Low tensile strength, poor elastic modulus, and complex concrete cracking work condition are almost unavoidable due to the intrinsic brittleness. To deal with concrete maintenance and durability, microbial self-healing concretes have been rapidly developed and widely applied recently. The microbial self-healing can specifically patch fractures as well as boost the concrete structure’s capacity, durability, and permeability. This paper presents the state-of-the-art in the microbe induced self-healing in cement-based composites. The microorganism and carriers were classified according to the working theory and repair effects. Additionally, the precise efficiency and effect of various technologies are also evaluated for microbial immobilization. Based on the literature review and summary from the perspective of microorganism, carriers, and immobilization methods, challenges and further works are discussed. Cement-based composites, including pastes, mortars, and concretes, are the most used construction materials in the world. However, it is also faced with surface cracks and deep internal micro cracks produced by gradient of temperature, plastic shrinkage, and settlement shrinkage. The cracks will absolutely impact a structure’s engineering performance and shorten service life, resulting in economic losses or even safety incidents . TherefoIn recent years, an innovative self-healing concrete based on microbial-induced carbonate precipitation (MICP) has become popular since calcium carbonate sedimentation was observed from Bacillus Pasteurella in the 1990s . A lot oThe basic illustration and working principle of microbial self-healing concrete is presented in The sustainable development of infrastructure requires the birth and development of concrete composite materials with self-healing capabilities. The significance of self-healing technology is to provide concrete infrastructure with the ability to adapt and respond to the environment, showing great potential and contributing to the creation of various sustainable materials and infrastructure. Due to an enormous amount of capital investment, continuous examination and safeguarding may be tricky to implement, particularly in the case of major construction projects; meanwhile, the development of microbial self-healing technology has become appealing due to the need for minimal labor and low capital expenditure.To understand the state-of-the-art of microbe-induced self-healing in cement-based composites, the development of microbial self-healing technology is reviewed in this article. The merits and defects of various forms of microbial and carrier materials are addressed, as well as the effects on the concrete remediation effect of the immobilization process. The aim of this paper is to promote the microbial self-healing technology as an alternative solution for ensuring the durability of concrete structures, as well as improve our understanding of the microbe induced self-healing in cement-based composites.3). According to the way calcium carbonate is produced, the general used bacteria could be primarily categorized into two sorts, i.e., urease bacteria and non-urease bacteria. Most of the urease bacteria and non-urease bacteria can resist the extreme environment inside the concrete and are thus suitable for carbonate precipitation in cement concreting.Microbial self-healing concrete is based on the bacterial-induced calcium carbonate precipitation . In natuVarious urease bacteria exist in nature, among which Bacillus pasteurii, Bacillus aerius, Bacillus sphaericus, Sporosarcina aquimarina, Bacillus megaterium, etc. are frequently proposed for the self-healing concrete. Bacillus pasteurii, a Gram-positive bacterium isolated from soil, can grow normally at temperatures ranging from 15 to 37 °C. The urease activities of Bacillus pasteurii is outstanding, which could rapidly decompose urea in the environment into ammonium and carbonate. Bacillus megaterium belongs to Gram-positive bacterium . B. spha3 precipitation and provide self-healing capacity in concretes. In metabolism, urease-catalyzing urea hydrolysis is secreted by urease organisms. As shown in Bacterial urease can hydrolyze urea, which will cause CaCOAccording to the research to induce the precipitation of calcium carbonate based on Bacillus cohnii, Bacillus pasteurii, and Bacillus sphaericus, in terms of the repaired width of cracks from microorganisms, the Bacillus cohnii self-healing performance in concrete specimens is more effective. The crack that Bacillus cohnii repaired had a width of 0.56 mm ; meanwhi3 and CO2 by using urease produced by themselves. In alkaline environment, the pH value of the solution with the increase of NH3 and CO2 exists in the form of CO32−.As for the non-urease bacteria, Bacillus pseudofirmus, Bacillus cohnii, Bacillus halodurans, Bacillus mucilaginous L3, Enterococcus faecalis, Geobacillus stearothermophilus, Bacillus subtilis, etc., are widely studied as non-urease bacteria inducing calcium carbonate precipitation. Bacillus subtilis is a Gram-positive bacterium that forms oval or cylindrical spores . NumerouFor non-urease bacteria, they will transform organic acids to form calcium carbonate precipitates through their own vital activities under oxygen-containing conditions. Calcium lactate or calcium acetate are often added to nutrients that non-urease bacteria can eventually convert to calcium carbonate. Equation (8) shows the reaction in which calcium lactate works as a carbon source .CaC6H10Most microorganisms are intolerant to alkaline environments. The Bacillus pseudoadamentosa has an exceptional ability to adapt to the alkaline conditions where the surviving pH value can be up to 11.0 . At 10 p3 crystals, whereas non-urease bacteria makes use of reactions by transforming organic acid into CaCO3 precipitation. However, the non-urease bacteria would not produce harmful gases such as NH3 and contributes an eco-friendly environment role in concrete.Overall, for the case of urease bacteria, it makes use of a series of reactions by itself to precipitate the CaCOMicroorganisms play an effective role in fixing concrete and preserving the mechanical properties and durability of concrete during the process of healing micro-crack concrete by microbial self-healing technology. Although a wide range of microorganisms can heal cracks greater than 300 μm under the right conditions, different types of microorganisms may have distinct healing effects. In microbial self-healing concrete, the healing results are influenced by significant factors such as whether to have carriers, how to use carriers, and how bacterial interacts with carriers.Inorganic porous carrier materials typically have porous surface properties and good absorption of water. The rich microporous structure will provide adequate room and sustain excellent connectivity for the growth and metabolism of microorganisms. Meanwhile, the comparatively thick surface can reduce the penetration of high alkali substances, which can significantly increase the tolerance of concrete bacteria.The lightweight porous aggregate carrier often belongs to the inorganic porous material; extended perlite, porous ceramist, diatomite, zeolite, pelelith, etc. are typical porous light aggregate carriers. These natural inorganic porous products are commonly used as a promising material in self-healing concrete for sustainable infrastructure, because they have strong compatibility with concrete and the characteristics of higher bacteria content, lower incorporated amount, and cost-effectiveness.The immobilization of bacteria inside expanded perlite (EP) shields bacteria from concrete’s high-pH climate and increases the self-healing to a large extent, enhancing the bending properties of concrete. Meanwhile, most of the bacterial treatments are restricted to the surface only up to few micrometers, and the use of expanded perlite can increase the healing rate in the deeper position of cracks. Numerous 100 mm cavities were found in expanded perlite particles using the Field Emission Scanning Electron Microscope (FESEM) and X-Ray Diffraction (XRD), which could provide free oxygen sufficient for bacteria inside the concrete and attachment space for the fixed bacteria to carry out their metabolic activities. At the same time, it can also make bacteria exposed to small amounts of water when cracks appear; thus, the expanded perlite exhibits excellent characteristics associated with high porosity and highwater absorption. The specimens incorporated with EP particles for B. Cohnii exhibit completely healed crack widths of up to 0.79 mm, which is larger than the value of 0.45 mm for specimens incorporated with expanded clay particles as  39]. A . A 39]. Diatomaceous earth (DE) particles are found to have a protective effect in a high-pH cement environment with porous properties; they have a strong capacity to sorb bacterial cells on the surfaces and provide a new microenvironment, which enables bacteria keep degrading urea . The finTo improve the loading content of the protective carriers, different pretreatment procedures, such as alkali erosion and sintering treatments, on lightweight porous aggregate were carried out beforehand. Ceramic particles as a carrier of bacteria were treated by NaOH solution with concentrations of 0.5 mol/L, 1.0 mol/L, and 1.5 mol/L to increase the number of loading bacteria . It is oBacillus pasteurella was found to survive in concrete (pH = 12) with the protection of zeolite and to produce calcium carbonate crystals after self-healing evaluation on crack-healed specimens at ages 4, 6, and 8 months cured in water, and the compressive strength improved with the addition of bacteria (10%) . HoweverPelelith can also function as a bacterial carrier to protect bacterial spores and investigate the repairing of concrete cracks. Compared to other carriers, the surface of pelelith is positively charged and its physical and chemical characterization are stable, making it more compatible with microorganisms and conducive to the settlement of calcium carbonate. Wu et al.  investigConsidering the factors such as local availability, cost, and protect impact of bacterial cells, advanced study focuses on bacteria that are immobilized via recycled coarse aggregate (RCA) and virgin fine aggregate (FA). It was found that using CA and 50% virgin FA as bacteria immobilizers exhibited the most effective crack repair method, which can heal a maximum crack width of 1.1 mm and restore 85% of the compressive strength while minimizing energy consumption and effectively lowering anthropogenic emission  is widely used as a waterproof material. The possibility of using silica gel or polyurethane as a carrier for bacterial protection was investigated by Wang . The actMicrocapsule is an artificial organic material, and this self-healing system has been developed mainly in polymers and composites, with the potential to provide bacteria with all around protection. Some microcapsule spores are used by researchers to isolate the outside world, which is helpful for resting and lurking spores . Spores Nanometer materials also contained artificial organic material which, due to the nanoscale size of the carrier, has certain advantages in improving the healing efficiency and performance of concrete. Khaliq et al.  have shoAs summarized in Although using the carrier would extend the life of microorganisms in an extremely alkaline environment, but the successful running time of existing bacteria is still inadequate relative to the real engineering application. Simultaneously, the inclusion of most carriers can affect the compressive strength of concrete samples to some degree, especially when multiple immobilized microorganisms die; thus, the resulting compressive strength of concrete will not fulfill the actual specifications for engineering. While microorganisms