A LaCl3-based lithium superionic conductor compatible with lithium metal.

Inorganic superionic conductors possess high ionic conductivity and excellent thermal stability but their poor interfacial compatibility with lithium metal electrodes precludes application in all-solid-state lithium metal batteries1,2. Here we report a LaCl3-based lithium superionic conductor possessing excellent interfacial compatibility with lithium metal electrodes. In contrast to a Li3MCl6 (M = Y, In, Sc and Ho) electrolyte lattice3-6, the UCl3-type LaCl3 lattice has large, one-dimensional channels for rapid Li+ conduction, interconnected by La vacancies via Ta doping and resulting in a three-dimensional Li+ migration network. The optimized Li0.388Ta0.238La0.475Cl3 electrolyte exhibits Li+ conductivity of 3.02 mS cm-1 at 30 °C and a low activation energy of 0.197 eV. It also generates a gradient interfacial passivation layer to stabilize the Li metal electrode for long-term cycling of a Li-Li symmetric cell (1 mAh cm-2) for more than 5,000 h. When directly coupled with an uncoated LiNi0.5Co0.2Mn0.3O2 cathode and bare Li metal anode, the Li0.388Ta0.238La0.475Cl3 electrolyte enables a solid battery to run for more than 100 cycles with a cutoff voltage of 4.35 V and areal capacity of more than 1 mAh cm-2. We also demonstrate rapid Li+ conduction in lanthanide metal chlorides (LnCl3; Ln = La, Ce, Nd, Sm and Gd), suggesting that the LnCl3 solid electrolyte system could provide further developments in conductivity and utility.

Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss.

The Food and Drug Administration­approved drug sirolimus, which inhibits mechanistic target of rapamycin (mTOR), is the leading candidate for targeting aging in rodents and humans. We previously demonstrated that sirolimus could treat ARHL in mice. In this study, we further demonstrate that sirolimus protects mice against cocaine-induced hearing loss. However, using efficacy and safety tests, we discovered that mice developed substantial hearing loss when administered high doses of sirolimus. Using pharmacological and genetic interventions in murine models, we demonstrate that the inactivation of mTORC2 is the major driver underlying hearing loss. Mechanistically, mTORC2 exerts its effects primarily through phosphorylating in the AKT/PKB signaling pathway, and ablation of P53 activity greatly attenuated the severity of the hearing phenotype in mTORC2-deficient mice. We also found that the selective activation of mTORC2 could protect mice from acoustic trauma and cisplatin-induced ototoxicity. Thus, in this study, we discover a function of mTORC2 and suggest that its therapeutic activation could represent a potentially effective and promising strategy to prevent sensorineural hearing loss. More importantly, we elucidate the side effects of sirolimus and provide an evaluation criterion for the rational use of this drug in a clinical setting.

Establishing Exceptional Durability in Ultralow-Temperature Organic-Sodium Batteries via Stabilized Multiphase Conversions.

Operation of rechargeable batteries at ultralow temperature is a significant practical problem because of poor kinetics of the electrode. Here, we report for the first time stabilized multiphase conversions for fast kinetics and long-term durability in ultralow-temperature, organic-sodium batteries. We establish that disodium rhodizonate organic electrode in conjunction with single-layer graphene oxide obviates consumption of organic radical intermediates, and demonstrate as a result that the newly designed organic electrode exhibits excellent electrochemical performance of a highly significant capacity of 130 mAh g-1 at -50 °C. We evidence that the full-cell configuration coupled with Prussian blue analogues exhibits exceptional cycling stability of >7000 cycles at -40 °C while maintaining a discharge capacity of 101 mAh g-1 at a high current density 300 mA g-1. We show this is among the best reported ultralow-temperature performance for nonaqueous batteries, and importantly, the pouch cell exhibits a continuous power supply despite conditions of -50 °C. This work sheds light on the distinct energy storage characteristics of organic electrode and opens up new avenues for the development of reliable and sustainable ultralow-temperature batteries.

Cathelicidin CATH-B1 Inhibits Pseudorabies Virus Infection via Direct Interaction and TLR4/JNK/IRF3-Mediated Interferon Activation.

Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination has been used to prevent PRV infection, the virus cannot be eliminated in pigs. Thus, novel antiviral agents as complementary to vaccination are urgently needed. Cathelicidins (CATHs) are host defense peptides that play an important role in the host immune response against microbial infections. In the study, we found that the chemical synthesized chicken cathelicidin B1 (CATH-B1) could inhibit PRV regardless of whether CATH-B1 was added pre-, co-, or post-PRV infection in vitro and in vivo. Furthermore, coincubation of CATH-B1 with PRV directly inactivated virus infection by disrupting the virion structure of PRV and mainly inhibited virus binding and entry. Importantly, pretreatment of CATH-B1 markedly strengthened the host antiviral immunity, as indicated by the increased expression of basal interferon-ß (IFN-ß) and several IFN-stimulated genes (ISGs). Subsequently, we investigated the signaling pathway responsible for CATH-B1-induced IFN-ß production. Our results showed that CATH-B1 induced phosphorylation of interferon regulatory transcription factor 3 (IRF3) and further led to production of IFN-ß and reduction of PRV infection. Mechanistic studies revealed that the activation of Toll-like receptor 4 (TLR4), endosome acidification, and the following c-Jun N-terminal kinase (JNK) was responsible for CATH-B1-induced IRF3/IFN-ß pathway activation. Collectively, CATH-B1 could markedly inhibit PRV infection via inhibiting virus binding and entry, direct inactivation, and regulating host antiviral response, which provided an important theoretical basis for the development of antimicrobial peptide drugs against PRV infection. IMPORTANCE Although the antiviral activity of cathelicidins could be explained by direct interfering with the viral infection and regulating host antiviral response, the specific mechanism of cathelicidins regulating host antiviral response and interfering with pseudorabies virus (PRV) infection remains elusive. In this study, we investigated the multiple roles of cathelicidin CATH-B1 against PRV infection. Our study showed that CATH-B1 could suppress the binding and entry stages of PRV infection and direct disrupt PRV virions. Remarkably, CATH-B1 significantly increased basal interferon-ß (IFN-ß) and IFN-stimulated gene (ISG) expression levels. Furthermore, TLR4/c-Jun N-terminal kinase (JNK) signaling was activated and involved in IRF3/IFN-ß activation in response to CATH-B1. In conclusion, we elucidate the mechanisms by which the cathelicidin peptide direct inactivates PRV infection and regulates host antiviral IFN-ß signaling.

Alterations of the bile microbiome is associated with progression-free survival in pancreatic ductal adenocarcinoma patients.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. METHODS: Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. RESULTS: PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. CONCLUSION: PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.

Phylogenomics and biogeographical diversification of Collabieae (Orchidaceae) and its implication in the reconstruction of the dynamic history of Asian evergreen broadleaved forests.

The tribe Collabieae (Epidendroideae, Orchidaceae) comprises approximately 500 species. Generic delimitation within Collabieae are confusing and phylogenetic interrelationships within the Collabieae have not been well resolved. Plastid genomes and nuclear internal transcribed spacer (ITS) sequences were used to estimate the phylogenetic relationships, ancestral ranges, and diversification rates of Collabieae. The results showed that Collabieae was subdivided into nine clades with high support. We proposed to combine Ancistrochilus and Pachystoma into Spathoglottis, merge Collabium and Chrysoglossum into Diglyphosa, and separate Pilophyllum and Hancockia as distinctive genera. The diversification of the nine clades of Collabieae might be associated with the uplift of the Himalayas during the Late Oligocene/Early Miocene. The enhanced East Asian summer monsoon in the Late Miocene may have promoted the rapid diversification of Collabieae at a sustained high diversification rate. The increased size of terrestrial pseudobulbs may be one of the drivers of Collabieae diversification. Our results suggest that the establishment and development of evergreen broadleaved forests facilitated the diversification of Collabieae.

Advances in the metabolic engineering of Saccharomyces cerevisiae and Yarrowia lipolytica for the production of ß-carotene.

ß-Carotene is one kind of the most important carotenoids. The major functions of ß-carotene include the antioxidant and anti-cardiovascular properties, which make it a growing market. Recently, the use of metabolic engineering to construct microbial cell factories to synthesize ß-carotene has become the latest model for its industrial production. Among these cell factories, yeasts including Saccharomyces cerevisiae and Yarrowia lipolytica have attracted the most attention because of the: security, mature genetic manipulation tools, high flux toward carotenoids using the native mevalonate pathway and robustness for large-scale fermentation. In this review, the latest strategies for ß-carotene biosynthesis, including protein engineering, promoters engineering and morphological engineering are summarized in detail. Finally, perspectives for future engineering approaches are proposed to improve ß-carotene production.

A comprehensive review on the recent advances for 5-aminolevulinic acid production by the engineered bacteria.

