) and colorectal cancer (CRC).

Identification method of new tumor antigen

Although MS-based technology can be used to identify new antigens, it is more difficult to identify them, especially for tumor samples with limited size, because of their relatively low abundance and limited sensitivity of MS. However, the development of new generation sequencing technology is helpful to identify and locate such tumor targets. All-exon DNA sequencing, combined with computational prediction algorithm, allows to identify specific genetic changes in cancer cells, which can produce mutant peptides and present them on tumor HLA-I molecules.

All somatic mutant genes can be analyzed by computer to predict the potential high affinity epitopes that may bind to HLA-I molecules of patients, so as to be recognized by T cells. With the use of large MS elution peptide database, HLA-I peptide binding prediction algorithm is constantly updated and improved, and other prediction algorithms try to consider biological variables related to the complexity of intracellular processes.

Another commonly used method is tumor RNA sequencing, which allows the selection of new antigens with the highest transcriptional expression. It is worth noting that although these prediction methods usually show very good accuracy in identifying presented and highly immunogenic new antigens, the number of new antigen targets they usually predict is 1 to 2 orders of magnitude higher than the actual number of real targets.

Discovering new antigens by trogocytosis is a new method in recent years. Trogocytosis is a biological phenomenon in the process of cell combination, in which cells share and transfer membrane and membrane-related proteins. Li et al. found that T cell membrane proteins were specifically transferred to tumor target cells, which presented homologous HLA-I/ peptide complexes. Using these T cell-target cell interactions, they created a new antigen discovery system by incubating T cells expressing orphan TCR with homologous target cells. By transferring fluorescent markers from T cells to target cells, this method can isolate these target cells and sequence homologous TCR ligands, thus establishing a new antigen library.

Isolation of tumor-specific T cells and TCR

Using HLA-I polymer, single cell TCR sequencing or antigen-negative humanized mice, tumor-reactive T cells and TCR can be identified from autologous, allogeneic or xenogeneic cell banks.

Using HLA-I multimer method, antigen-specific CD8+T cells can be directly separated by multimer staining and flow cytometry. Before isolating the paired full-length TCR sequences, these polyclonal T cells were tested for homologous peptide recognition and anti-tumor function. TCR with high affinity and specificity can be obtained by using a highly sensitive PCR-based single cell TCR analysis method (TCR-SCAN).

Another method uses humanized mouse TCR gene bank, which will not cause T cell clone deletion or tolerance in humans. Therefore, Li et al. used the whole human TCRα/β gene locus and chimeric HLA-A2 transgene to construct transgenic mice to isolate human TCR against human TAA.

Single cell sequencing method represents a more promising method to isolate tumor-specific TCR coding genes by Qualcomm method. Using RNA bait libraries targeting each individual V and J element in TCRα and TCRβ loci, TCR coding genomic elements can be selectively isolated from excised genomic DNA(gDNA) fragments for subsequent paired terminal deep sequencing. This makes it possible to identify antigen-specific TCR from human materials or oligoclonal T cell populations of TCR humanized mice.

Infantile T cells can also be used as TCR sources for TCR-T therapy. TAA and new antigen-specific T cells can be derived and amplified from low-frequency precursors in peripheral blood of cancer patients, and can be reinfused or used as the source of antigen-specific TCR. Because cancer patients usually show immunosuppression or dominant T cell tolerance, the original sequence of HLA-I matched healthy donors also represents a reliable source, because it has a huge diversity of TCR sequences, and theoretically T cells have any antigen specificity, including new tumor antigens. A Qualcomm-quantity technology platform has been developed to find the original sequence, so as to quickly and effectively identify the rare but valuable TCR for personalized adoptive T cell therapy.

Cloning of TCR

Most TCR-based gene therapy methods rely on in vitro transduction of T cells with viral vectors, and adenovirus is the earliest vector used for gene therapy. However, due to their inability to integrate transgenes into the host genome, TCR expression will be lost during T cell proliferation. In addition, the immune genetic characteristics of adenovirus also limit its application as a gene therapy vector. In contrast, retroviruses show greater prospects as gene transfer vectors, because they can infect a variety of cells and have the ability to insert transgenes into the host genome, thus making the ectopic TCRα/β chain stably expressed.

Retroviral vectors derived from γ -retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This method has been used to transfer various genes, including suicide gene, TCR and CARs. The main disadvantage is that they cannot transduce non-proliferative target cells, which excludes the application of resting T cells in TCR-T therapy. In addition, retrovirus insertion mutation may cause potential side effects.

Recently, lentiviral vectors (LV) have attracted more attention as gene transfer vectors, because they can transfer genes into mitotic and non-splinter cell. Various techniques, such as Golden Gate cloning and LR cloning, are usually used to construct a vector for inserting TCRα/β gene.

Adeno-associated virus (AAV) is another widely used virus vector. Compared with adenovirus vector, AAV has lower immunogenicity and wider cell tropism, so it has been widely used in tumor gene therapy. In order to promote the integration of transgenes, people have developed self-complementary AAV vector (scAAV) to make AAV independent of the complementary strand synthesis of host cells. scAAV is more effective than traditional AAV in preclinical model.

At the same time, some non-viral gene editing methods have also been developed. MRNA electroporation has been proved to achieve transient expression of TCR and CAR, thus minimizing the risk of persistent virus components. Clinical data show that both TCR-T and CAR T cells modified by mRNA are feasible and safe, and there is no obvious evidence that they have non-targeted toxicity to normal tissues. However, the lack of continuous TCR expression may limit the curative effect and require repeated infusion. In addition, the non-viral sleeping beauty retrotransposon system is also used for the transduction of TCR and CARs.