may be shielded from changes in the external environment and retain their biological action by the inorganic porous material carrier, the structure also creates considerable transfer resistance to the activities of bacterial existence. In addition, organic carrier materials have strong stability with microorganisms, but they are vulnerable to aging and decrease the repair effect. Therefore, the mechanical properties of carrier materials, their microorganism compatibility, and the resulting degree of concrete need to be further researched.The carrier mechanical properties can be changed by the qualitative alteration of surface groups or microporous composition of carrier materials, but it may come with a higher cost. Microcapsule technology is a great breakthrough in the future development direction of the carrier, it can effectively resist the mechanical force of concrete mixing, keep the microorganism active, and it has almost the highest healing rate among all the healing agents. The development direction of organic carrier materials in the future can be focused on the preparation of capsules, the mechanical properties of capsules, and the created empty space after healing. Meanwhile, the scale of the carrier can also be a great innovation. The incorporation of micro-scale carriers has a negative effect on the mechanical properties of concrete, while metal nanoparticles have a positive effect on the mechanical properties of concrete and its high compatibility with the concrete matrix. Therefore, the development of a nanoscale bio-concrete carrier is very promising and necessary. To facilitate the production and deployment of self-healing concrete technologies, we need pay more attention to find productive carrier materials and acceptable doses.A lot of microbial immobilization methods have been reported to immobilize the microorganisms into carriers to make microbes highly dense, to preserve microbes’ biological activity, and to proliferate microbes under ideal conditions . In micrCurrently, the vacuum impregnation method is one of the most commonly used technologies. The brushing method also has been used in microbiological self-healing concrete. The brushing method usually refers to the bacterial suspension and calcium source; nutrients are respectively brushed on the surface of the cement specimen, which can achieve the effect of repairing the specimen surface cracks. Among them, Qian and Ren  smeared ATM is often used with a shaker to mix the bacterial suspension with the carrier; then, it mixes the mixture with nutrients before adding it to the concrete. The adsorption experiment conducted by Wang et al.  showed tIn the process of microbial self-healing concrete, the immobilization procedure is also very important. The success rate and practicality of the microbial and carrier mixture would be influenced by the rational choice and implementation of the immobilization method. The combination of the microorganism and the carrier, which performs the protective role of the carrier, increases the survival rate of the microorganism, and eventually reaches the complete fix, will be supported by the proper method of immobilization. The selection of the immobilization approach only has some effect on the experimental results relative to the microbial species and carrier species that play a decisive role in the maximum repair width of concrete. Thus, when using same immobilization method, there may be a noticeable change in the maximum repair width of the concrete. Otherwise, if using the same type and quantity of microorganism, carrier, and nutrients, due to the different immobilization methods, in which the immobilization process, the immobilization effect, and the mechanism are different, there may be a various maximum repair width seeing , compresIn addition to the detailed description of microbial species, carrier types, and microbial immobilization methods that would impact the self-healing capacity, the working conditions especially temperature, water, the addition of nutrients, and even pressure are also important. The spores need to revive when the crack is producing. However, at different temperatures and different amounts of water, the spore recovery rate would be different, which will affect the calcium carbonate production rate. Furthermore, the amount and types of nutrients also should be considered; the addition of nutrients could promote the growth and mineralization efficiency of bacteria, as well as their ability to produce healing product. As result self-healing effect of concrete cracks could be improved. Moreover, in laboratory research, pre-cracking methods are also an important influencing factor. Many scholars use an electro-hydraulic servo testing machine, compressive servo testing machine, and automated bending compression testing machine to construct cracks. Each pre-cracking method will produce different crack widths and depths. When the crack is too large, the repair ability of microorganisms may not be enough to allow the crack to accumulate calcium carbonate, which makes the experiment unable to accurately evaluate the self-repair efficiency. Low pressure in a high-altitude area will affect the performance of cement mortar . It is nThere are two main categories to evaluate the self-healing capacity, which include the material detection method and physical inspection method. For the material detection method, scanning electron microscope (SEM), energy-dispersive spectroscopy (EDS), X-ray diffraction (XRD), and thermogravimetric analysis (TGA) are very common ways to investigate the morphology, energy distribution, and composition of crystals precipitated in cracks. SEM is a kind of observation method to obtain the microscopic morphology characterization of material by scanning with a high-energy electron beam. EDS uses X-ray photons to map the size distribution of energy. XRD is a technique for determining the crystal structure based on the diffraction patterns obtained from the emission of electromagnetic waves. TGA is a method of measuring the mass of a substance in relation to temperature or time. In addition, the physical inspection method concentrates on testing the self-healing capacity of concrete specimens, which includes compressive strength, flexural strength, water absorption, water permeability, durability, maximum repair width, maximum repair depth, etc. Meanwhile, the chloride penetration resistance can also be used to evaluate the self-healing capacity. Fahad et al. innovated the steady-state migration test under higher potential, and the self-healing capacity showed it can provide a more precise result .With the development of microbial self-healing technology, more and more microbial self-healing concretes have been applied in real projects. Since 2015, more than ten self-healing concrete demonstration projects have been reported in the Netherlands, the United Kingdom, Belgium, China, and other countries. It was applied to a variety of environments, including tunnels, water channels, foundations, etc. ,66,67.H. M Jonker developed a self-healing concrete with the spores of bacillus and natural fibers, and he successfully applied it as lining for an irrigation canal in the highlands in Ecuador. There are no signs of cracking on the surface of the lining after one year ,69. A reQian applied the produced microbial self-healing concrete to the side wall of the ship lock. It was observed that the cracking of the concrete was completely healed after 60 days, and the leakage of the crack was effectively blocked . These pThe current practical application of these microbial self-healing concretes provides a technical basis and reference for future large-scale usage as  showing,There is limited ability for a certain number of microorganisms to decompose the substrate and generate calcium carbonate. Sufficient bacteria need to be mixed to repair cracks. However, if too many microorganisms are present, the death of the inactive microorganisms would have some effects on concrete, including the mechanical properties, the permeability of water, etc. If very few microorganisms are mixed, the need for fixing cracks cannot be fulfilled. Therefore, the problem of the relationship between the specific number of microorganisms in the organization and the number of cracks must be solved.Nutrients are required components for microbial-mediated calcium carbonate precipitation in terms of microbial self-healing. However, the quantitative relationship between nutrients and microorganisms is still uncertain. The number of substrates would be abundant if microorganisms are insufficient, resulting in resource waste and an increase in cost. If the substrate is insufficient, the deposition of calcium carbonate will decrease, and the self-healing effect will deteriorate.There is a limited lifetime of microorganisms in concrete. Aeration is one of the most important factors influencing the survival rate. If a technology can be developed or a mechanism can be discovered to increase the lifetime of concrete microorganisms, it is possible to increase the self-healing effect and reduce the repair costs of concrete fractures later on.In concretes, there are mainly cracks on the exterior (not just on the surface) that have an effect on the whole. In this scenario, the procedure of surface brushing cannot fulfill the criteria for self-healing. However, in the concrete core, the carrier containing microorganisms and nutrients has only a limited repair impact, but the strength and permeability of concrete would have a great adverse effect. The self-healing impact of the central component of concrete, which can encourage advanced technologies and improve healing ability, can also be studied.It is unknown about the real survival rate of encapsulated bacteria after being introduced to concretes and the lifestyles of embedded bacteria within the concrete matrix. Up to date, although there are a lot of reports to explain the internal self-healing process of microorganisms in cement-based composites, researchers just presented certain inferences. The internal self-healing process of repair still needs to be clarified. The activity range, the mode of activity, the consumption process of edible nutrients, the path of repair, the speed of repair, and the cause of changes in the speed of repair for activated concrete microorganisms are still unclear. If the repair mechanism of microorganisms can be understood at the micro stage, it can clarify the reason that the surface of the cracks may heal entirely under the uniform distribution of microorganisms in concrete, whereas the deep cracks heal just half. Then, the experiment operation would be improved in order to achieve high performance and complete crack repair.The extent of a single microbial remediation is still unclear. If the scope of repair is precisely defined, the optimum self-healing effect can be accomplished by clarifying the optimal density of distribution of microorganisms on the basis that concrete performance is not affected by the carrier and nutrients. Or even if the carrier and nutrients have an effect on the concrete’s efficiency, the optimal self-healing effect can be calculated by a comprehensive consideration of the optimal density of microbial distribution. It is important to explain the relationship between the certain amounts of calcium carbonate produced by microorganisms and the producing time, and it is crucial to analyze the distribution type of calcium carbonate produced by microorganisms at the micro level. Whether calcium carbonate accumulates only in one direction or in all directions, which can determine the microbe quantity and achieve the best self-healing effect must be determined.The electro-hydraulic servo testing machine, compressive servo testing machine, automated bending compression testing machine, fishing line, iron