Metabolic Pathway Coupled with Fermentation Process Optimization for High-Level Production of Retinol in Yarrowia lipolytica.

Retinol is a lipid-soluble form of vitamin A that is crucial for human visual and immune functions. The production of retinol through microbial fermentation has been the focus of recent exploration. However, the obtained titer remains limited and the product is often a mixture of retinal, retinol, and retinoic acid, necessitating purification. To achieve efficient biosynthesis of retinol in Yarrowia lipolytica, we improved the metabolic flux of ß-carotene to provide sufficient precursors for retinol in this study. Coupled with the optimization of the expression level of ß-carotene 15,15'-dioxygenase, de novo production of retinol was achieved. Furthermore, Tween 80 was used as an extractant and butylated hydroxytoluene as an antioxidant to extract intracellular retinol and prevent retinol oxidation, respectively. This strategy significantly increased the level of retinol production. By optimizing the enzymes converting retinal to retinol, the proportion of extracellular retinol in the produced retinoids reached 100%, totaling 1042.3 mg/L. Finally, total retinol production reached 5.4 g/L through fed-batch fermentation in a 5 L bioreactor, comprising 4.2 g/L extracellular retinol and 1.2 g/L intracellular retinol. This achievement represents the highest reported titer so far and advances the industrial production of retinol.

Additives for Aqueous Zinc-Ion Batteries: Recent Progress, Mechanism Analysis, and Future Perspectives.

Aqueous zinc-ion batteries (ZIBs) stand out as a promising next-generation electrochemical energy storage technology, offering notable advantages such as high specific capacity, enhanced safety, and cost-effectiveness. However, the application of aqueous electrolytes introduces challenges: Zn dendrite formation and parasitic reactions at the anode, as well as dissolution, electrostatic interaction, and by-product formation at the cathode. In addressing these electrode-centric problems, additive engineering has emerged as an effective strategy. This review delves into the latest advancements in electrolyte additives for ZIBs, emphasizing their role in resolving the existing issues. Key focus areas include improving morphology and reducing side reactions during battery cycling using synergistic effects of modulating anode interface regulation, zinc facet control, and restructuring of hydrogen bonds and solvation sheaths. Special attention is given to the efficacy of amino acids and zwitterions due to their multifunction to improve the cycling performance of batteries concerning cycle stability and lifespan. Additionally, the recent additive advancements are studied for low-temperature and extreme weather applications meticulously. This review concludes with a holistic look at the future of additive engineering, underscoring its critical role in advancing ZIB performance amidst the complexities and challenges of electrolyte additives.

Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore.

The covalent attachment of ubiquitin-like LC3 proteins (microtubule-associated proteins 1A/1B light chain 3) prepares the autophagic membrane for cargo recruitment. We resolve key steps in LC3 lipidation by combining molecular dynamics simulations and experiments in vitro and in cellulo. We show how the E3-like ligaseautophagy-related 12 (ATG12)-ATG5-ATG16L1 in complex with the E2-like conjugase ATG3 docks LC3 onto the membrane in three steps by (i) the phosphatidylinositol 3-phosphate effector protein WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), (ii) helix α2 of ATG16L1, and (iii) a membrane-interacting surface of ATG3. Phosphatidylethanolamine (PE) lipids concentrate in a region around the thioester bond between ATG3 and LC3, highlighting residues with a possible role in the catalytic transfer of LC3 to PE, including two conserved histidines. In a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12-ATG5-ATG16L1 machinery establishes a high level of regulatory control.

De Novo Biosynthesis of Lutein in Yarrowia lipolytica.

Lutein is a high-value tetraterpenoid carotenoid that is widely used in feed, cosmetics, food, and drugs. Microbial synthesis of lutein is an important method for green and sustainable production, serving as an alternative to plant extraction methods. However, an inadequate precursor supply and low catalytic efficiency of key pathway enzymes are the main reasons for the low efficacy of microbial synthesis of lutein. In this study, some strategies, such as enhancing the MVA pathway and localizing α-carotene synthase OluLCY within the subcellular organelles in Yarrowia lipolytica, were adopted to enhance the synthesis of precursor α-carotene, which resulted in a 10.50-fold increase in α-carotene titer, reaching 38.50 mg/L. Subsequently, by improving hydroxylase activity with truncated N-terminal transport peptide and locating hydroxylases to subcellular organelles, the final strain L9 producing 75.25 mg/L lutein was obtained. Eventually, a lutein titer of 675.40 mg/L (6.13 mg/g DCW) was achieved in a 5 L bioreactor by adding the antioxidant 2,6-ditert-butyl-4-methylphenol. This study realizes de novo synthesis of lutein in Y. lipolytica for the first time and achieves the highest lutein titer reported so far.