Gene editing can insert large gene fragments into target cells specifically and efficiently through homologous directional repair (HDR). TCR-T cells developed by CRISPR/CAS9 have been proved to specifically recognize tumor antigens in vitro and induce a productive anti-tumor response in vivo.

Verification method of TCR

After TCR cloning, extensive preclinical verification is needed to prove the specificity and safety of engineered TCR-T cells. Verification includes evaluating the affinity of TCR by titration of homologous peptide antigens and measuring the killing effect of a group of HLA-I matched tumor cell lines. If there is no such tumor cell line, the target cells can transductively express related antigens and related HLA-I molecules. The new antigen can also be expressed in autologous antigen presenting cells to evaluate the antigen reactivity of TCR.

The safety test includes testing the ability of candidate TCR-T to identify HLA-I matching primary tissues, so as to ensure that there is no normal tissue as the target, which may lead to non-targeted toxicity. In at least two clinical trials of TCR-T cell therapy, there was a cross reaction between normal brain cells and heart cells, which led to the death of patients. These test results emphasize the importance of extensive safety tests before TCR enters clinical trials.

Safety of TCR-T 　

The ACT of TCR-T cells showed high tumor killing, but some serious adverse events also appeared in some clinical studies. It is very important to optimize TCR affinity in engineered T cells, and receptor affinity can determine the safety and effectiveness of T cell therapy. In terms of curative effect, affinity TCR interaction is enough to activate T cells, but strong affinity is needed to maintain the expansion of T cells.

In phase I/II ACT clinical trials, engineered T cells with low affinity show safer characteristics, but their anti-tumor response is weak. By identifying the TCR-pMHC interaction of T cells, engineered T cells can be divided into high affinity type and low affinity type. In addition, some technologies have been developed to improve the safety of TCR-T.

The safety switch mechanism based on engineered T cells is an attractive strategy. Thymidine kinase gene from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.

Although HSV-TK shows safety in cell-based immunotherapy, it is necessary to introduce phosphorylated nucleoside analogues. Another safer induced T cell safety switch is called inducible caspase-9(iC9). IC9 is a modified human FK binding protein, which can be activated by a small molecule compound AP1903, and this process depends on the mitochondrial apoptosis pathway.

The immunogenicity of iC9 suicide gene is low, and the immune response to transgenic cells is reduced. IC9-based safety switch has been proved to be more potential for cell therapy than previous suicide genes.

Clinical status of TCR-T cell therapy 　

As of August 9, 2021, there are 175 studies using TCR-T therapy in ClinicalTrials, 71 of which are specific TCR for specific TAA or new antigen, and 32 studies have been completed. NY-ESO-1 is the most common targeted antigen, which is expressed in many cancers, including myeloma and melanoma. Other tumor testis-associated antigens, such as PRAME and MAGE proteins, melanoma differentiation antigens MART-1 and gp100, and recent cancer drivers, such as WT1, KRAS and TP53, are also popular TCR-T targets.　 　 　 　 　 　 　 　 　 　 　

A total of 83 sponsors/collaborators initiated or participated in the research of TCR-T cell therapy, including the National Institutes of Health (NIH), government organizations, industries and universities/academic institutions. At present, the National Cancer Institute (NCI) has supported 53 TCR-T projects, accounting for 20% of all ongoing projects.

Among the 29 pharmaceutical companies developing TCR-T therapy, GlaxoSmithKline and Adaptimunime initiated the most clinical trials, with 11 and 7 respectively. Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV)-16 E7 protein in the treatment of metastatic human papillomavirus-related epithelial cancer was reported. In this study, 6 of the 12 patients who received treatment showed objective clinical response and observed steady tumor regression. This is a landmark clinical trial of TCR-T cell therapy, which proves that targeted virus antigen has good clinical effect on patients with virus-related cancer. Other viral antigens explored as TCR targets include HPV-E6 protein, antigens from Epstein-Barr virus (EBV) and human endogenous retrovirus (HERV) targets, such as Herv-E.

MART-1 and NY-ESO-1 TCR-T therapy targeting TAAs also showed clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer. The total effective rate (ORR) of TCR-T clinical trial is between 0 and 60%. It is worth noting that most of these TCR-T clinical trials only enrolled a small number of patients (2 to 25), so ORR may not be statistically accurate. Therefore, larger-scale phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.

Challenges and potential solutions of TCR-T cell therapy 　

Although immunotherapy based on TCR-T cells has shown certain clinical efficacy in most patients receiving treatment, it still faces many challenges in many fields. These challenges include: (1) Immunotoxicity caused by targeting normal tissues; (2) The expression of TCR in engineered T cells is insufficient or transient; (3)T cell exhaustion and dysfunction; (4) tumor immune escape, and (5) most cancer patients lack effective tumor-specific antigens as targets. Overcoming these challenges will be the key to greater clinical success in the future.　 　 　 　 　 　　

Discovery of new targets

At present, the target of peptide antigen for effective and safe immunotherapy of TCR-T is very limited. At present, most of the targets used are TAA. Although it is up-regulated in tumor tissues, it still maintains a low level of expression in normal tissues, which may lead to autoimmune toxicity. Therefore, the new antigen seems to be the safest target for TCR-T cancer treatment. However, the main challenges of developing new antigens in TCR-T clinic include: (1) the mutation of new antigens is individualized to a great extent, and there are differences among cancer patients, so it is difficult to develop widely used immunotherapy products; (2) The expression of new antigens in tumor tissues is often heterogeneous.