5-Aminolevulinic acid (5-ALA) is a non-proteinogenic amino acid essential for synthesizing tetrapyrrole compounds, including heme, chlorophyll, cytochrome, and vitamin B12. As a plant growth regulator, 5-ALA is extensively used in agriculture to enhance crop yield and quality. The complexity and low yield of chemical synthesis methods have led to significant interest in the microbial synthesis of 5-ALA. Advanced strategies, including the: enhancement of precursor and cofactor supply, compartmentalization of key enzymes, product transporters engineering, by-product formation reduction, and biosensor-based dynamic regulation, have been implemented in bacteria for 5-ALA production, significantly advancing its industrialization. This article offers a comprehensive review of recent developments in 5-ALA production using engineered bacteria and presents new insights to propel the field forward.

Rare case of simultaneous occurrence of chronic neutrophil leukemia and T lymphoblastic lymphoma: case report and literature review.

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

Development and applications of genome-scale metabolic network models.

The genome-scale metabolic network model is an effective tool for characterizing the gene-protein-response relationship in the entire metabolic pathway of an organism. By combining various algorithms, the genome-scale metabolic network model can effectively simulate the influence of a specific environment on the physiological state of cells, optimize the culture conditions of strains, and predict the targets of genetic modification to achieve targeted modification of strains. In this review, we summarize the whole process of model building, sort out the various tools that may be involved in the model building process, and explain the role of various algorithms in model analysis. In addition, we also summarized the application of GSMM in network characteristics, cell phenotypes, metabolic engineering, etc. Finally, we discuss the current challenges facing GSMM.

Antibacterial activity of the antimicrobial peptide PMAP-36 in combination with tetracycline against porcine extraintestinal pathogenic Escherichia coli in vitro and in vivo.

The increase in the emergence of antimicrobial resistance has led to great challenges in controlling porcine extraintestinal pathogenic Escherichia coli (ExPEC) infections. Combinations of antimicrobial peptides (AMPs) and antibiotics can synergistically improve antimicrobial efficacy and reduce bacterial resistance. In this study, we investigated the antibacterial activity of porcine myeloid antimicrobial peptide 36 (PMAP-36) in combination with tetracycline against porcine ExPEC PCN033 both in vitro and in vivo. The minimum bactericidal concentrations (MBCs) of AMPs (PMAP-36 and PR-39) against the ExPEC strains PCN033 and RS218 were 10 µM and 5 µM, respectively. Results of the checkerboard assay and the time-kill assay showed that PMAP-36 and antibiotics (tetracycline and gentamicin) had synergistic bactericidal effects against PCN033. PMAP-36 and tetracycline in combination led to PCN033 cell wall shrinkage, as was shown by scanning electron microscopy. Furthermore, PMAP-36 delayed the emergence of PCN033 resistance to tetracycline by inhibiting the expression of the tetracycline resistance gene tetB. In a mouse model of systemic infection of PCN033, treatment with PMAP-36 combined with tetracycline significantly increased the survival rate, reduced the bacterial load and dampened the inflammatory response in mice. In addition, detection of immune cells in the peritoneal lavage fluid using flow cytometry revealed that the combination of PMAP-36 and tetracycline promoted the migration of monocytes/macrophages to the infection site. Our results suggest that AMPs in combination with antibiotics may provide more therapeutic options against multidrug-resistant porcine ExPEC.

Unveiling the Occurrence and Non-Negligible Role of Amino Sugars in Waste Activated Sludge Fermentation by an Enriched Chitin-Degradation Consortium.

Polysaccharides in extracellular polymeric substances (EPS) can form a hybrid matrix network with proteins, impeding waste-activated sludge (WAS) fermentation. Amino sugars, such as N-acetyl-d-glucosamine (GlcNAc) polymers and sialic acid, are the non-negligible components in the EPS of aerobic granules or biofilm. However, the occurrence of amino sugars in WAS and their degradation remains unclear. Thus, amino sugars (∼6.0%) in WAS were revealed, and the genera of Lactococcus and Zoogloea were identified for the first time. Chitin was used as the substrate to enrich a chitin-degrading consortium (CDC). The COD balances for methane production ranged from 83.3 and 95.1%. Chitin was gradually converted to oligosaccharides and GlcNAc after dosing with the extracellular enzyme. After doing enriched CDC in WAS, the final methane production markedly increased to 60.4 ± 0.6 mL, reflecting an increase of ∼62%. Four model substrates of amino sugars (GlcNAc and sialic acid) and polysaccharides (cellulose and dextran) could be used by CDC. Treponema (34.3%) was identified as the core bacterium via excreting chitinases (EC 3.2.1.14) and N-acetyl-glucosaminidases (EC 3.2.1.52), especially the genetic abundance of chitinases in CDC was 2.5 times higher than that of WAS. Thus, this study provides an elegant method for the utilization of amino sugar-enriched organics.