High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering.

(2S)-Eriodictyol, a polyphenolic flavonoid, has found widespread applications in health supplements and food additives. However, the limited availability of plant-derived (2S)-eriodictyol cannot meet the market demand. Microbial production of (2S)-eriodictyol faces challenges, including the low catalytic efficiency of flavone 3'-hydroxylase/cytochrome P450 reductase (F3'H/CPR), insufficient precursor supplementation, and inadequate NADPH regeneration. This study systematically engineered Yarrowia lipolytica for high-level (2S)-eriodictyol production. In doing this, the expression of F3'H/CPR was balanced, and the supply of precursors was enhanced by relieving feedback inhibition of the shikimate pathway, promoting fatty acid ß-oxidation, and increasing the copy number of synthetic pathway genes. These strategies, combined with NADPH regeneration, achieved an (2S)-eriodictyol titer of 423.6 mg/L. Finally, in fed-batch fermentation, a remarkable 6.8 g/L (2S)-eriodictyol was obtained, representing the highest de novo microbial titer reported to date and paving the way for industrial production.

Exosomal circ_0000722 derived from periodontal ligament stem cells undergoing osteogenic differentiation promotes osteoclastogenesis.

Periodontal ligament stem cells (PDLSCs), which are considered promising stem cells for regeneration of periodontal bony tissue, can also manipulate alveolar bone remodeling by exosomes. In this study, we investigated interactions between PDLSCs under osteogenic differentiation and osteoclast precursors. The results showed that conditioned medium from PDLSCs under 5d osteogenic induction promoted osteoclastogenesis of RAW264.7 cells. The exosomes extracted from those conditioned media showed similar effects on osteoclastogenesis. Furthermore, exosomes from PDLSCs under 5d of osteogenic induction showed significantly high expression of circ_0000722, compared with exosomes from PDLSCs before osteogenic induction. Downregulation of circ_0000722 significantly attenuated the effect of PDLSC-derived exosomes on the osteoclastogenesis of RAW264.7 cells. Our findings suggested that exosomal circ_0000722 derived from periodontal ligament stem cells undergoing osteogenic differentiation might promote osteoclastogenesis by upregulating TRAF6 expression and activating downstream NF-κB and AKT signaling pathways.

Experimental and theoretical insight into carbamazepine degradation by chlorine-based advanced oxidation processes: Efficiency, energy consumption, mechanism and DBPs formation.

Chlorine has been widely used in different advanced oxidation processes (AOPs) for micropollutants removal. In this study, different chlorine-based AOPs, namely medium pressure (MP) UV/chlorine, low pressure (LP) UV/chlorine, and in-situ chlorination, were compared for carbamazepine (CBZ) removal efficiency, energy consumption, and disinfection by-products (DBPs) formation. All three processes could achieve nearly 100% CBZ removal, while the reaction time needed by in-situ chlorination was double the time required by UV/chlorine processes. The energy consumed per magnitude of CBZ removed (EE/O) of MP UV/chlorine was 13 times higher than that of LP UV/chlorine, and relative to that of in-situ chlorination process. Accordingly, MP and LP UV/chlorine processes generated one to two orders of magnitude more hydroxyl radicals (•OH) and reactive chlorine species (RCS) than in-situ chlorination. Besides, RCS were the dominant reactive species, contributing to 78.3%, 75.6%, and 71.6% of CBZ removal in MP, LP UV/chlorine, and in-situ chlorination, respectively. According to the Gibbs free energy barriers between CBZ and RCS/•OH calculated based on density functional theory (DFT), RCS had more reaction routes with CBZ and showed lower energy barrier in the main CBZ degradation pathways like epoxidation and formation of iminostilbene. When applied to secondary wastewater effluent, UV/chlorine and in-situ chlorination produced overall DBPs ranging from 104.77 to 135.41 µg/L. However, the production of chlorate during UV/chlorine processes was 15 times higher than that during in-situ chlorination.