Nevertheless, recent reports have highlighted the emergence of new immunogenic antigens widely shared by tumor cells, including mutated KRAS and TP53. Many other studies have also demonstrated the immunogenicity of shared new antigens that can be used to generate potential therapeutic tumor-specific TCR. With the development of next generation sequencing technology, especially single cell DNA sequencing, transcriptome sequencing and mature in vitro verification methods, TCR-T immunotherapy targeting personalized new antigens may become a popular cancer treatment method in the next few years. In addition, the emerging TAA class, such as carcinoembryonic antigen, may also constitute a feasible target for the future development of TCR-T.

Maximize therapeutic TCR expression

The correct pairing of transgenic α and β chains is one of the main challenges that hinder the development of TCR-T cells. Since each transduced T cell includes two endogenous TCR chains and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences. Another related problem is that improper α/β chain TCR pairing will compete for CD3 complex, thus reducing the surface expression and signal transduction of therapeutic TCR.

There are several methods to properly pair the transduced TCR chains, including: (1) the constant region of partially murine TCR; (2) adding cysteine residues to promote the introduction of disulfide bonds in TCR chains; (3) changing the secondary structure of the constant region of endogenous TCR; (4) adding a signal domain to the intracellular part transduced with TCR; (5) Introducing TCR-α/β chain into substitute effector cells or constructing single-stranded TCR.

Methods to enhance the expression of therapeutic TCR include: (1) codon optimization of TCR-α and TCR-β chain transgene, and (2) changing the configuration of TCR-α/TCR-β vector to optimize expression.

Reduce adverse events

Usually, targeting non-tumor toxicity is the main key obstacle of TAA, and this risk urges researchers to study common new antigens more carefully. At present, several oncogene hot spot mutations are being studied as potential TCR targets, such as phosphoinositide -3- kinase (PI3K), KRAS and TP53. In addition, genetically engineered TCR-T cells with suicide genes are an important safety measure. Obviously, it is very important to develop reliable, identifiable, personalized, highly specific and immunogenic tumor antigen targets to reduce adverse events related to TCR-T cell therapy.

Graft-versus-host disease of allogeneic T cells

Using allogeneic T cells is a very promising scheme, which can overcome manufacturing problems, patient-related immune cell defects and treatment delays. In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced allogeneic reactive lymphocytes and rejection of engineered lymphocytes by host immune system.

The deletion of endogenous TCR gene, HLA-I locus or CD52 molecule is one of the strategies to avoid the failure of TCR-T transplantation, which can be achieved by many methods, such as gene editing or using siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.

　 summarize

In recent years, engineered T cells have shown excellent curative effect in the treatment of hematological tumors. TCR regulation is very important for T cell reactivation, immune response and its clinical effect on foreign antigens. TCR-T cells have incomparable advantages over CAR-T cells, and show great potential in preclinical and clinical research.

However, there are still several key challenges to improve the anti-tumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCR, how to identify the common tumor-specific antigen and TCR in the patient population, and how to regulate the expression of TCR and achieve the best function. The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.

References:

1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol.　2021; 12: 658753.

2. Evolution of CD8+　T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells.　2021 Sep; 10(9): 2379.

　　
The People’s Liberation Army (PLA) has accumulated rich operational experience after a year and a half of fighting, especially since it turned to a strategic offensive. Mao Zedong made a systematic and scientific summary of these experiences. From December 25th to 28th, 1947, the Central Committee of the Communist Party of China held an enlarged meeting in Yangjiagou, Mizhi County, northern Shaanxi, at which Mao Zedong made a report on "Current Situation and Our Tasks". In this report, the famous "Ten Military Principles" were put forward. The main contents are: fight scattered and isolated enemies first, and then fight concentrated and powerful enemies; Take small cities, medium-sized cities and vast villages first, and then take big cities; The main goal is to annihilate the enemy’s effective forces, not to preserve or seize cities and places; Concentrate absolute superior forces in each battle, surround the enemy on all sides, and strive to wipe out the enemy, so as not to escape the net; Don’t fight unprepared battles, don’t fight uncertain battles; Carry forward the style of fighting bravely, not afraid of sacrifice, not afraid of fatigue and continuous fighting; Strive to annihilate the enemy in the movement, while paying attention to position attack tactics; On the issue of siege, all enemy strongholds and cities with weak defenses are firmly seized, all enemy strongholds and city cameras with medium defenses are seized, and all enemy strongholds and cities with strong defenses are seized when conditions are ripe; Replenish ourselves by capturing all the enemy’s weapons and most of their personnel. The source of our army’s manpower and material resources is mainly at the front. Be good at using the gap between the two campaigns to rest and train troops.
The full text of the top ten military principles is 593 words. In incisive language, Mao Zedong made the strategic and tactical principles of the People’s Liberation Army clear, which is both easy to understand and easy to remember. It is completely different from his opponent Chiang Kai-shek’s long speech. In the later stage of strategic decisive battle and strategic pursuit, the People’s Liberation Army flexibly applied ten military principles, further enriched and developed this theoretical treasure, and finally relied on this treasure to completely defeat eight million Kuomintang troops.
From the sixteen-character formula to the ten military principles, it marks the improvement of the strategic and tactical theory of the people’s army, and marks that Mao Zedong’s military thought reached an unprecedented height during the War of Liberation. Therefore, it is not difficult for people to understand why Chiang Kai-shek, who was an excellent cadet studying in the Japanese military academy and the president of the Whampoa Military Academy, was finally defeated by Mao Zedong, who had never been to a military academy for a day. Batman, a British military expert, commented: "Mao Zedong is an era figure who holds all the keys to unlock the military mysteries of this era." (Xinhua News Agency)

Editor: Cao Jin

[Original of Truck House] Because pulling agricultural and sideline products can enjoy high-speed and free policy treatment, many card friends are also more willing to pull green links, but we should keep our eyes open about pulling green links.