The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells.

RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.

Rhodanine Derivatives Containing 5-Aryloxypyrazole Moiety as Anti-inflammatory and Anticancer Agents.

In this study, a series of rhodanine derivatives containing 5-aryloxypyrazole moiety were identified as potential agents with anti-inflammatory and anticancer properties. Most of the synthesized compounds demonstrated anti-inflammatory and anticancer activity. Notably, compound 7 g (94.1 %) exhibited significant anti-inflammatory activity compared with the reference drugs celecoxib (52.5 %) and hydrocortisone (79.4 %). Compound 7 g, at various concentrations, effectively inhibited nitric oxide (NO) production in a dose-dependent manner. Western blot results showed that compound 7 g could prevents LPS-induced expression of inflammatory mediators in macrophages. Enzyme-linked immunosorbent assay (ELISA) assay suggested that 7 g is a promising compound capable of blocking the downstream signaling of COX-2. In summary, these findings indicate that compound 7 g could be a promising candidate for further investigation.

Synthesis and Biological Evaluation of Isoaurone Derivatives as Anti-inflammatory Agents.

Twenty-eight isoaurone derivatives with 1,2,4-triazole moieties were synthesized using a fragment-based design strategy, and their anti-inflammatory activity was investigated. The anti-inflammatory effect of the most active derivatives, 14e (41.82%), was dose-dependent and higher than the values for celecoxib (31.82%). Compound 14e was almost non-toxic and inhibited different concentrations of nitric oxide (NO). The western blotting results demonstrated that cyclooxygenase-2 (COX-2) expression was elevated when the macrophages were exclusively treated with LPS. However, compound 14e effectively suppressed the LPS-induced COX-2 upregulation. Subsequent investigation revealed that 14e is a promising compound capable of inhibiting the downstream signaling of COX-2. With the above interesting biological profile, molecular 14e could be a promising lead to develop novel anti-inflammatory agents.

Discrete-Time Visual Servoing Control with Adaptive Image Feature Prediction Based on Manipulator Dynamics.

In this paper, a practical discrete-time control method with adaptive image feature prediction for the image-based visual servoing (IBVS) scheme is presented. In the discrete-time IBVS inner-loop/outer-loop control architecture, the time delay caused by image capture and computation is noticed. Considering the dynamic characteristics of a 6-DOF manipulator velocity input system, we propose a linear dynamic model to describe the motion of a robot end effector. Furthermore, for better estimation of image features and smoothing of the robot's velocity input, we propose an adaptive image feature prediction method that employs past image feature data and real robot velocity data to adopt the prediction parameters. The experimental results on a 6-DOF robotic arm demonstrate that the proposed method can ensure system stability and accelerate system convergence.

Porphyrin-Thiophene Based Conjugated Polymer Cathode with High Capacity for Lithium-Organic Batteries.

Organic electrode materials are promising for next-generation energy storage materials due to their environmental friendliness and sustainable renewability. However, problems such as their high solubility in electrolytes and low intrinsic conductivity have always plagued their further application. Polymerization to form conjugated organic polymers can not only inhibit the dissolution of organic electrodes in the electrolyte, but also enhance the intrinsic conductivity of organic molecules. Herein, we synthesized a new conjugated organic polymer (COPs) COP500-CuT2TP (poly [5,10,15,20-tetra(2,2'-bithiophen-5-yl) porphyrinato] copper (II)) by electrochemical polymerization method. Due to the self-exfoliation behavior, the porphyrin cathode exhibited a reversible discharge capacity of 420 mAh g-1, and a high specific energy of 900 Wh Kg-1 with a first coulombic efficiency of 96 % at 100 mA g-1. Excellent cycling stability up to 8000 cycles without capacity loss was achieved even at a high current density of 5 A g-1. This highly conjugated structure promotes COP500-CuT2TP combined high energy density, high power density, and good cycling stability, which would open new opportunity for the designable and versatile organic electrodes for electrochemical energy storage.

2D Mesoporous Zincophilic Sieve for High-Rate Sulfur-Based Aqueous Zinc Batteries.