Thrifty effect of subanesthetic-dose S-ketamine on postoperative opioids and its safety and analgesic effectiveness: A prospective, triple-blind, randomized controlled, polycentric clinical trial.

Aim: To investigate the thrifty effects of subanesthetic-dose S-ketamine on postoperative opioids and its safety and analgesic efficacy. Methods: Four-hundred and twenty patients were divided into the control group (CON group), the S-ketamine 0.2 mg/kg group (ES0.2 group), and the S-ketamine 0.3 mg/kg group (ES0.3 group) randomly. Major indicators include the Visual Analogue Scale (VAS), the times of compression with analgesic pumps after surgery, and analgesic drug consumption from anesthesia induction to 48 h after surgery. Minor records include vital signs, the use of vasoactive drugs, the Ramsay scores, the occurrence of adverse events including nervous system reaction, and the patient's satisfaction with anesthesia. Results: Compared with the CON group, VAS scores decreased in the ES0.2 and ES0.3 groups (p < 0.05). At 10 min after extubation, the VAS scores of the ES0.3 group were lower than that of the ES0.2 group (p < 0.05). The total number of compression with analgesic pumps of the ES0.3 group was lower than that of the CON group (p < 0.05). The opioid consumption after surgery of the ES0.3 group was lower than those of the CON group and the ES0.2 group (p < 0.05). The ES0.3 group's heart rate (HR) was faster but the use of vasoactive, drug consumption was less than the other two groups (p < 0.05). There were no significant differences in the incidence of postoperative adverse events and anesthetic satisfaction among the three groups. Conclusion: Subanesthetic-dose S-ketamine at 0.2-0.3 mg/kg especially the 0.3 mg/kg in general anesthesia induction can safely and effectively reduce postoperative pain and save postoperative opioid consumption.

The management of gingival fenestration: A series of three cases.

OBJECTIVES: The aim of this article is to introduce three treatments for patients with gingival fenestration as a result of chronic apical periodontitis. Gingival fenestration is a relatively uncommon soft tissue lesion in which the root apex is exposed in the oral environment after the destruction of the overlying buccal bone plate and mucosa. At present, no clear etiology or treatment guidelines exist for gingival fenestration. This article reports three successfully treated cases of gingival fenestration associated with chronic periapical infection. This report can help contribute to treatment guidelines for gingival fenestration. METHODS: All cases were treated with apicoectomy in conjunction with a connective tissue graft (CTG). According to the different conditions of the patients, we used some slightly different treatment methods during the operation. In case 1, we treated gingival fenestration in the mandibular left first premolar by endodontic therapy with root-end resection and retrograde filling and regenerative surgical therapy using a xenograft and CTG. In case 2, we treated gingival fenestration in the maxillary left lateral incisor by endodontic therapy with root-end resection and retrograde filling in vitro and regenerative surgical therapy using advanced platelet-rich fibrin (A-PRF) and CTG. In case 3, we treated gingival fenestration in the mandibular left second premolar by endodontic therapy with root-end resection and retrograde filling and regenerative surgical therapy using CTG. RESULTS: Endodontic treatment was combined with periodontal surgery to achieve predictable treatment results. After 13 to 25 months of follow-up, all cases showed that the gingival fenestration had healed well, and the patients had no discomfort. CONCLUSIONS: These three cases show the possibility of using apical excision combined with a CTG and/or bone graft/PRF in the treatment of gingival fenestration. Reporting these three cases may help advance the field of treatments for gingival fenestration.

Food Insecurity, telomere length and the potential modifying effects of social support in National Health and Nutrition Examination Survey.