Since it is a "green channel", there must be many restrictions. It is impossible for all agricultural products to take the green channel. Recently, card friends in Shaanxi have suffered in this respect.

Recently, when a netizen dragged Apple through Shaanxi Ankang Expressway toll station, the toll collector said that the card friend’s vehicle could not enjoy the green channel treatment. Although the load of the vehicle met the requirements of Lutong, the toll must be paid in full.

Here, many card friends are puzzled. Ran He is listed in the catalogue of fresh agricultural products. Why does Ankang toll collector decide that the car apple does not belong to Lutong? Is this apple kicked out of the catalogue of agricultural products by Ankang?

The toll collector said that it is true that apples are green products, but the apples on the car have rotted in a large area and do not meet the definition of "fresh".freshIs the first condition to take the green link.Since you don’t meet the requirements, why can you enjoy green treatment?

The staff of Shaanxi Traffic and Transportation Service Hotline responded to the incident, saying that there is no dispute that apples belong to Lutong products. According to the on-site toll collector’s inspection, the apples loaded on the vehicle are all rotten apples, commonly known as "falling fruit". Therefore, even if the load of the whole vehicle is within the standard range, the cargo occupies more than 80% of the car volume, but because the fruits on the vehicle are rotting in a large area and are very stale, it is compliant not to let Lutong go.

The staff of Shaanxi Expressway Baihe Management Office introduced that enjoying the green channel policy refers to fresh vegetables and fruits, and the staff checked the vehicles, and the loaded goods (apples) had obvious rot.It does not meet the requirements of "liveliness" stipulated in the document, so it is feasible not to give green channel treatment.

According to the spirit of the document "Notice on Further Optimizing the Green Passage Policy of Fresh Agricultural Products Transportation" issued by the three ministries and commissions, fresh agricultural products enjoying the "green passage" policy refer to fresh vegetables, fruits, fresh aquatic products, live livestock and poultry, fresh meat, eggs and milk. If it is found that it is mixed or counterfeit and does not meet the policy requirements, it needs to be handled according to the regulations.

That is to say, the toll collectors have the right to inspect the vehicles carrying Lutong. As long as the loaded goods do not meet the requirements and specifications in the Catalogue of Fresh Agricultural Products, or the bearing quality does not meet the minimum load requirements of the documents, they are not allowed to take the green channel and must pay the toll.

● 　Postscript

Not all green products are green links. There used to be pineapple, pineapple and cherry cherries, but now there are fresh and rotten ones. I wonder what card friends think about the fact that rotten fruits are not green links. You can make your voice heard in the comments section. (Text/Wei Qingbo Source/Shaanxi Expressway Baihe Management Office)

1111 Super Shopping Carnival Feast, reduced by 100 at 599, sent to Kajia jackets at 1800, and found more good goods at Kajia Mall: https://j.youzan.com/k9OEp8.

CCTV News:Yesterday (October 4th), the reporter learned from China Railway Kunming Bureau Group Co., Ltd. that China-Laos Railway has sent 7.39 million passengers and transported 8.51 million tons of goods, including 1.54 million tons of cross-border goods. In September, 1.25 million tons of goods were transported, breaking the monthly record, and the number of goods increased from more than 100 in the early days to more than 1,200.

On October 3rd, China-Laos Railway "Lanmei Express" international freight train broke through 200 trains. The "Lan-Mei Express Line" has been favored by many cross-border enterprises since it was launched. It has expanded from an initial on-demand operation to a fixed operation at least three times a week, and the cargo transportation has covered Laos, Thailand, Myanmar, Malaysia, Cambodia and Singapore.

Nowadays, the first thing for consumers to buy a car is to see whether this car is rich in configuration, and it is no exception to nature. Let’s look down with Xiaobian.

Let’s take a look at Komik’s appearance first. Komuk’s front face looks very clean and refreshing as a whole, and the air intake grille uses a straight waterfall shape, which is very recognizable. Coupled with fashionable headlights, it has a great visual impact. The car is equipped with LED daytime running lights, automatic opening and closing, delayed closing and so on. Coming to the side of the car body, the size of the car body is 4409 mm * 1781 mm * 1606 mm. The car adopts fashionable and dynamic lines, and the side circumference looks very sharp. With large-sized thick-walled tires, the shape is quite simple. In the design of the rear end, the rear end looks very comfortable, the taillights look very simple, and with the unique exhaust pipe, it is very simple and fashionable.

Coming to Komuk, Komuk’s interior looks solid and the visual effect is very good. The car looks very good outside the steering wheel, made of plastic, and looks a little more unique. Let’s take a look at the central control. The design of the center console is reasonable, which makes the interior design quite layered and conforms to the mainstream aesthetics. The dashboard and seats are equally eye-catching, and the car is equipped with a stylish dashboard with excellent display effect. The car adopts imitation leather seats, which are wrapped in place, with exquisite materials and comfortable ride.

Komik is matched with an automatic manual transmission (AT) gearbox, with a maximum power of 80KW and a maximum torque of 141N.m, with good power performance.