nail, and other techniques are used by many academics in experimental research to generate cracks. However, in practical engineering, these man-made cracks are not the same as the cracks occur naturally. Therefore, it is important to make the same crack as the actual situation, which can increase the effective rate of crack repair in practical applications in engineering.The laboratory environment is the primary environment in which self-healing processes are studied. However, the concrete should be used in very different environments, such as marine water, rivers, soil, or frozen soil. In addition, it is necessary to consider some special situation, for example, the freeze–thaw cycles. Water can enter the concrete and dissolve the concrete matrix in each freezing period and thawing cycle due to changes in internal and external pressures. In this situation, the assessment of the effectiveness of a healing agent’s consolidation capacity is essential. Therefore, in order for practical engineering to have a great self-healing effect, these conditions should be simulated during research. The performance of microorganisms in various conditions should receive more consideration, and the final repair effect should be tested in the laboratory process.In addition to the performance of the self-healing process, the current production cost of the bacterial self-healing agent is also a challenge. To satisfy economic constraints, improved production methodologies will need to be developed, particularly with regard to the large-scale cultivation of bacteria, nutrients, and labor intensity. Strategies to increase bacterial self-healing efficiency and reduce costs need to be developed, which will accelerate the adoption of MICP-applied concrete in the future.In the field of microbial self-healing, due to the strong alkaline and poor living environment in concrete interiors, it is necessary to identify a microorganism with tenacious vitality, can resist strong alkalinity, and has an excellent repair effect. Otherwise, the interior of concrete is basically an anaerobic environment, so anaerobic bacteria will be more suitable for concrete self-healing. In addition, the mixed bacteria have more tenacious survival ability and can complete the task better, so we can use two or more microorganisms mixed in a certain proportion to make a mixed bacterium and try to study the repair effect. Genetic modification is also feasible, inserting exogenous DNA to achieve the necessary properties of the microorganisms needed for self-healing concrete. At the same time, the main reason for the lack of large-scale application of microbial self-healing concrete is its high production cost, especially the high cost of the cultivation of microorganisms and the use of nutrients. Therefore, it is necessary to find a lower cost of microbial culture methods and relatively cheap nutrients where the technology can have a better and wider application.The fundamental purpose of the carrier is to protect the survival of microorganisms under mechanical stress and high alkaline environment. In order to provide an excellent living environment and place for microorganisms, the carrier should have high porosity and great biocompatibility. The acquisition cost and application cost of the carrier should also be evaluated. In addition, the choice of carrier needs to consider the practical use of concrete. The performance of the level of concrete in different facilities and structures are different. Each structure has special features in some performance aspects and the effect carriers showed ultimately is different. Therefore, it is necessary to develop specific carriers for microbial self-healing materials with a series of special structures to exploit the structural strengths of each carrier. In the future, it will be important to improve the microbial immobilization methods or develop a new one that is easy to operate with higher efficiency.(1)3 crystals through a series of reactions, whereas non-urease bacteria convert organic acids into CaCO3 precipitates through their own hypoxic reactions. However, ammonia gas will be produced in this process when using urease bacteria, which is very undesire in artificial building materials. In the future direction of development, it is necessary to seek a more green and scientific way to fix ammonia, or through gene modification, insert exogenous DNA to achieve the necessary properties of microorganisms needed for self-healing concrete, such as alkalinity resistance, anaerobic, environmental protection, etc. The cultivation and nutrients of microorganisms account for a large part of the cost of microbial concrete materials. To realize the economical and practical use of this material, it is necessary to find a cheaper cultivation method and nutrients.The species and survival rate of microorganisms in microbial concrete materials need to be optimized. The microorganisms can be divided into urease bacteria and non-urease bacteria. Urease bacteria precipitate CaCO(2)The microbial carrier is an important factor that affects the self-healing efficiency of microbial concrete materials, which deserves more research. At present, carriers are mainly divided into organic carriers and inorganic carriers, which can work in different applications. Choosing a suitable carrier in the corresponding environment can improve the efficiency of self-healing to a certain extent. Despite the fact that the carrier can prolong the survival time of microorganisms in an extremely alkaline environment, the successful operation time of existing bacteria is still insufficient compared with actual engineering applications. It is necessary to develop more bio-affinity, high stability, and good compatibility carrier materials—for example, by changing the surface group or micropore composition of the carrier material, which can promote the production and application of self-healing concrete technology.(3)Microbial immobilization is an indispensable step in making microorganism self-healing concrete. Although there are many microbial immobilization methods at present, all of the methods and preparation conditions have corresponding standards, and each method has its own characteristics and merits. This paper focuses on the analysis of three commonly used methods which include ATM, MEM, and VIM and lists their repair effect. When the same microorganisms, carriers, and nutrients are used, and other variables are controlled the same, it will not have much impact on the final repair effect by changing the microbial immobilization method only. During microbial immobilization, special attention should be paid to the experimental operation process and method to avoid the decrease of the success rate of immobilization caused by unscientific and unprecise experiments, which will impact the final repair effect.(4)The microbial self-healing materials in the specific repair effect of microorganisms, survival ability, impact factor, and lifestyle in the concrete matrix are still unclear. The real application of self-healing concrete in civil engineering is still limited, and standardized methods for evaluate the healing capacity have not been established. The survival time of microorganisms in the concrete is limited. The current technology makes it difficult to know the actual survival rate of the bacteria after being introduced into the concrete. It is also difficult to determine the optimal distribution density of microorganisms. The research on the internal repair mechanism of concrete contributes to the development of more economical and practical microbial concrete.This paper focused on three main factors in the self-healing cement concretes including microorganisms, carriers, and microbial immobilization methods. The main conclusions are drawn as follows.


Hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signaling plays an important role in the metastatic formation and therapeutic resistance to uveal melanoma. Here, we review the various functions of MET signaling contributing to metastatic formation, as well as review resistance to treatments in metastatic uveal melanoma.Hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signaling promotes tumorigenesis and tumor progression in various types of cancer, including uveal melanoma (UM). The roles of HGF/MET signaling have been studied in cell survival, proliferation, cell motility, and migration. Furthermore, HGF/MET signaling has emerged as a critical player not only in the tumor itself but also in the tumor microenvironment. Expression of MET is frequently observed in metastatic uveal melanoma and is associated with poor prognosis. It has been reported that HGF/MET signaling pathway activation is the major mechanism of treatment resistance in metastatic UM (MUM). To achieve maximal therapeutic benefit in MUM patients, it is important to understand how MET signaling drives cellular functions in uveal melanoma cells. Here, we review the HGF/MET signaling biology and the role of HGF/MET blockades in uveal melanoma. Uveal melanoma (UM), which arises from melanocytes in the choroid 85–90%), ciliary body (5–8%), and iris 3–5%), is the most common primary intraocular malignant tumor in adults . Five-ye–5%, is t–90%, cilBRAF), neuroblastoma RAS viral oncogene homolog (NRAS), and neurofibromatosis type 1 (NF1), more than 90% of UM cases commonly harbor mutations in the alpha subunit of heterotrimeric G proteins, GNAQ/GNA11, that are involved in early UM development. These G proteins play an essential role in cellular signal transduction, and GNAQ/GNA11 mutations drive carcinogenesis and cell proliferation [CYSLTR2) and phospholipase C beta 4 (PLCB4) were also found, and these lead to the activation of GNAQ/GNA11 signaling [BAP1), splicing factor 3b subunit 1 (SF3B1), or eukaryotic translation initiator factor 1A X-linked (EIF1AX), and these mutations tend to correlate with the development of metastasis [BAP1 on chromosome 3p21.1 in 26 of 31 (84%) metastasizing UM tumors and was correlated with the development of systemic metastasis and poor outcome [BAP1 aberrancy may result in a metastasis-prone DNA methylation state [Unlike cutaneous melanoma, which has driver mutations in v-raf murine sarcoma viral oncogene homolog B1  has also been found in 3 of 80 UM samples from The Cancer Genome Atlas (TCGA) and 2 of 42 UM tumors from the Rotterdam Ocular Melanoma Study group (ROMS) database [SRSF2 somatic mutation, the correlation of this mutation with the development of metastasis is unknown. Other research data indicated that 8q amplification in UM tumors was associated with the high risk of metastasis [tastasis . In contd in MUM . In addidatabase ,18. Due tastasis .In non-malignant situations, hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signaling is essential for embryogenesis, muscle development, nervous system formation, hematopoietic cell differentiation, and bone remodeling ,20. In mHGF is located on chromosome 7q21.11 and consists of 18 exons and 17 introns. HGF was discovered as a mitogen of hepatocytes for liver regeneration. It was identified in the sera of 70%-hepatectomized rats as a mitogen of adult rat hepatocytes [HGF is a large multidomain protein that was discovered more than three decades ago. The gene-encoding atocytes . HGF is atocytes , fibroblatocytes . Pro-HGFatocytes  , the type II transmembrane enzymes matriptase, and hepsin ,30,31 Fa. HGFA iHGF is produced in various pathological events in the liver. For example, when 70% of the liver was removed, HGF mRNA levels markedly increased in intact distant organs, such as the lung, kidneys, and spleen. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, interferon-gamma, and tumor necrosis factor-alpha (TNF-α) are involved in the upregulation of HGF gene expression in stroma cells. These pro-inflammatory cytokines trigger HGF production in intra-hepatic tissues via the paracrine loop and in extra-hepatic organs via the endocrine loop .MET codes a tyrosine kinase transmembrane receptor of HGF, composed of a 50-kDa α-subunit and 145-kDa β-subunit , and immunoglobulin-like fold-plexin-transcription factor (IPT) domain [MET encodes the JM region, which contains key regulatory elements, including Y1003. MET dysregulation through splice-site alterations causes loss of transcription of exon 14, which leads to exon 14 skipping. MET activation with exon 14 skipping inhibits MET negative regulation, demonstrating uncoupled Cbl protein binding, decreased ubiquitination, and inefficient targeting for degradation of MET. Therefore, this exon 14 skipping enhances HGF-induced MET phosphorylation and prolongs MET activation. In this regard, cancer cells which have exon 14 skipping are sensitive to a MET inhibitor [MET is present in a variety of tumors and have been shown to correlate with poor prognosis [Proto-oncogene -subunit b. The pr) domain ,36. The ) domain . The int) domain   domain . Exon 14nhibitor . In addirognosis ,41. HGF/rognosis .The complexity of MET signaling is a crosstalk with other receptors and membrane proteins. In complex multi-cellular organisms, the formation of a heterodimeric complex permits interaction and crosstalk between different receptors of the same subfamily. In some cases, HGF/MET signaling is mediated by other membrane proteins that respond to extracellular signals. A single (monomeric) MET interacts with these various cell-surface proteins. These membrane proteins include integrins, the proteoglycan CD44, G protein-coupled receptors (GPCRs), and other tyrosine kinase receptors such as insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), and Erb-B2 receptor tyrosine kinase 3 (ERBB3) interact with a single (monomeric) MET and activate the downstream signal pathways . Co-exprHGF/MET signaling plays a key role in the development of metastasis in uveal melanoma . RobertsForming a metastatic lesion from a primary lesion involves multiple steps, including proliferation, invasion, migration, intravasation, dissemination, extravasation, and colonization in the distant organ. First, the cancer cells need to invade and migrate to adjacent tissues. Cell adhesion helps establish tight connections both between cells and cells and between cells and the matrix . TherefoHGF/MET signaling controls cell migration and cell adhesion mainly through PI3K/AKT pathways in UM cell lines . HGF alsEpithelial-mesenchymal transition (EMT) is an essential step to migration, invasion, and extravasation from a primary lesion. The molecular hallmarks of EMT include E-cadherin down-regulation and up-regulation of mesenchymal-related proteins such as vimentin and N-cadherin to acquire mesenchymal-like characteristics allowing cells to move from the original site to a distant site . AcquiriSeveral studies indicated that the HGF/MET signaling pathway promotes EMT through up-regulation of the E-cadherin repressor and mediates the switch from E-cadherin to N-cadherin in cutaneous melanoma cell lines ,52. Li eIt is of note that the E-cadherin expression and epithelial-mesenchymal transition in UM are controversial. Harbour et al. indicated that the up-regulation of CDH1 and membranous E-cadherin expression in primary UMs are associated with class 2 characteristics, having a high metastatic risk ,55. In fIn general, cells stay close to the tissue to which they belong since the communication between neighboring cells as well as between cells and ECM provides essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. Therefore, the escape mechanism from anoikis is important for tumor cell survival in the bloodstream and different organs. It has been reported that anoikis resistance can be induced through HGF activating both extracellular signaling-receptor kinase (ERK) and PI3K .The PI3K/AKT/mTOR (mechanistic targeting of rapamycin) pathway that is activated by HGF/MET signaling is one of the most important pathways involved in pro-survival features, as it integrates most of the signals derived from integrins and growth factor receptors. This pathway is essential to regulate several cellular functions, such as cell survival and cell growth. AKT activation can modulate the activity of transcription factors that stimulate anti-apoptotic genes or directly phosphorylate pro-apoptotic proteins, such as Beclin (Bcl)-2 antagonist of cell death (Bad) and procaspase-9, inhibiting their function . The actHGF/MET signaling is also a potent inducer of endothelial cell growth and promotes angiogenesis and lymphangiogenesis, in addition to vascular endothelium growth factor (VEGF) and b-FGF signaling . FurtherKoh and Lee showed that HGF upregulates matrix metalloproteinase-9 (MMP-9) in 2 metastatic gastric carcinoma cell lines . MMP-9 iTo understand the structure–function relationship of the ligand, cancer therapy targeting HGF/MET signaling has been developed . There aMET-amplified and MET exon-14-altered cancers. Crizotinib was not effective as adjuvant therapy for patients with high-risk UM (NCT02223819). Currently, a phase 2 study of crizotinib or binimetinib with protein kinase C (PKC) inhibitor in patients with solid tumors harboring GNAQ/GNA11 mutations or protein kinase C (PRKC) fusion is ongoing (NCT03947385).There are many different types of MET signal inhibitors developed over the past decade and have been investigated in ongoing clinical studies. Type I MET inhibitors preferentially bind to the active confirmation of MET kinase, while type II MET inhibitors bind to the inactive confirmation . CrizotiMET-amplified and MET autocrine xenograft tumor models [Merestinib and cabozantinib, type II MET inhibitors, have preclinical activity against several kinase domain mutations . Merestinib (LY2801653) is an oral kinase inhibitor with anti-proliferative and anti-angiogenic activity in r models ,72. Merer models . Ohara er models . Currentr models .Cabozantinib is a multi-kinase inhibitor that inhibits MET and vascular endothelium growth factor receptor 2 (VEGFR2) phosphorylation. Cabozantinib, therefore, inhibits the migration, invasion, and proliferation in a dose-dependent manner . CabometMET exon 14 skipping (METex14).Additionally, Tabrecta (capmatinib) is approved for patients with metastatic NSCLC with Various treatment approaches have been tested for MUM using targeted therapy and immune checkpoint inhibitors. However, the efficacy of these therapies is limited due to pre-existing and/or acquired therapeutic resistance mechanisms. Especially, the tumor microenvironment plays an important role in resistance to cancer therapeutics, including chemotherapy, radiation therapy, targeted therapy, and immunotherapy. In particular, HGF produced by hepatic stellate cells and stromal cells is known to induce resistance to cancer therapy. In this regard, the majority of currently available mouse systems might not be suitable to investigate the role of HGF/MET signaling in cancer treatment resistance mechanisms since mouse HGF has limited binding affinity to human MET . PotentiHGF/MET signaling induces chemotherapy resistance . Xu et aGNAQ/GNA11 mutations; therefore, targeted therapy against this pathway might be effective in UM. Since GNAQ/GNA11 mutations are not easily targetable, research has focused on downstream pathways, such as MAPK, PKC, PI3K, and AKT signaling. Despite impressive growth suppression in in vitro and preclinical mouse models, these signal inhibitors only showed marginal effects on patients with MUM. For example, selumetinib, a mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, did not improve overall survival in MUM patients [More than 90% of UM cells harbor patients . Clinicapatients . Furtherpatients . These cpatients ,86. We ppatients . It is apatients . Furtherpatients .It is also true that treatments with single-agent HGF/MET signaling inhibitors failed to show dramatic improvement in the treatment of cancer patients. It has been reported that autophagy, one of several cellular adaptive responses to therapeutic stresses caused by anti-cancer agents, is critical for the resistance to HGF/MET-targeted therapy . The mecMET proto-oncogene [Radiation therapy causes DNA damage and induces apoptotic cell death . Therefooncogene .HGF/MET signaling is also involved in immune responses in the tumor microenvironment, potentially having a protumor effect. HGF/MET signaling can recruit neutrophils to the tumor microenvironment from the bone marrow . MET-expOn the other hand, there are controversial data suggesting that MET/HGF signaling is also considered to induce an antitumor effect. MET is required for chemoattraction and cytotoxicity of neutrophils in response to its ligand, HGF. HGF/MET-induced neutrophils activation produces nitric oxide that kills tumor cells directly. MET deletion in neutrophils leads to the enhancement of tumor growth and metastasis . There aHGF/MET signaling plays an important role in MUM through various mechanisms. It is also involved in not only metastatic formation but also in resistance to other therapies. Clinical trials targeting HGF/MET signaling are ongoing in patients with MUM. These trials may lead to improvement of overall survival in MUM through an impactful synergy effect with another therapy and by overcoming therapeutic resistance.


Antibiotics are lifesaving therapeutic drugs that have been used by human for decades. They are used both in the fight against bacterial pathogens for both human and for animal feeding. However, of recent, their effects on the gut microbial compositions and diversities have attracted much attention. Existing literature have established the dysbiosis (reduced diversity) in the gut microbiota in association with antibiotic and antibiotic drug doses. In the light of spelling out the varying effects of antibiotic use on gut microbiota, this review aimed at given an account on the degree of gut microbial alteration caused by common antibiotics. While some common antibiotics are found to destroy the common phyla, other debilitating effects were observed. The effects can be attributed to the mode of mechanism, the class of antibiotic, the degree of resistance of the antibiotic used, the dosage used during the treatment, the route of administration, the pharmacokinetic and pharmacodynamics properties and the spectrum of the antibiotic agent. Health status, stress or the type of diet an individual feeds on could be a great proportion as confounding factors. While it is understood that only the bacterial communities are explored in the quest to establishing the role of gut in health, other gut microbial species are somehow contributing to the dysbiosis status of the gut microbiota. Until now, long term natural fluctuations like diseases outbreaks and mutations of the strain might as well rendered alteration to the gut independent of antibiotic treatments. Antibiotics have been used for decades to prevent the proliferation of bacterial pathogens and thus treatment of bacterial infections. They are used to improve the efficiency of animal feeds  and antibiotic resistance genes happen abundantly in GIT. This has brought number of clinical implications since probiotics, commensals and opportunistic pathogens can survive against antimicrobial medications through transferring resistance genes. Although, gene therapy and personalized medicine could remedy antibiotics resistance, probiotic induced resistant mechanism will require broad interventional study to ascertain the host-specific antibiotic resistant , IncI1-type plasmids p2EC1-1 and p94EC-2 respectively . The predicted mechanisms in vertical antibiotic resistant strain transfer from mother to offspring through transfer of AMR strains through breast milk, preterm births and antibiotic exposure. Transfer in utero and during birth (placenta and vagina), through breast milk and transfer of antibiotics in utero  of the pig gut microbiome and these are resistant genes against aminoglycoside and Tetracycline . Persisting resistant bacteria were observed with an increasing trend  . Four days into antibiotic treatment, no sequences corresponding to Bifidobacterium and Clostridium cluster XIVa was detected. However, a marked increase in Enterobacteriaceae was observed. Bacteriodes remained consistent throughout the treatment. Prior to antibiotic initiation, Bacteriodes fragilis were predominant, whereas by day 4, Bacteriodes distasonis became dominant. After cessation of antibiotics, a reversal of the changes was observed, except for Bifidobacterium, which did not return.  