OBJECTIVE: Telomere length (TL) is a posited pathway through which chronic stress results in biological dysregulation and subsequent adverse health outcomes. Food insecurity is associated with shorter TL. Social support, which is defined by the size and function of an individual's social network, is associated with better health outcomes. The present study assesses whether social support modifies the relationship between food security and TL. DESIGN: Cross-sectional study design. Linear regression was used to assess the association between food insecurity and TL, stratified by social support level. A multiplicative interacted model was used to formally test modification. SETTING: Data come from the National Health and Nutrition Examination Survey 1999-2000 and 2001-2002 waves. PARTICIPANTS: Adults aged 60 years and older who have measurements for TL. RESULTS: Our sample comprised 2674 participants, and 63·5 % of the total sample had low social support, with 13·3 % being food insecure. In fully adjusted models, food insecurity was negatively though modestly associated (P = 0·13) with TL. Associations between food insecurity and TL were significantly modified by social support (interaction P = 0·026), whereby food insecurity had a stronger effect among individuals with high social support (coefficient = -0·099 (95 % CI: -0·161, -0·038)) compared to low social support (coefficient = -0·001, (95 % CI: -0·033, 0·032)). CONCLUSION: Food insecurity is modestly associated with shorter TL. Contrary to our hypothesis, food insecurity had more deleterious effects on TL among participants with high social support than low social support. Results may indicate that the food insecure population is a higher needs population, and increased social support reflects these needs rather than providing protective effects.

The in vitro metabolism of GMDTC in liver microsomes of human, monkey, dog, rat and mouse: Metabolic stability assessment, metabolite identification and interspecies comparison.

Sodium (S)- 2-(dithiocarboxylato((2 S,3 R,4 R,5 R)- 2,3,4,5,6-pentahydroxyhexyl)amino)- 4(methylthio)butanoate (GMDTC) is a compound that removes cadmium from kidney cells. This study aims to investigate the metabolic stability and metabolite identification of GMDTC in various liver microsomes, including those from human, monkey, dog, rat and mouse. The results show that the T1/2 values of GMDTC in human, monkey, dog, rat and mouse liver microsomes were 16.54, 18.14, 16.58, 15.16 and 16.00 min, respectively. While the hepatic extraction ratios (ERh) of GMDTC measured after 60 min incubation in these liver microsomes were 0.82, 0.70, 0.80, 0.75 and 0.79, respectively, indicating that GMDTC exhibits rapid hepatic metabolism and high hepatic clearance with no significant interspecies differences. Subsequent metabolite identification by high-resolution mass spectrometry revealed the presence of three metabolites, designated M1∼M3. The major metabolite products of GMDTC were found to be M1 and M2. The relative abundances of the hydrolysis products (M1 and M2) in human, monkey, dog, rat and mouse liver microsomes were found to be 97.18%, 97.99%, 95.94%, 96.31% and 93.43%, respectively, indicating that hydrolysis is the primary metabolic pathway of GMDTC in liver microsomes in vitro, and with no significant interspecies differences.

Synthesis, Properties, and Application of Small-Molecule Hole-Transporting Materials Based on Acetylene-Linked Thiophene Core.

Three small molecule organic compounds based on conjugated acetylene-linked methoxy triphenylamine terminal groups with different substituted thiophene cores were synthesized and firstly applied as hole-transporting materials (HTMs). The electron-deficient acetylene linkers can tune the energy levels of frontier molecular orbitals. The physical property measurements show that the HTMs (CJ-05, CJ-06, and CJ-07) possess good stability, hydrophobicity, and film-forming ability. Further, the HTMs were applied in the MAPbI3-based perovskite solar cells (PSCs), and the best power conversion efficiency (PCE) of 6.04%, 6.77%, and 6.48% was achieved, respectively, which implies that they exhibit great potential in photovoltaic applications.

Urinary microbiota and metabolic signatures associated with inorganic arsenic-induced early bladder lesions.

Inorganic arsenic (iAs) contamination in drinking water is a global public health problem, and exposure to iAs is a known risk factor for bladder cancer. Perturbation of urinary microbiome and metabolome induced by iAs exposure may have a more direct effect on the development of bladder cancer. The aim of this study was to determine the impact of iAs exposure on urinary microbiome and metabolome, and to identify microbiota and metabolic signatures that are associated with iAs-induced bladder lesions. We evaluated and quantified the pathological changes of bladder, and performed 16S rDNA sequencing and mass spectrometry-based metabolomics profiling on urine samples from rats exposed to low (30 mg/L NaAsO2) or high (100 mg/L NaAsO2) iAs from early life (in utero and childhood) to puberty. Our results showed that iAs induced pathological bladder lesions, and more severe effects were noticed in the high-iAs group and male rats. Furthermore, six and seven featured urinary bacteria genera were identified in female and male offspring rats, respectively. Several characteristic urinary metabolites, including Menadione, Pilocarpine, N-Acetylornithine, Prostaglandin B1, Deoxyinosine, Biopterin, and 1-Methyluric acid, were identified significantly higher in the high-iAs groups. In addition, the correlation analysis demonstrated that the differential bacteria genera were highly correlated with the featured urinary metabolites. Collectively, these results suggest that exposure to iAs in early life not only causes bladder lesions, but also perturbs urinary microbiome composition and associated metabolic profiles, which shows a strong correlation. Those differential urinary genera and metabolites may contribute to bladder lesions, suggesting a potential for development of urinary biomarkers for iAs-induced bladder cancer.