The car is equipped with driving mode selection, remote control key, rear wiper, engine start and stop, traction control (ASR/TCS, etc.) and other configurations, which greatly improves the convenience of using the car.

The car introduced today is remarkable in terms of space, configuration and power, and home travel is also a good helper. If you are interested, you might as well experience it.

1905 movie network news People are never short of police comrades who "cut the demon and get rid of the demon" all the way like "Monkey King". Song Rukun, the Weifang Public Security Bureau, has been fighting in the front line of criminal investigation to crack down on serious violent crimes since he joined the company in 1997. He has participated in the organization and detection of more than 220 serious criminal cases and arrested more than 2,000 criminal suspects in various criminal cases, playing an indispensable and key role in detecting a series of serious and serious cases such as intentional homicide, kidnapping and robbery.

There is also such a "Sun Dasheng" in a movie to be released on December 21st. In the trailer of the "Demon-slaying and Demonizing" version, Sun Dasheng, a criminal justice policeman played by Wang Qianyuan, took the "the Monkey King" key chain in his hand and comforted the children whose father was bullied by evil forces in the canteen: "Uncle, it’s the police who specialize in catching bad guys." The next part of the trailer shows standing up for justice,

Sun Dasheng, who "killed the demon" all the way: In the old garage, facing the vicious gangsters with sticks, Sun Dasheng responded tactfully, flew over the car to avoid pursuit and fought fiercely with the gangsters; On the rooftop, on the way to hunt down Zhao Tai, a sinister rich second generation played by Bao Beier, he was violently blocked by Zhao Tai’s bodyguards, and Sun Dasheng mercilessly grabbed the gangster’s head and gave him a beating; In the square, Zhao Tai had no way to escape, but still insisted on resisting arrest. Sun Dasheng stepped forward to fight for his life, and he must carry out the "demon-cutting and demon-removing" to the end!

Those powerful "monsters" are not "big shots", but "big shots" should be those police comrades who "cut off demons and get rid of demons" all the way. It is precisely because these people’s policemen like Sun Dasheng fight to the end for justice and evil forces that people can enjoy a peaceful and harmonious life with peace of mind. I also hope that the police uncles can protect themselves and pay tribute to the people’s police in the process of eliminating evils!

　　On August 9th, as a sub-activity of the 6th Global cross-border electronic commerce Conference, the first global cross-border e-commerce youth innovation and development summit forum was held in Zhengzhou E Trade Expo Center.

　　More than 300 people from international organizations, heads of well-known logistics enterprises at home and abroad, young talent leaders of cross-border e-commerce, senior youth entrepreneurship and employment guidance experts, and university scholars gathered together to discuss new ideas and ideas for the development of cross-border e-commerce industry in the new era around the theme of "New Economy, Creating Youth and Winning the Future", and share innovative ideas and scientific research achievements such as cross-border e-commerce brands going to sea, trade transformation, and young talent entrepreneurship and employment.

　　Today’s Henan needs a group of outstanding young talents with creativity and high skills more than ever before. "Young people are the main force in the cross-border e-commerce industry. This forum is to build a platform for cooperation and exchange for them, and further lead the young people in the cross-border e-commerce industry to actively participate in the strategy of innovation-driven, rejuvenating the province through science and education, and strengthening the province with talents, and contribute their youth to accelerating the construction of national innovative highlands and institutional open highlands." Hairun Hua, member of Henan Provincial Committee of the Communist Youth League and secretary of Zhengzhou Cross-border E-commerce Industry Working Committee, the initiator of this forum, said.

　　"We must encourage young people in the new era to show their youthful vitality and voice their voices in the practice of joining the cross-border e-commerce industry, and actively provide a good communication platform for young talents to learn cross-border e-commerce knowledge under the new situation and improve their professional skills in the industry." Li Jianwei, executive vice president of the Provincial College Graduates Employment Promotion Association, said.

　　In recent years, cross-border e-commerce in Henan has grown against the trend under the situation of epidemic prevention and control, and provided assistance for global epidemic prevention. The construction of the "Online Silk Road" has been deepening. Lu Shuifu, deputy secretary of the Party Committee of Henan Bonded Group, said that he hopes that this forum can widely mobilize and lead young people to become pioneers of scientific and technological innovation, so that the "youth" power can be deeply integrated with the "youth" industry, and innovation can become an inexhaustible motive force for blooming youth; The group will continue to explore new ways and means to serve young people in the cross-border e-commerce industry, and strive to formulate standards for training young talents in this industry.

　　"In today’s big data environment, many young talents have flooded into the e-commerce industry. The phenomenon of live broadcast in online celebrity has become a social craze, which is a brand-new shopping experience for overseas consumers." Yuan Chunlin, a doctoral tutor at Henan University, said. In his speech, he shared the research results on the formation process, effect and management logic of quasi-social experience in the live broadcast situation in online celebrity.

　　On the same day, Xingyao Yifeng Group signed strategic cooperation contracts with Kaifeng Education and Sports Bureau, Luohe Vocational and Technical College, Kaifeng University and Zhengzhou Vivian Dawson International Textile City on school-enterprise cooperation, youth talent training, and the joint construction of cross-border e-commerce incubation base and e-commerce industrial park. (Reporter Song Min)

　　Cctv newsAccording to the Supreme People’s Procuratorate and the Supreme People’s Procuratorate, five typical cases of procuratorial organs punishing the crime of manufacturing and selling fake and inferior agricultural materials according to law were issued. Since 2022, procuratorial organs across the country have approved the arrest of 179 cases of 313 people involved in agricultural crimes and prosecuted 465 cases of 843 people. It is suggested that the administrative law enforcement organs transfer 99 criminal cases with 112 people; Supervise the public security organs to file 76 cases with 85 people.