genotype (Hoang et al. Akkermansia muciniphila expansion. However, despite this pathological evidence with imipenem, it does not affect numbers of regulatory T cells and SCFAs (Shono et al. Sellimonas intestinalis BR72T resistant to antibiotics imipenem (Versluis et al. One of the outstanding performance for imipenem is that, among many common antibiotics, it was found to treat Escherichia, Campylobacter and Vibrio carries mcr-like genes. With the knowledge that in Sutterella. wadsworthensis mcr-like genes fused to a PAP2-like domain will lay forward some insights into the genetic mobility and strain-specific colisitn resistant (Andrade et al. Phascolarctobacterium succinatutens, Prevotella copri, Prevotella stercorea and expansion of Acidaminococcus fermentans and Treponema succinifaciens in a study of colistin on gut microbiome composition in pig. In addition, the dominant signaling pathway induced by colisitin intervening group were mitogen-activated protein kinase signaling pathway-yeast, various types of N-glycan biosynthesis, pathogenic Escherichia coli infection, protein processing in endoplasmic reticulum and oxidative phosphorylation (Guo et al. A combination of colistin and amoxicillin was found to induced antibiotic resistome and altered gut microbiota. This shift could not be completely recovered to baseline even after FMT treatment (Li et al. The type of antibiotic, the mode of mechanism and the level of resistance determines how it affects the targeted population and the residential microbes. Besides the type-specific effects or alteration of gut microbiota by specific antibiotics, the dosage and duration of antibiotic treatment, route of administration, the pharmacokinetic and pharmacodynamics properties and the spectrum of the antibiotic agent all confer variable alteration to the gut microbiota. The variation in individual gut response on the baseline antibiotics treatment should as well be considered as confounding factors. These are the health status of the person and stress or the type of diet the individual feeds on predominantly. This will lessen the forms of bias in the clinical trials set to establish the effects of antibiotics on the gut. Consequently, depending on the results gathered from short-term intervention alone might not be enough. In essence, long-term natural fluctuations while empirically data are strictly recorded will add more weight on the anticipated Metadata.The study of resistant genes prior to treatment and after, will answer questions as to the confounding factors leading to such mutations. In fact, in the absences of one bacterial population, gene transfer seems to be prominent among the other groups and in the effect, giving rise to varying resistant genes. More scholarship attention should be centered on effects of antibiotics of the gut microbiota leading to antibacterial resistance. Unlike bacteria, studies have established that gut virome is stable over 12 to 26 months and even individual specific, meaning there is no ‘core gut virome’. Bacteriophages are seen to exert effects on FMT treatment of CDI (Zuo et al. Antibiotics are meant to target the bad bacterial population. However, their chemical composition will alter the interspecies relationship. Furthermore, there are still very limited to based arguments on. Most of the virus living in the human gut are bacteriophages. When considering the principle of antibiotics, it has similar functions with these bacteriophages. However, there is a knowledge gap as to understanding the interaction among the pathogens, the benign bacteria, and the bacteriophages. The study of microbiota is no doubt beyond the characterization of diverse communities; it should encompass the total sum of the dynamic interaction among all the microbes, the host and the external factors. We might say that it is still at the infancy since only bacteria are explored to a larger extent. We still don’t know the viral species co-inhabiting human cells. Since the bacteriophages presentable over time, is not exactly the same with the other person, what phage composition is there to limit the bacterial growth? What phyla of bacteria are affected in order to establish a healthy-like gut is a potential research scholarship. In order to have an insight into what the futures of our gut microbiota with respect to the physiological response to disturbance and the changes that these disturbances might bring in, a baseline temporal variation is required (Zaura et al. A baseline of gut virome is exactly what we need to ascertain as to what composition signals a healthy gut. This begs for a broad study that must consider the lifestyle of the cohort at study. The geographical differences and ethnicity since the data will serve as the baseline for the preceding researches. Apparently, the alteration inflicted upon by antimicrobial intervention will be evaluated. Furthermore, knowing what a healthy gut is comprised of, with respect to virome will lead ways to the study of gut-related viral diseases. However, from the emerging data, almost 99% of the gut virus is unknown. To rely on the existing sequence database in establishing the baseline is worth not taken. Assembling the reads into overlapping DNA sequences in a bid to predict protein-coding genes for uniformity is hoped to provide clues as to the type virus.The interventions that this review will predict in order to reduced the antibiotic induced dysbiosis in the gut are; the use of prophylactic antibiotics should be reduced and devising alternatives to antibiotics during pregnancy. Again, studies should be designed to elucidate on the influence of gut microbiome composition and resistome being affected by antibiotic treatment during pregnancy and lactation. Also the mechanisms in which antibiotics can reach mothers milk and concentrations are enough to affect the breast milk microbiome. It will be prudent enough to know with time, how antibiotic influence microbial diversity and the recovery. Moreover, at strain level, transfer of resistant bacteria in utero should be investigated as to affecting early gut colonization. This should be jointly studied with the risk factors for transmission. Altogether, these could help in establishing healthy gut among mothers and their offsprings.In summary, our review showed that both gram-positive and gram-negative bacteria are disrupted with broad-spectrum antibiotics as oppose to narrow spectrum antibiotics. However, what limits interventions to mitigate towards these damages the gut microbiota is our inadequate knowledge in antibiotic activity spectra, the resistant mechanisms of gut microbes against various used antibiotics and the extent of damages specific antibiotics caused. While non antibiotics such as probiotics contribute to microbiome-facilitated antibiotic resistance, the interactions between drugs and microbiome are found to be bidirectional. Antibiotics can disrupt gut microbiota and microbes as well can modulate the drugs thereby modifying the chemical composition and leads to the antimicrobial resistance. Now, our hopes are precision medicine, resistant gene therapy and system biology approaches to leverage the host microbe interaction with an effective and safe treatment strategies.


Dialister, Megasphaera, and Turicibacter, and lactate-producing Sharpea as well as Akkermansia, Weissella, and Pediococcus were increased in the MET group. The metabolic analyses show that maternal methyl-donor micronutrient addition increased the concentrations of individual and total SCFAs of 21-day piglets and increased metabolism mainly involving amino acids, pyrimidine, and purine biosynthesis. Collectively, maternal methyl-donor micronutrient addition altered gut microbiota and the fecal metabolic profile, resulting in an improved weaning weight of offspring piglets.This study aimed to investigate the effects of maternal methyl-donor micronutrient supplementation during gestation on gut microbiota and the fecal metabolic profile in offspring piglets. Forty-three Duroc × Erhualian gilts were assigned to two dietary groups during gestation: control diet (CON) and CON diet supplemented with MET . The body weights of offspring piglets were recorded at birth and weaning. Besides this, fresh fecal samples of offspring piglets were collected at 7, 14, and 21 days. The gut microbiota composition, metabolic profile, and short-chain fatty acid (SCFA) profiles in the fecal samples were determined using 16S rDNA sequencing, liquid chromatography-mass spectrometry metabolomics, and gas chromatography methods, respectively. The results showed that maternal methyl-donor micronutrient supplementation increased the microbiota diversity and uniformity in feces of offspring piglets as indicated by increased Shannon and Simpson indices at 7 days, and greater Simpson, ACE, Chao1 and observed species indices at 21 days. Specifically, at the phylum level, the relative abundance of Firmicutes and the Firmicutes to Bacteroidetes ratio were elevated by maternal treatment. At the genus level, the relative abundance of SCFA-producing  The gut microbiota and fecal metabolic profile of neonates are closely related to immunity, disease, growth, and development. The colonization of microbial communities in the intestines is a key process in infant development ; the intMethyl-donor micronutrients (MET), including folate, choline, betaine, methionine, cobalamin, pyridoxine, and so forth, are demonstrated to participate in the synthesis of nucleotides, proteins, and lipids via epigenetic mechanisms ; meanwhiIn our previous study, we found no differences in the reproduction performance of sows between CON and MET . However, maternal MET supplementation during pregnancy promotes skeletal muscle differentiation and maturity in newborn and weaning pigs and improves the growth performance of the offspring . This meThis study was conducted under the Chinese guidelines for animal welfare. All animal experiments were approved by the Animal Care and Use Committee of Jiangxi Agricultural University .−1 methionine , 16.3 mg kg−1 folic acid , 2,230 mg kg−1 choline , 0.15 mg kg−1 vitamin B12 , and 1,180 mg kg−1 vitamin B6 . The dosage of methyl-donor micronutrients was added according to previous studies  were artificially inseminated and then allotted by body weight to two dietary treatments. The two experimental diets were supplemented with or without methyl-donor micronutrients in the basal diet. There were 21 and 22 gilts in the control group (CON group) and Methyl-donor micronutrients group (MET group), respectively. The MET-supplemented diet contained 4,700 mg kg studies  three tiAfter parturition, body weights (BW) were measured at birth and weaning (24 days). Six litters per group were selected, and one median-birth-weight piglet from each litter were sampled for feces collection at days 7, 14, and 21 and then snap-frozen in liquid nitrogen and stored at −80°C for gut microbiota, short-chain fatty acid (SCFA), and metabolomics analyses. Fecal 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS) metabolomics were performed according to the manufacturer's instructions .Serum from newborn and weaning offspring was analyzed for S-adenosylmethionine (SAM) and homocysteine (Hcy) using the enzyme-linked immunosorbent assay (ELISA) kits purchased from MLBIO .