Establishment of LC-MS/MS Method for Determination of GMDTC in Rat Plasma and Its Application in Preclinical Pharmacokinetics.

Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC) is the first compound to use cadmium repellent as an indication. In this paper, we established and validated a bioanalytical method for the determination of GMDTC in rat plasma, and used it to determine the drug concentrations in the plasma of rats after intravenous dosing in different genders and dosages. After pretreating the plasma samples with an acetonitrile-water-ammonia solution (70:30:1.25, v/v/v), liquid chromatographic separations were efficiently achieved with a XBridge C18 column using a 5 min gradient system of aqueous ammonium bicarbonate and 95% acetonitrile-water solution (95:5, v/v) as the eluent. The GMDTC and metolazone (internal standard, IS) detection were carried out using high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS), monitored at m/z 390.06-324.1 (for the GMDTC, tR: 2.03 min) and m/z 366.0-259.2 (for IS, tR: 3.88 min). The GMDTC was stable under various testing conditions, and this analytical method conforms to the verification standard of biological analysis methods. The half-life (t1/2) was determined to be 0.54-0.65 h for the intravenous, mean distribution volume and clearances were 1.08-2.08 L/kg and 1-3 L/h/kg, respectively. The AUC0-t and AUC0-∞ found after increasing the dosage exhibited a linear relationship with the administered dose. There were no statistically significant differences in the values obtained for the different genders at dosages of 50, 100 and 250 mg/kg, respectively (p > 0.05). This is the first report of a bioanalytical method to quantify GMDTC in rat plasma using LC-MS/MS, which provides useful information for the study of its pharmacological effects and clinical applications.

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation.

The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson's disease. The structural interaction between the sole transmembrane autophagy protein, autophagy-related protein 9A (ATG9A), and components of the Unc-51-like autophagy activating kinase (ULK1) complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.4-Å x-ray crystallographic structure of the ternary structure of ATG9A carboxyl-terminal tail bound to the ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme carboxyl-terminal part of the ATG9A tail the "HORMA dimer-interacting region" (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by ß sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.

Enhancing Lithium-Sulfur Battery Performance by MXene, Graphene, and Ionic Liquids: A DFT Investigation.

The efficacy of lithium-sulfur (Li-S) batteries crucially hinges on the sulfur immobilization process, representing a pivotal avenue for bolstering their operational efficiency and durability. This dissertation primarily tackles the formidable challenge posed by the high solubility of polysulfides in electrolyte solutions. Quantum chemical computations were leveraged to scrutinize the interactions of MXene materials, graphene (Gr) oxide, and ionic liquids with polysulfides, yielding pivotal binding energy metrics. Comparative assessments were conducted with the objective of pinpointing MXene materials, with a specific focus on d-Ti3C2 materials, evincing augmented binding energies with polysulfides and ionic liquids demonstrating diminished binding energies. Moreover, a diverse array of Gr oxide materials was evaluated for their adsorption capabilities. Scrutiny of the computational outcomes unveiled an augmentation in the solubility of selectively screened d-Ti3C2 MXene and ionic liquids-vis à vis one or more of the five polysulfides. Therefore, the analysis encompasses an in-depth comparative assessment of the stability of polysulfide adsorption by d-Ti3C2 MXene materials, Gr oxide materials, and ionic liquids across diverse ranges.

Self-assembly and structure of a clathrin-independent AP-1:Arf1 tubular membrane coat.