　　The typical cases of this batch are: Wang Moumou’s case of producing and selling fake and inferior seeds; Xie Moumou and others produce and sell fake and inferior products, which is an illegal business case; Gong and others produced and sold fake and inferior products; Zhang Moumou et al. produced and sold fake and inferior fertilizers and counterfeited registered trademarks; Chai Moumou produced and sold fake and inferior products.

　　Five typical cases involved many fields such as pesticides, veterinary drugs, seeds and fertilizers, which fully demonstrated the positive actions of procuratorial organs in severely punishing the crime of manufacturing and selling fake and inferior agricultural materials according to law, participating in comprehensive management in the field of agricultural materials safety, actively protecting farmers’ legitimate rights and interests, and ensuring national food security and seed industry security. In the case of Wang Moumou’s production and sale of fake and inferior seeds, the defendant Wang Moumou bagged his own "Xisen No.6" potato commercial potato and sold it to farmers as "Xisen No.6" potato seed potato. Results After planting, a small number of seeds did not germinate, and some seeds showed yellowing of plants, black rot of roots and underground potato rot. It was determined that the seeds involved caused farmers to lose more than 470,000 yuan. The Procuratorate of Jingbian County, Shaanxi Province prosecuted the defendant Wang Moumou for the crime of producing and selling fake and inferior seeds. On August 30, 2022, the court sentenced the defendant Wang Moumou to six years in prison and fined him 60,000 yuan. At the same time, in view of the institutional loopholes and weak links in law enforcement in the administrative supervision of local seed production and sales reflected in the case, the procuratorial organs issued procuratorial suggestions to relevant departments to help improve the administrative supervision mechanism.

　　Procuratorial organs punish according to lawTypical cases of manufacturing and selling fake and inferior agricultural materials

　　Case 1

　　Wang Moumou produces and sells.Fake and inferior seeds case

　　In March, 2021, the defendant Wang Moumou bagged his own "Xisen No.6" potato commercial potato and sold it as "Xisen No.6" potato seed potato to farmers such as Zhang Moumou in Jingbian County, Shaanxi Province, with a total sales amount of more than 83,000 yuan. Zhang Moumou and other farmers have planted more than 129 mu of land. After planting, a small number of seeds did not germinate, and some seeds appeared yellowing, black root rot and underground potato block rot during their growth. Appraised by Agricultural Technology Service Center of Yulin City, Shaanxi Province, the field potato variety is "Xisen No.6", and the main cause of infection with black shank disease is seed potato carrying bacteria. The average yield of potatoes planted by farmers such as Zhang Moumou was 1,225.9 kg per mu, which was appraised by Jingbian Agricultural and Rural Bureau. According to the price determination by Jingbian County Price Service Center, the loss price per mu caused by the seeds involved was more than 3,600 yuan, which caused a total loss of more than 470,000 yuan for farmers such as Zhang Moumou.

　　On May 26, 2022, the People’s Procuratorate of Jingbian County, Shaanxi Province prosecuted the defendant Wang Moumou for the crime of producing and selling fake and inferior seeds. On August 30, 2022, the Jingbian County People’s Court made a first-instance judgment, and sentenced the defendant Wang Moumou to six years in prison and fined 60,000 yuan for the crime of producing and selling fake and inferior seeds. After the judgment was announced, the defendant Wang Moumou did not appeal and the judgment came into effect.

　　travel to watch industry

　　Xie Moumou and others produce,sellFake and inferior products,Illegal business case

　　From January 2020 to July 2021, the defendant Mao Moumou and others used the online platform to sell paraquat stock solution, and the sales amount ranged from 1.2 million yuan to 150,000 yuan respectively. Defendants Xie Moumou and Zhang Moumou bought paraquat stock solution from Mao Moumou and others without obtaining a pesticide business license, and sold it as herbicide pesticides such as "diquat" after processing. The sales amount was more than 540,000 yuan and 450,000 yuan respectively. From January 2020 to July 2022, the defendant Song bought the above pesticides from Xie Moumou and Zhang Moumou and sold them to others without obtaining a pesticide business license, with a sales amount of 1.37 million yuan. The above defendants all know that paraquat is prohibited from being sold and used in China, and Song Moumou and others know that the above pesticides contain paraquat. Tested by Yancheng Product Quality Supervision and Inspection Institute, Jiangsu Province, all the pesticides involved contained paraquat, but did not contain diquat or glufosinate.

　　On August 9 and November 14, 2022, the People’s Procuratorate of Baoying County, Jiangsu Province respectively prosecuted the defendants Xie Moumou and Zhang Moumou for producing and selling fake and inferior products, Song Moumou for selling fake and inferior products, and Mao Moumou and others for illegal business operations. On December 16th, 2022, Baoying County People’s Court made a judgment of first instance, and sentenced Xie Moumou and Zhang Moumou to seven and six years’ imprisonment respectively for the crime of producing and selling fake and inferior products, and sentenced Song Moumou to six years’ imprisonment for the crime of selling fake and inferior products, and sentenced Mao Moumou and others to three to six months’ imprisonment respectively for the crime of illegal business operation, and some defendants were given probation (Song Moumou and Mao Moumou were given mitigated punishment due to meritorious service, confession and punishment). The above defendants were all fined. After the verdict was pronounced in the first instance, none of the defendants appealed and the verdict came into effect.