® DNA PCR-Free Sample Preparation Kit  and quantified using a Qubit @ 2.0 Fluorometer (Thermo Scientific). Finally, 250 base pair paired-end sequencing was performed using the Illumina HiSeq 2500 platform.The total genomic DNA was extracted from fecal samples with the Cetyltrimethylammonium Bromide (CTAB) method. DNA concentration and purity were monitored on an agarose gel. The DNA was then diluted accordingly using sterile water. The bacterial 16S rDNA gene of various regions (3–4) was amplified by polymerase chain reaction (PCR) using a specific primer . The PCR product was detected with 2% agarose gel and purified with the Qiagen Gel Extraction Kit  following the manufacturer's instructions. The library was generated by TruSeqhttp://qiime.org/scripts/split_libraries_fastq.html). Paired-end reads were merged using Fast Length Adjustment of Short reads . The clean data were obtained by specific splice and filtering of the raw sequence data. Sequences with ≥97% similarity were assigned to the same operational taxonomic units (OTUs) and the OTU was screened for further annotation; analysis was performed using Uparse software . The abundance information of OTUs was normalized using the serial number standard corresponding to the sample with the least sequence and both alpha  and beta diversity  and unweighted pair-group method with arithmetic means) were performed based on the normalized data of OTU abundance information. The alpha and beta diversity were calculated with QIIME and displayed with R software (Version 2.15.3). PCoA was based on unweighted UniFrac distances using the WGCNA, stat, and ggplot2 packages in R. To determine the significance test of community structure differences between groups, permutational multivariate analysis of variance  was performed in R to calculate P-values. Additionally, to further explore the differences in the community structure (phylum and genus) between the two groups of samples, the linear discriminant analysis (LDA) effect size (LEfSe) method was used to compare the differences in the taxonomic levels; the LDA score was set at 2.0 for a biomarker. In LEfSe analysis, the non-parametric factorial Kruskal–Wallis (KW) sum-rank test was used to detect all species with significant differential abundance, and the Wilcoxon rank-sum test was used to investigate biological consistency among subclasses.Sequencing data were analyzed using the quantitative insights into microbial ecology (QIIME)  for 15 min to obtain a supernatant. Then 25% of metaphosphoric acid solution was added in a ratio of 9:1 before centrifugation at 3,000 g for 10 min. The supernatant was aspirated with a syringe and filtered through a 0.45 mm filter membrane. Acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, and total SCFA were determined using capillary column gas chromatography , column temperature = 120°C, injector temperature = 220°C, detector temperature = 250°C, and each injection volume was 1 μL.The standard substances of SCFAs are as follows: acetic acid , propionic acid , isobutyric acid , butyric acid , isovaleric acid , and valeric acid .Aliquots of 100 mg of fecal samples were homogenized with 200 μL of ultra-pure water and mixed with 800 L methanol/acetonitrile  to remove the protein. After centrifugation , the supernatant was collected for analysis.Analyses were performed using liquid chromatography  coupled with quadrupole time-of-flight . For hydrophilic interaction liquid chromatography (HILIC) separation, samples were analyzed using a 2.1 × 100 mm ACQUIY UPLC BEH Amide 1.7 μm column . Chromatographic conditions and Q-TOF mass spectrometry conditions were as outlined by Liu et al. , electrot-test analysis were performed. Significantly different metabolites were identified based on the combination of a statistically significant threshold of variable influence on projection (VIP) values obtained from the OPLS-DA model and two-tailed Student's t-test  from the raw data. VIP > 1.00 and P < 0.05 were considered as significantly different metabolites. VIP > 1.00 and 0.05 < P < 0.10 were regarded as differential metabolites.The raw MS data were converted to MzXML format using ProteoWizard MSConvert and processed using the XCMS online package (version 1.20.1) for further processing. Metabolites were identified by accuracy mass (<25 ppm) and secondary spectral matching to retrieve a self-built database from the laboratory (Shanghai Applied Protein Technology). After data preprocessing by Pareto-scaling, multidimensional statistical analysis [orthogonal partial least squares discriminant analysis (OPLS-DA)] and Student's t-test. The individual sow was considered as the experimental unit for growth performance, one piglet per pen was used as the experimental unit for SCFA and methyl metabolite profile and microbial and metabolite analysis. Statistical analysis was performed on SPSS 24.0 software (SPSS Inc.). Correlations between altered metabolites screened from fecal metabonomic and perturbed gut microbe genera screened from 16S rDNA gene sequencing analysis were assessed by Spearman's correlation analysis. GraphPad Prism 8.0  was used to plot the images. Data are shown as means ± SEM. A value of P < 0.05 was considered statistical significance.Data were tested for normality using the Shapiro–Wilk test before statistical analysis. The growth performance, SCFA, and serum methyl metabolite profile between CON and MET piglets was assessed by independent-samples P > 0.05). However, the body weight at weaning was greater for piglets from sows fed the MET vs. CON diet (P < 0.05)  .P = 0.089, P < 0.05). Moreover, the serum SAM concentration in piglets at birth and weaning was increased in the MET group .Maternal MET supplementation during gestation decreased serum Hcy concentration in the offspring at birth (P < 0.05). The ACE, Chao1, observed species, and Simpson indices were higher in 21-day piglets from sows fed the MET vs. CON diet (P < 0.05).The alpha diversity indices of fecal microbiota in suckling piglets are shown in R2 = 0.17, P < 0.05) and 21 days .P < 0.05)  .unidentified_Prevotellaceae, Lactobacillus, Bacteroides, unidentified_Muribaculaceae, unidentified_Ruminococcaceae, Fusobacterium, Streptococcus, Phascolarctobacterium, Alloprevotella, unidentified_Spirochaetaceae  (The 10 most abundant genera in the feces of offspring piglets are aetaceae . The rel < 0.05) .Differences in the relative abundances of the microbial community components of CON and MET offspring were further analyzed by LEfSe. Compared with the CON group, including unknown bacteria, 14 microbial phlotypes were higher and 14 were lower in the 7-day suckling piglets from MET-fed sows . At the Dialister, Ralstonia, Megasphaera, Intestinimonas, Terrisporobacter, Anaerotrumcus and families Peptostretococcaceae, Chitinophagales and order Chitinophagaceae (P < 0.05), decreased genera Faecalibacterium, Rothia, Sedimentibacter, Aerosharea, unidentified-Prevotellaceae, Chlamydia and families Chlamydiaceae, Prevotellaceae, unidentified-Solibacterales and order Solibacterales, Chlamydiales and class unidentified-Chlamydiae, phylum Chlamydiae (P < 0.05). At the age of 14 days, the suckling piglets from sows fed MET had significantly higher family Christensenellaceae (P < 0.05); at the age of 21 days, the suckling piglets from sows fed MET had increased genera Streptococcus, Romboutsia, Agathobacter, Akkermansia, Sharpea, Rothia, Rubrobacter, Paraeggerthella, Pediococcus, Kurthia, Mogibacterium, Turicibacter, Foumirerlla and families Streptococcaceae, Akkermansiaceae, Micromonosporaceae, unidentified-Rubrobacterales, Micrococcaceae, Pseudomonadaceae, Flavobacteriaceae and orders Lactobacillales, Clostridiales, Verrucomicrobiales, Micromonosporaceae, Oceanospirillales, Rubrobacterales, Gaiellales, Micrococcales, Pseudomonadales and classes Bacilli, Clostridia, Rubrobacteria, Verrucomicrobia, unidentified-Actinobacteria, Thermoleophilia and phyla Firmicutes, Verrucomicrobia (P < 0.05), decreased genera Odoribater, Parabacteroides, unidentified-Cyanobacteria, Ochrobactrum and families Tanerellaceae, unidentified-Cyanobacteria, Rikenellaceae and order unidentified-Cyanobacteria, Bacteroidales and classes unidentified-Cyanobacteria, Bacteroidia and phyla Cyanobacteria, Bacterioidetes (P < 0.05).Specific differentiated phylotypes were identified in 7-day suckling piglets from sows fed the MET vs. CON diet: increased genera P > 0.05). However, the concentration of acetate, butyrate, and total SCFA were increased in the feces of 14-day piglets from sows fed the MET vs. CON diet (P < 0.05). Besides this, maternal MET supplementation increased the concentration of acetate, propionate, isobutyrate, butyrate, isovalerate, valerate, valerate, and total SCFA in the feces of 21-day piglets (P < 0.05).As displayed in As graphed in p-value of the Student's t-test, the biologically important difference metabolites were mined. Including significantly differential and differential metabolites, a total of 24 differentiated metabolites were identified from two data sets in 7-day suckling piglets (http://www.genome.jp/kegg/) to pathways in offspring that may have been influenced by maternal MET during gestation. These findings revealed that the potential biomarkers contribute to various processes, including biosynthesis of amino acids, amino acid metabolism, pyrimidine metabolism, purine metabolism, amino sugar and nucleotide sugar metabolism, bile secretion, thiamine metabolism, vitamin B6 metabolism, riboflavin metabolism, nicotinate and nicotinamide metabolism, sulfur metabolism, and glutathione metabolism . Pyridoxal closely related to vitamin B6 metabolism was increased 1.770- fold in MET compared with the CON group (P < 0.05). Indoleacetic acid closely related to tryptophan metabolism was decreased 0.191-fold in MET piglets compared with CON piglets (P < 0.05). Riboflavin metabolism (flavin adenine dinucleotide and flavin mononucleotide) were decreased 0.59- and 0.42-fold in MET piglets compared with CON piglets (P < 0.05). In the 14-day suckling piglets, critical metabolites  closely related to biosynthesis of amino acids were increased by 4.95- and 2.16-fold in the MET group compared with the CON group, respectively (P < 0.05). Thymine, 2'-deoxyuridine, uracil, urea, and deoxycytidine, which are involved in pyrimidine metabolism, were increased in the MET compared with the CON group by 2.36-, 3.22-, 2.68-, 1.45-, and 7.63-fold, respectively (P < 0.05), and concentrations of adenosine, adenine, and deoxyinosine, which are involved in purine metabolism, were increased in the MET compared with the CON group by 1.39-, 3.81-, and 1.18-fold, respectively (P < 0.05). Critical metabolites  closely related to bile secretion were decreased in the MET group. In addition, critical metabolites closely related to amino acid and vitamin B6 metabolism were increased in the MET group compared with the CON group (P < 0.05). In the 21-day suckling piglets,: critical metabolites related to biosynthesis of amino acids, amino acid metabolism, and vitamin B6 metabolism, were increased in the MET group compared with CON group although bile secretion was decreased in MET piglets (P < 0.05).Specific differentiated metabolites were identified in 7-day suckling piglets of CON-fed and MET-fed sows: Deoxycytidine closely related to pyrimidine metabolism was increased 5.187-fold in MET piglets compared with CON piglets . Indoleacetic acid was negatively associated with the genera Dialister and Terrisporobacter and positively correlated with the genera Sedimentibacter, unidentified-Prevotellaceae, and Chlamydia (P < 0.05). The genera Dialister, Megasphaera, and Terrisporobacter were positively correlated with vitamin B6 (P < 0.05). In addition, the genus Sedimentibacter was positively correlated with flavin adenine dinucleotide and flavin mononucleotide (P < 0.05). In the 21-day suckling piglets . 