Sulfur-based aqueous zinc batteries (SZBs) attract increasing interest due to their integrated high capacity, competitive energy density, and low cost. However, the hardly reported anodic polarization seriously deteriorates the lifespan and energy density of SZBs at a high current density. Here, we develop an integrated acid-assisted confined self-assembly method (ACSA) to elaborate a two-dimensional (2D) mesoporous zincophilic sieve (2DZS) as the kinetic interface. The as-prepared 2DZS interface presents a unique 2D nanosheet morphology with abundant zincophilic sites, hydrophobic properties, and small-sized mesopores. Therefore, the 2DZS interface plays a bifunctional role in reducing the nucleation and plateau overpotential: (a) accelerating the Zn2+ diffusion kinetics through the opened zincophilic channels and (b) inhibiting the kinetic competition of hydrogen evolution and dendrite growth via the significant solvation-sheath sieving effect. Therefore, the anodic polarization is reduced to 48 mV at 20 mA cm-2, and the full-battery polarization is reduced to 42% of an unmodified SZB. As a result, an ultrahigh energy density of 866 Wh kgsulfur-1 at 1 A g-1 and a long lifespan of 10,000 cycles at a high rate of 8 A g-1 are achieved.

Amorphous Chloride Solid Electrolytes with High Li-Ion Conductivity for Stable Cycling of All-Solid-State High-Nickel Cathodes.

Solid electrolytes (SEs) are central components that enable high-performance, all-solid-state lithium batteries (ASSLBs). Amorphous SEs hold great potential for ASSLBs because their grain-boundary-free characteristics facilitate intact solid-solid contact and uniform Li-ion conduction for high-performance cathodes. However, amorphous oxide SEs with limited ionic conductivities and glassy sulfide SEs with narrow electrochemical windows cannot sustain high-nickel cathodes. Herein, we report a class of amorphous Li-Ta-Cl-based chloride SEs possessing high Li-ion conductivity (up to 7.16 mS cm-1) and low Young's modulus (approximately 3 GPa) to enable excellent Li-ion conduction and intact physical contact among rigid components in ASSLBs. We reveal that the amorphous Li-Ta-Cl matrix is composed of LiCl43-, LiCl54-, LiCl65- polyhedra, and TaCl6- octahedra via machine-learning simulation, solid-state 7Li nuclear magnetic resonance, and X-ray absorption analysis. Attractively, our amorphous chloride SEs exhibit excellent compatibility with high-nickel cathodes. We demonstrate that ASSLBs comprising amorphous chloride SEs and high-nickel single-crystal cathodes (LiNi0.88Co0.07Mn0.05O2) exhibit ∼99% capacity retention after 800 cycles at ∼3 C under 1 mA h cm-2 and ∼80% capacity retention after 75 cycles at 0.2 C under a high areal capacity of 5 mA h cm-2. Most importantly, a stable operation of up to 9800 cycles with a capacity retention of ∼77% at a high rate of 3.4 C can be achieved in a freezing environment of -10 °C. Our amorphous chloride SEs will pave the way to realize high-performance high-nickel cathodes for high-energy-density ASSLBs.

Systems engineering of Escherichia coli for high-level shikimate production.

To further increase the production efficiency of microbial shikimate, a valuable compound widely used in the pharmaceutical and chemical industries, ten key target genes contributing to shikimate production were identified by exploiting the enzyme constraint model ec_iML1515, and subsequently used for promoting metabolic flux towards shikimate biosynthesis in the tryptophan-overproducing strain Escherichia coli TRP0. The engineered E. coli SA05 produced 78.4 g/L shikimate via fed-batch fermentation. Deletion of quinate dehydrogenase and introduction of the hydroaromatic equilibration-alleviating shikimate dehydrogenase mutant AroET61W/L241I reduced the contents of byproducts quinate (7.5 g/L) and 3-dehydroshikimic acid (21.4 g/L) by 89.1% and 52.1%, respectively. Furthermore, a high concentration shikimate responsive promoter PrpoS was recruited to dynamically regulate the expression of the tolerance target ProV to enhance shikimate productivity by 23.2% (to 2 g/L/h). Finally, the shikimate titer was increased to 126.4 g/L, with a yield of 0.50 g/g glucose and productivity of 2.63 g/L/h, using a 30-L fermenter and the engineered strain E. coli SA09. This is, to the best of our knowledge, the highest reported shikimate titer and productivity in E. coli.