　　Case 3

　　Gong and others produce,sellFake and inferior products case

　　Defendant Gong Mou registered and established Henan A Chemical Co., Ltd. (hereinafter referred to as A Company) in Huaiyang County, Henan Province, and Gong Mou was the actual controller. Defendant Gong Mouhui (Gong’s fourth brother) established Zhengzhou B Chemical Co., Ltd. (hereinafter referred to as Company B), with Gong Mouhui as the actual controller. A company has a production department, a warehousing and logistics department, a finance department and a sales department. Gong manages the company in a family style, and each department is in the charge of Gong and his family. Defendant Gong Moulong (Brother Gong) is in charge of the production department; Defendant Gong Moufeng (Gong’s second brother) is in charge of the warehousing and logistics department; Gong is responsible for the sales department of Company A and its subordinate brand sales companies; Company B sells pesticides and fertilizers produced by Company A, and Gong Mouhui is responsible for the sales department of Company B and its subordinate brand sales companies; The finance department is directly under the responsibility of Gong, forming a family-owned gang with strict grades and mature scale that produces and sells fake and inferior fertilizers and pesticides. The formula of pesticide and fertilizer produced by Company A is provided by Gong. In the production process, in order to save costs and make high profits, Gong used the means of purchasing cheap and unqualified raw materials, adding little or no marked raw materials and so on.

　　After sampling and testing all the pesticides and fertilizers seized by Company A, 288 kinds of unqualified pesticides were detected, with a failure rate of 70.16% and 510 kinds of unqualified fertilizers, with a failure rate of 96.22%. After sampling and testing all the pesticides and fertilizers seized by Company B, 153 kinds of unqualified pesticides were detected, with a failure rate of 52.58% and 225 kinds of unqualified fertilizers, with a failure rate of 96.57%. After the audit, it was found that the sales amount of unqualified pesticides and fertilizers of Company A was more than 59 million yuan, and that of unqualified pesticides and fertilizers of Company B was more than 11 million yuan, totaling more than 70 million yuan.

　　It was also found out that Gong also paid bribes to non-state staff, forged seals of state organs and forged seals of companies and institutions.

　　On May 24, 2021, the People’s Procuratorate of Pingdingshan City, Henan Province filed a public prosecution against Gong Mou, Gong Mouhui and others. On August 25, 2021, Pingdingshan Intermediate People’s Court made a first-instance judgment, and sentenced the defendant Gong to life imprisonment, deprived of political rights for life, and confiscated all personal property; Whoever commits the crime of bribery by non-state employees, the crime of forging the seals of state organs, and the crime of forging the seals of companies and institutions were sentenced to fixed-term imprisonment of 10 months, one year and one year respectively, and were also fined and punished for several crimes. They decided to execute life imprisonment, deprive them of political rights for life, and confiscate all their personal property. The defendant Gong Mouhui was sentenced to 15 years in prison and fined 20 million yuan for the crime of producing and selling fake and inferior products. The remaining defendants were sentenced to fixed-term imprisonment ranging from ten to three years for the crime of producing and selling fake and inferior products, and were fined, and some defendants were suspended. After the verdict was pronounced in the first instance, some defendants appealed, and the Henan Higher People’s Court ruled on April 12, 2022 that the appeal was rejected and the original judgment was upheld.

　　Case 4

　　Zhang Moumou and others produce,sellFake fertilizer,Case of counterfeiting registered trademark

　　In 2019, the defendant Mou Moumou learned that the defendant Zhang Moumou was engaged in various fertilizers, so he wanted to order fertilizers with a total nutrient content of 40% in Zhang Moumou. In order to facilitate sales, the two agreed to use a packaging bag printed with the registered trademark "ZGNZ" and marked the total nutrient content of fertilizer on the packaging bag as 51%. Later, Zhang Moumou contacted the defendant Wang Moumou to produce packaging bags, and the defendants Zhao Moujia and Zhao Mouyi produced and filled fertilizers. Knowing that Zhang Moumou had not been approved by the owner of the registered trademark ZGNZ, Wang still produced more than 10,000 fertilizer packaging bags printed with the trademark. Zhao Moujia and Zhao Mouyi sold more than 392 tons of canned compound fertilizer to Zhang Moumou at a price of more than 920,000 yuan when they knew that the nutrient content of the fertilizer they produced did not match the label on the packaging bag. Zhang Moumou sold it to Mou for 1.12 million yuan. From February to April, 2019, Mou sold some chemical fertilizers to more than 160 farmers in panshi city, meihekou city and other places, with a sales amount of more than 1.06 million yuan.

　　After inspection by Jilin Provincial Product Quality Supervision and Inspection Institute, the fertilizer involved was unqualified. Confirmed by panshi city Municipal Market Supervision Administration, the seized fertilizer is a commodity with counterfeit registered trademark. After identification, the affected farmers reduced the production of corn by more than 4 million kilograms and rice by more than 1,500 kilograms, resulting in a total economic loss of more than 5.6 million yuan.

　　From April to May, 2020, the People’s Procuratorate of panshi city, Jilin Province prosecuted the defendant Zhang Moumou and other four people for the crime of producing and selling fake and inferior fertilizers, and Wang Moumou for the crime of counterfeiting registered trademarks. On June 30, 2021, the People’s Court of panshi city sentenced the defendant Zhang Moumou to nine years and ten months in prison for the crime of producing and selling fake and inferior fertilizers, and fined him 570,000 yuan. Sentenced the defendant Wang Moumou to three years in prison for the crime of counterfeiting a registered trademark and fined him 50,000 yuan; The other three defendants were also sentenced to fixed-term imprisonment ranging from five years and six months to seven years and six months, and fined. After the judgment of the first instance, five defendants appealed. On November 17, 2021, the court of second instance made a judgment. In view of Wang’s voluntary return of all illegal gains and his true repentance during the second instance, he was sentenced to three years’ imprisonment, suspended for three years, and fined 50,000 yuan. All other judgments in the first instance were upheld.　