1-Methylnicotinamide was negatively associated with the genera Agathobacter, Paraeggerthella, and Pediococcus and positively correlated with the genera Odoribater and Ochrobactrum (P < 0.05). Nine genera, including Streptococcus, Akkermansia, Rothia, Rubrobacter, Pediococcus, Mogibacterium, Turicibacter, and Foumirerlla were positively correlated with vitamin B6 (P < 0.05).A Spearman's correlation matrix was generated to explore the correlation between the bacterial genera and candidate compounds that were affected by maternal nutrition. As shown in  piglets , sarcosiIn a previous study, we found no differences in reproductive performance of sows between CON and MET; however, we observed that the offspring of sows fed with the MET diet grew faster than control offspring, and maternal MET exposure can promote skeletal muscle differentiation and maturity and improve the skeletal muscle mass of weaning piglets . PreviouThe gut microbiota diversity is highly related to host health and metabolic capacity . The lowDialister and Megasphaera in the feces than CON offspring, and MET offspring at 21 days had a significantly higher abundance of Romboutsia, Akkermansia, Sharpea, Turicibacter weissella, and pediococcus in the feces than CON offspring. Dialister populations utilize succinate and produce propionate, Megasphaera can convert lactic acid to propionate via the acrylate pathway  of NCBI, and the SRA accession number is The animal study was reviewed and approved by the Animal Care and Use Committee of Jiangxi Agricultural University .JY and TZ designed the study. QH, LJ, and JH performed the animal feeding experiment and sample analysis. FX assisted with SCFAs analysis. QH collected the data and wrote the manuscript. ZW and JC finalized the manuscript. All authors agree to be accountable for the content of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Uncomplicated cystitis is one of the most common reasons for antibiotic treatment in otherwise healthy women. Nationwide studies on antibiotic treatment for this infection and in relation to factors beyond the infection itself have hitherto not been available. Methods: This was a nationwide open cohort study consisting of 352,507 women aged 15–50 years with uncomplicated cystitis (2006–2018). The outcome was a redeemed antibiotic prescription within five days from the cystitis diagnosis. Logistic regression models were used to examine the relationship between the outcome and the predictor variables. Results: This study identified 192,065 redeemed treatments (54.5%). Several sociodemographic variables were associated with antibiotic treatment. For example, women with the lowest income had an odds ratio (OR) of 1.26 (95% CI 1.23–1.28) compared to those with the highest income. History of cervical cancer and high parity were also associated with lower treatment rates. Conclusion: This study presents novel factors beyond the infection which seem to affect the antibiotic treatment for uncomplicated cystitis in women. Future studies to investigate possible mechanisms are warranted in order to properly use our findings. This may help healthcare workers and planners to provide a more equal treatment plan for this common infection, which may reduce misuse of antibiotics, decrease costs and improve efforts against antibiotic resistance. The worldwide increase in antibiotic consumption and resistance is of great concern . SeveralEscherichia coli followed by Staphylococcus saprophyticus, and are thus often effectively treated with a short duration of antibiotic therapy [Urinary tract infection (UTI) is a leading cause of antibiotic use . Uncompl therapy ,13,14,15 therapy ,17 and 5 therapy ,18,19. I therapy . However therapy ,11. As s therapy .Sweden’s tax-financed healthcare services have the goal to provide healthcare on equal terms for the entire population, irrespective of sociodemographic factors or previous ailments. However, we have recently found that sociodemographic factors are associated with uncomplicated cystitis in primary healthcare settings . SociodeThis study found that antibiotic treatment rates for uncomplicated cystitis varied amongst different sociodemographic groups of women. Most noteworthy were the associations with country of origin, region of residence and socioeconomic status. Parity and cervical cancer also seemed to have an impact on the treatment rates. This suggests that antibiotic treatment for uncomplicated cystitis could be affected by factors that may be beyond the infection itself.To our knowledge, worldwide, this is the first population-based study to investigate antibiotic treatment for uncomplicated cystitis in women diagnosed in primary healthcare settings and specifically the association with sociodemographic factors. The previous absence of large-scale studies in this field is likely due to the hitherto lack of nationwide primary healthcare diagnoses. Sociodemographic disparities have, however, been found in general antibiotic prescription in Sweden , which sSeveral explanations might exist behind the findings of our study. In general, the differences in antibiotic treatment between groups could partly be attributed to differences in healthcare access and quality between healthcare providers and demographic regions. It is also possible that certain groups of women have lower adherence rates to redeem antibiotic prescriptions than others for several reasons. For example, the distance to pharmacies could affect the willingness in a patient to travel to and thus redeem an antibiotic prescription (lack of adherence). Another reason might be age differences and cultural differences concerning the patients’ expectations to treatment options for their symptoms. For example, the somewhat higher treatment rate in young women could be due to less experience or knowledge in self-treatment compared to older women, thus increasing their desire to receive antibiotic therapy for their symptoms. Furthermore, as has been suggested before , it is aAn important limitation with the present study is that it did not have access to data on the symptoms or clinical presentation in the patients. Thus, it was not possible to assess whether the observed differences in antibiotic treatment depended on differences in the patients’ symptoms. Secondly, we did not have access to data on adherence rates. Although it was shown that almost all antibiotic prescriptions were redeemed by patients in a CDC report from 2017 , smallerAntibiotics are important drugs that save many lives and lower morbidity due to infections . AlthougMainly thanks to the Swedish strategic program against antibiotic resistance  was defined as the first UTI antibiotic redeemed (measured as prescription from a physician dispensed at a pharmacy) within five days after a diagnosis of uncomplicated cystitis. The outcome is generally referred to as “antibiotic treatment” in the manuscript. The STROBE statement for cohort studies was considered . This reThe first diagnosis of acute uncomplicated cystitis, hereafter referred to as uncomplicated cystitis, in women was identified in the Swedish Primary Health Care Register during the study period. The data sources were similar to those used in a previous study that investigated the risk of uncomplicated cystitis . The 10tThe following antibiotic groups were assessed based on their ATC code: penicillins with an extended spectrum (J01CA), for example, pivmecillinam; beta-lactam/b-lactam inhibitor combinations (J01CR); cephalosporins ; trimethoprim derivatives (J01EA), i.e., trimethoprim; sulphonamides and trimethoprim combinations (J01EE), i.e., trimethoprim/sulphamethoxazole; fluoroquinolones (J01MA), for example, ciprofloxacin; and nitrofuran derivatives (J01XE), i.e., nitrofurantoin. Five-level ATC codes were available for the whole period, and seven-level ATC codes were available during the first eight years (2006–2013) of the study period. The five-level ATC codes were used to include the potential antibiotic alternatives for uncomplicated cystitis listed in international  and/or SThe predictors investigated were measured at baseline, i.e., time of the cystitis diagnosis. Age groups were defined as being between 15 and 24, 25 and 34, 35 and 44 or 45 and 50 years of age. Socioeconomic status was defined by individual education and family income. Educational level was classified into three different categories based on the duration of school years attended: compulsory schooling or less ≤9 years); short or partially completed high school education (10–11 years); or completed high school education or more, such as university or college education (≥12 years). For those aged 15–17 years in the youngest age group, the highest educational level of the parents was used. Family income was categorized into four groups based on a weighted average income in each family [ years; sThe study population was identified in the Swedish Primary Healthcare Register, which includes nationwide clinical diagnoses from primary healthcare consultations in Sweden. The coverage of the data varied by time period and region. The starting time points differed because the patient records were digitalized in different time periods in the different regions. The register contained 72% of the population in Sweden in 2015 and around 90% of the population at the end of the study . The folDescriptive statistics  were calculated in each category of the different variables. To test for the association between the predictor variables and the outcome (redeemed antibiotic prescription for uncomplicated cystitis), logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). The study period started on 1 January 2006 and proceeded until redeemed antibiotic prescription (within five days), death, emigration or end of the study period on 31 December 2018. Three models were used, where Model 1 was a univariate model, Model 2 was adjusted for age and Model 3 was adjusted for age and the other covariates. Missing values (range 0.0–1.3%) were not excluded. For education (0.9%) and income (1.3%), they were instead included in the groups with the lowest levels of education and income, respectively. Unknown region of residence (0.7%) was included in the category large cities. Unknown country of origin  was included in the category Sweden. A two-tailed p-value of <0.05 was considered for statistical significance. We used SAS version 9.4  for all statistical analyses.The present study was a non-intervention nationwide register study of pseudonymized secondary data obtained from Swedish authorities and was approved by the ethical review board in Lund. All methods were performed in accordance with the relevant guidelines and regulations.The funding sources of this study were all non-commercial and had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. All authors confirm that they had full access to all the data in the study and accept responsibility to submit the paper for publication.This study found that certain sociodemographic factors, parity, and cervical cancer might affect antibiotic treatment for uncomplicated cystitis in women. These findings represent important new information on factors beyond the infection itself that might affect the treatment of this bacterial infection in women. Future studies to investigate possible mechanisms are warranted in order to properly use our findings. The findings may help to provide a more equal treatment plan for this common infection, which may spare women from misuse of antibiotics and decrease the costs for both patients and the healthcare system. Strategic programs could also use our findings in efforts against antibiotic resistance.