The adaptor protein (AP) complexes not only form the inner layer of clathrin coats but also have clathrin-independent roles in membrane traffic whose mechanisms are unknown. HIV-1 Nef hijacks AP-1 to sequester major histocompatibility complex class I (MHC-I), evading immune detection. We found that AP-1:Arf1:Nef:MHC-I forms a coat on tubulated membranes without clathrin and determined its structure. The coat assembles via Arf1 dimer interfaces. AP-1-positive tubules are enriched in cells upon clathrin knockdown. Nef localizes preferentially to AP-1 tubules in cells, explaining how Nef sequesters MHC-I. Coat contact residues are conserved across Arf isoforms and the Arf-dependent AP complexes AP-1, AP-3, and AP-4. Thus, AP complexes can self-assemble with Arf1 into tubular coats without clathrin or other scaffolding factors. The AP-1:Arf1 coat defines the structural basis of a broader class of tubulovesicular membrane coats as an intermediate in clathrin vesicle formation from internal membranes and as an MHC-I sequestration mechanism in HIV-1 infection.

Clathrin-associated AP-1 controls termination of STING signalling.

Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate immunity during infection, cancer and immunotherapy1-10. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation11-16. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction17-20. The mechanism that ends STING signalling at the Golgi remains unknown. Here we show that adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation. We find that AP-1 sorts phosphorylated STING into clathrin-coated transport vesicles for delivery to the endolysosomal system, where STING is degraded21. We identify a highly conserved dileucine motif in the cytosolic C-terminal tail (CTT) of STING that, together with TBK1-dependent CTT phosphorylation, dictates the AP-1 engagement of STING. A cryo-electron microscopy structure of AP-1 in complex with phosphorylated STING explains the enhanced recognition of TBK1-activated STING. We show that suppression of AP-1 exacerbates STING-induced immune responses. Our results reveal a structural mechanism of negative regulation of STING and establish that the initiation of signalling is inextricably associated with its termination to enable transient activation of immunity.

Remodelling metabolism for high-level resveratrol production in Yarrowia lipolytica.

Resveratrol is a polyphenol with numerous applications in food, pharma, and cosmetics. Lack of precursors and low titer are the main problems hindering industrial scale resveratrol production. Based on previous prescreening, expressing the combination of FjTAL, Pc4CL1 and VvSTS achieved the best resveratrol titer. This was further improved to 235.1 mg/L through engineering the shikimic acid pathway, applying a modular enzyme assembly of Pc4CL1 and VvSTS, enhancing p-coumaric acid supply and diverting glycolytic flux toward erythrose-4-phosphate. The titer was increased to 819.1 mg/L following two rounds of multicopy integration of resveratrol biosynthesis and malonyl-CoA supply, respectively. The titer reached 22.5 g/L with a yield on glucose of 65.5 mg/g using an optimum fed-batch strategy in a 5 L bioreactor with morphology control. This research is the highest report on the de novo production of resveratrol in Yarrowia lipolytica and the findings lay a solid foundation for other producing polyphenols.

Effects of neuron autophagy induced by arsenic and fluoride on spatial learning and memory in offspring rats.

There are numerous studies showing that exposure to arsenic (As) or fluoride (F) damages the nervous system, but there is no literature investigating the effects of combined As and F exposure to induce autophagy on neurotoxicity in the offspring. In this study, we developed a rat model of As and/or F exposure through drinking water from before pregnancy to 90 days postnatal. The offspring rats were randomly divided into nine groups. Sodium arsenite (NaAsO2) (0, 35, 70 mg/L) and Sodium fluoride (NaF) (0, 50, 100 mg/L) were designed according to 3 × 3 factorial design. Our results suggested that the presence of F might antagonize the excretion of total As in urine, and As-F co-exposure led to severe pathological damage in brain tissue and reduced spatial learning and memory ability. At the same time, the experiments showed that As and F increased Beclin1 expression and LC3B ratio to activate autophagy; both P62 and Lamp2 expression were increased, suggesting that autophagy lysosomal degradation was blocked; SYN and JIP1 expression were significantly decreased, disrupting synaptic structure and function. Axonal autophagosome reverse transport regulation might be affected by combined As-F exposure, exacerbating neuronal synaptic damage and inducing neurotoxicity. Further analysis showed that there was an interaction between As and F exposure-induced changes in autolysosome-related proteins in the hippocampus, which showed antagonism, and the antagonism of the high As combined exposure groups were stronger than that of the low As combined exposure groups. In conclusion, our study showed that combined As and F exposure might induce reverse transport impairment of autophagy on axons, leading to autophagy defects, which in turn led to disruption of synaptic morphology and function, induced neurotoxicity, and there was an interaction between As and F, the type of its combined effect was antagonism.