　　Case 5

　　Chai Moumou produces and sells.Fake and inferior products case

　　From the second half of 2020 to December 2021, the defendant Chai Moumou, knowing that a new pharmaceutical company he operated only had the qualification of selling veterinary drugs, but had no production qualification, produced a small white bag of penicillin potassium without the manufacturer, production date and batch number, and sold it as a fake drug such as florfenicol powder produced by other companies. During this period, the defendant Chai Moumou also provided two companies with the qualification to produce veterinary drugs, and then sold them to a new pharmaceutical company. Chai Moumou sold the above veterinary drugs produced by himself and other companies in the name of a new pharmaceutical company, with a sales amount of more than 490,000 yuan. After inspection, the relevant veterinary drug ingredients were not detected or the content did not meet the requirements of People’s Republic of China (PRC) Veterinary Drug Code. It was identified by the agricultural and rural departments that the colistin sulfate premix, amoxicillin soluble powder and florfenicol powder produced and sold by the defendant Chai Moumou were fake or inferior veterinary drugs.

　　On June 1, 2022, the People’s Procuratorate of shanting, Zaozhuang City, Shandong Province filed a public prosecution against Chai Moumou for the crime of producing and selling fake and inferior products. On July 14th, 2022, the People’s Court of shanting, Zaozhuang City made a first-instance judgment, and found that Chai Moumou had truthfully confessed the facts of the crime, actively returned the illegal income, pleaded guilty and pleaded guilty. He was sentenced to two years and ten months’ imprisonment and fined 170,000 yuan for the crime of producing and selling fake and inferior products. After the verdict was pronounced in the first instance, the defendant Chai Moumou did not appeal and the judgment came into effect.

　　Poster production: Feng Juan

　　Xinhua News Agency, Tianjin, February 28th (Reporter Zhou Runjian) The "brightest" two stars in the night sky — — What is the visual feeling of Venus and Jupiter’s "romantic embrace"? Here comes the opportunity. On the evening of March 2, these two bright celestial bodies will meet at close range in the western sky and perform "Stars attract each other".

　　Dai Jianfeng, an astronomy enthusiast in Chongqing, accompanied Jin Mu in Namco, Tibet on the evening of July 5, 2015. (Photo courtesy of myself)

　　Astronomical science experts said that this is the most wonderful planetary conjunction this year, and it is also one of the astronomical phenomena worth watching this year. Because the two stars are very bright, there is no need to use an astronomical telescope, and you can enjoy this wonderful scene with the naked eye.

　　Wang Junfeng, an astronomy enthusiast in Beijing, shot the golden wood in Fangshan, Beijing in the early morning of May 1, 2022. (Photo courtesy of myself)

　　Most of the time, if the sun and the moon are not counted, Venus and Jupiter rank first and second respectively among the stars visible to the naked eye. During the period from the end of February to the beginning of March this year, in the western sky in the evening, Venus, the closest to the earth, and Jupiter, the "big man" of the solar system, are gradually "approaching" and meet at 19: 00 on March 2. Visually, they are the closest. This is another close contact between the two planets after Venus and Jupiter were very close in the early morning of May 1, 2022.

　　Jin Mu’s companion moon was photographed by Guangdong astronomy enthusiast Shen Quanzhi in Lianhua Mountain, Panyu, Guangzhou on the evening of February 22, 2023. (Photo courtesy of myself)

　　Yang Jian, an astronomy enthusiast in Tianjin, accompanied Jin Mu in Nankai, Tianjin on the evening of February 25th, 2023. (Photo courtesy of myself)

　　Xiu Lipeng, a member of the Chinese Astronomical Society and an expert in astronomical science, said that the astronomical phenomenon of Venus and Jupiter at close range is not uncommon, and it has occurred almost every year in recent years. Although the frequency of occurrence is high, it is not always suitable for public observation in China. This is because when they coincide, they are sometimes too close to the sun, sometimes occur in the daytime or early morning, and sometimes "fall" in the southern hemisphere, which makes observation difficult or impossible.

　　Cartoon production: Hu Yanzhu

　　This coincidence occurred in the evening, and the time period was very friendly, which was just suitable for observation in China. At this time, the brightness of Venus is -3.9, Jupiter is -2.1, and the angular distance between the two stars is only 33 seconds, which is similar to the apparent diameter of the full moon (0.5 degrees). At sunset, the horizon height of Venus and Jupiter reaches 28 degrees, and the observation time is nearly 2 hours. Because these two planets are very bright, even in cities with serious light pollution, they can be easily captured with the naked eye.

　　Dai Jianfeng, an astronomy enthusiast in Chongqing, accompanied Jin Mu in Yuanmou Tulin, Yunnan on the evening of February 17th, 2023. (Photo courtesy of myself)

　　"Because Venus is closer to the sun and the earth, it runs faster, while Jupiter is farther away from the sun and the earth, and its running speed is slightly slower, so after this conjunction, these two planets will ‘ Go their separate ways ’ It seems to be drifting away. If we can shoot them at the same time every day during this time, we can find that their trajectory is a ‘ X’ Form. " Xiu Lipeng said.