At present, there is no clear design standard for segmental joints of large-diameter shield tunnels under high water pressure. In this paper, a theoretical calculation model for the bending stiffness of segmental joints under high water pressure is proposed. The numerical simulation method is used to investigate the failure and crack formation processes of single-layer and double-layer lining segments under large axial forces. The effects of axial force, bolt strength, and concrete strength on the bending stiffness of joints are then studied using a theoretical calculation model of segmental joints. The results show that under extremely high water pressure, the influence of double lining on joint stiffness is limited. It is more rational and safe to compute the bending stiffness of segmental joints using this theoretical model rather than the numerical simulation method. The parameter analysis reveals that increasing the bolt strength has a minor impact on bending stiffness and deformation, whereas increasing the concrete strength has the opposite effect. The influence of ultimate bearing capacity and deformation decreases non-linearly as the axial force increases. Tunnels play an essential role in the transportation infrastructure. For example, traffic tunnels such as roads or railways are built under the sea or rivers to speed regional connections and economic development in China, mainly using the large-diameter shield construction technology.The shield tunnel lining structure consists of segments assembled into rings through joints. In the actual working state, the segmental joint is subjected to a combination of axial force, shear force, and bending moment. The mechanical behavior of the concrete joint shows complex nonlinearity, which affects the mechanical properties of shield tunnel lining structures. Therefore, the mechanical characteristics of segmental joints have always been a vital issue and important research topic in shield tunnel design.Previous studies ,2,3,4 haThe joint stiffness is related to the bearing capacity of the shield tunnel design and the operation performance under normal operating conditions. Especially for subsea tunnels under high water pressure, the bending stiffness of the joint directly affects the waterproof performance of the tunnel and thus affect the operation and maintenance of the whole tunnel.The calculation model of segmental joints without lining was proposed by Murakami and Koizumi . The modAt present, Feng et al.  believe With improved computer ability, the accuracy, convenience, and low cost of numerical simulation are also highlighted. Many studies ,20,21,22This paper conducts three-dimensional simulations for different axial loads and single- and double-layer linings of large-diameter shield tunnels under high water pressure. The proposed joint bending stiffness mechanical model is used to calculate the corresponding bending stiffness of the joints under different axial forces, concrete strengths, and bolts. The sensitivity of various factors to the stiffness of the segmental joints is analyzed, which provides a reference for the segment design of large-diameter shield tunnels under high water pressure.The flat-shaped segment is used instead of the actual arc-shaped segment. In fact, this simplification was used in previous experiments. Because the evident structural response of the joint is restricted to the terminal area, according to Saint-Venant’s principle , there iThe single-layer lining segment model and the double-layer lining segment model were created to investigate lining effects on segments and joints, respectively. Concrete and bolts are employed the SOLID65 and LINK180 elements, respectively. The segment concrete material adopted the empirical analogy method, referring to the 15 m large shield tunnel selection specifications of the Shanghai Chongming Yangtze River Crossing Tunnel. The lining material is C60 concrete, and the mechanical properties are shown in The segment ring of the shield tunnel is composed of segments such as the cap block, adjacent block, and standard block, which are generally connected by straight bolts, bent bolts, and oblique bolts (pin-type bolts). However, straight bolts were chosen for simulation in this study due to the convenience of numerical simulation.The stress–strain uniaxial curve formula of concrete follows.The size of the rectangular hand hole is 200 mm × 80 mm × 160 mm. The bolt used is an 8.8-grade M24 high-strength bolt with a yield strength of 640 MPa and a diameter of 27 mm. Water and soil pressure is the axial force exerted on the segment. The horizontal axial force loading ranges from 10,000 to 20,000 kN, and the load increment value is 2000 kN. There are six groups of axial-force-loading conditions. The vertical force load increases by 200 kN each time until the concrete of the joints crushes, or the bolt pulls out. The loading diagram of single-layer lining and double-layer lining is shown in The stress concentration state of the contact surface between the bolt and the hand hole is precisely the opposite of the hand hole. When the bolt is not stressed, the stress on the contact surface of the bolt and the hand hole is greater than the stress on the middle and lower nodes, as shown in N = 10,000 kN. At the beginning of the joint under force, the joint cracks first emerged at the point of stress concentration and extended lengthwise from both ends of the short side of the hand hole. Because of the restriction effect at the support, lateral cracks appeared outside the section. With the gradual transfer of the stress concentration area after the segmental joint is opened and the bolt begins to bear the strain, the form of the crack also changes. The vertical cracks generated by the pulling force of the hand hole begin to form on the side of the joint as the tension carried by the bolt increases, as shown in The crack distribution in simulation is consistent with the scaled experiment test by Wang et al. . Figure The specimen is the straight bolt with rectangular hand hole test piece in the experiment. In the numerical simulation, the peak load and peak displacement of the straight bolt and rectangular hand hole specimen are larger than the actual test. There are two reasons that may explain this observation:(1) In the test, the concrete specimen often spalls in a large area when it reaches about 80% of the peak load. However, this factor is not considered in the numerical simulation, which causes the peak load to be too large.(2) The randomness and variability of the concrete specimen itself, and the peak load and peak displacement in the test are the averages of the three specimens. However, the randomness and variability of the concrete specimen itself were not considered in the numerical simulation.M–ϕ curves of joints under different axial pressures are shown in The (1)The deformation of the segmental joint conforms to the plane section assumption without considering the influence of the hand strain and the bolt disengagement factors.(2)The nonlinear constitutive equation of concrete can be linearly simplified by the equivalent principle of deformation energy.(3)The influence of elastic liner, tenon-grooves interface, and locating block on joint mechanical behavior are ignored.(4)According to the numerical analysis of the three sections, the high water pressure shield tunnel adopts the single-layer lining.(5)The bolt is under tension without compression.The constitutive relation curve of concrete follows:C50, C60, the correlation coefficient needs to be modified using the strain energy principle. The modified formula is:When the strength grade of concrete is less than or equal to 0h is the distance from the segment’s compression zone edge to the bolt’s centroid, and h is the segment’s section height.In The segments of a large-diameter deep-buried shield tunnel present small eccentric compression. In this situation, concrete failure in the compression zone of the segmental joint under positive bending moment is generally earlier than the bolts. Therefore, the joint from stress to failure can be assumed at four stages and the secant method to calculate bending stiffness applies. The bolts in the segmental joints are simplified to elastic–ideal plastic materials. The bending stiffness of the joint under different stress states follows:Stage 1: Whole section in compression.tσ is the compressive stress at the lower part of the segmental joint, and bσ is the compressive stress at the upper part of the segmental joint. Nc is the resultant force of the concrete under compression, and yc is the distance from the point of action of the resultant concrete force to the upper edge of the segmental joint.As shown in Simplified balance equation:The boundary conditions to be satisfied in this stage are Stage 2: The joint is opened, but the bolt is not forced.The stress of concrete in the compression zone is simplified to a triangular stress distribution. At this stage, the concrete is always in the elastic stage.From equilibrium equations:The bending moment:Combining Equations (13) and (14):The boundary conditions to be satisfied in this stage are: The equilibrium equation of force follows:According to the plane section supposition:Let The curvature is obtained from The boundary conditions are: Stage 4: Concrete yielded in the compression zone at the segmental joint; bolt did not yield.Combining Equations (21)–(23):The iterative solution can solve for the concrete height M is:The action point of resultant force follows:The curvature is obtained from The boundary conditions are Under the negative bending moment, the shield segmental joint experiences two stages. Since the derivation process is similar to the positive bending moment, the negative bending moment derivation process is omitted.Stage 1: Whole section in compression.M and N loads is:The curvature of the section under The boundary conditions to be satisfied in this stage are: Stage 2: The top of the joints is open, and the concrete is still elastic.The relationship between curvature and bending moment is:The boundary conditions to be satisfied in this stage are: M–ϕ curves. From the perspective of practical engineering, the theoretical calculation is safer. The mechanical parameters of segmental materials are shown in N = 6000~14,000 kN, increasing at a rate of 2000 kN. According to the axial load, M–ϕ, θ–MK, θ–ϕK and curves under different axial force conditions are obtained by the theoretical analysis model, as shown in The axial load range selected in this section is It can be seen that the ultimate bearing capacity and ultimate deformation under negative bending moment conditions are more sensitive to the increase of axial force. At the same time, with the increase of axial force, the ultimate bearing capacity and ultimate deformation both decrease nonlinearly.C50 and C70 concrete with compressive strength C50 to C60. The influence of increased concrete strength is diminished again as bolt tension increases. In conclusion, the sensitivity of the influence of the increase of concrete strength on the flexural bearing capacity and flexural stiffness of the joint is positively correlated.It can be seen from Select the same diameter M24 bolt, and the strength grade is 10.9 and 8.8. The comparison of the calculated results is as The numerical simulation of the segmental joint provides a basis for the theoretical analysis of joint bending stiffness. The theoretical model of the bending stiffness of the segmental joint proposed in this paper can reflect its bending performance well.(1) In terms of bearing capacity, the secondary lining has limited effect on improving the bearing capacity of the joint, which is not used as a bearing structure.(2) Under the condition of large axial force, the axial force gradually changes from improving the joint bearing capacity to causing joint failure.(3) The ultimate bearing capacity and bending stiffness increased by concrete strength are also affected by the strength of the bolts. Therefore, if high-strength concrete is used, it is necessary to consider matching reasonable high-strength bolts to avoid having the bolt yielding first.(4) Increasing concrete strength significantly improves the overall flexural bearing capacity and stiffness of the segmental joint. In contrast, bolt diameter and bolt strength have little effect on the flexural bearing capacity and stiffness of the joint, especially under large axial force.(5) The failure process and crack development of the segmental joint model in the numerical simulation are consistent with the experimental data, which proves its reliability.