Correction: Wang et al. Role of Berberine Thermosensitive Hydrogel in Periodontitis via PI3K/AKT Pathway In Vitro. Int. J. Mol. Sci. 2023, 24, 6364.

In the original publication, there was a mistake in Figure 3 as published [...].

Improved protective properties of Mg alloy AZ31 using bis-[triethoxysilylpropyl] tetrasulfide silane films modified with nano TiO2 by electrochemically assisted deposition.

Magnesium (Mg) and its alloys were favored by biomedical practitioners thanks to availability of bioactivity and degradability. However, the mismatch between the degradation properties of Mg alloys and the rate of osteogenesis often led to implant failure and bacterial infections within the desired period. The goal of this study was to improve the corrosion resistance of Mg alloys, providing theoretical guidance for solving the problems of implantable Mg-based materials. In this experiment, we prepared a dense and uniform BTESPT/TiO2 film layer on the surface of Mg substrate by electrochemically assisted deposition. The BTESPT/TiO2 film layer provided a physical barrier to avoid direct contact between AZ31 and the corrosive medium. When the addition amount was 2 g/L TiO2, the coating had the best corrosion resistance behavior, its corrosion current density could be up to 9.973×10-8 A/cm2. The BTESPT/TiO2 revealed good cell viability as well as osteogenic differentiation potential on MC3T3-E1 cells.

The association between testosterone and serum soluble klotho in the females: evidence from the NHANES database.

Objective: This research aimed to elucidate the relationship between testosterone levels and serum soluble klotho (S-klotho) concentrations in females aged 40-79 years using the National Health and Nutrition Examination Survey (NHANES) dataset. Design: Associations between testosterone and S-klotho were assessed through multivariable linear regression methodologies, spanning nonadjusted, minimally adjusted, and fully adjusted models. Settings: The investigation was conducted as a cross-sectional analysis utilizing the NHANES database. Participants: From 20,146 NHANES participants between 2013 and 2016, 2,444 females met the stipulated inclusion and exclusion criteria. Results: Free androgen index (FAI) showcased a negative correlation with S-klotho levels across all regression models (nonadjusted: ß -7.08, 95% CI -13.39- -0.76; minimally adjusted: ß -9.73, 95% CI -16.6- -2.84; fully adjusted: ß -7.63, 95% CI -14.75-0.51). Conversely, total testosterone did not exhibit significant associations with S-klotho across the models. In the nonadjusted model, estradiol was positively associated with S-klotho concentrations (ß 0.14, 95% CI 0.05-0.23), but this significance was not retained in subsequent regression models. Conclusion: Findings suggest that in U.S. females aged 40-79 years, FAI negatively correlates with S-klotho concentrations, while there is the lack of significant associations for total testosterone and estradiol.

Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the amelioration of AKT-induced nonalcoholic fatty liver disease by total flavonoids in vine tea.

Nonalcoholic fatty liver disease (NAFLD) is the main reason for chronic liver diseases and malignancies. Currently, there is a lack of approved drugs for the prevention or treatment of NAFLD. Vine tea (Ampelopsis grossedentata) has been used as a traditional Chinese beverage for centuries. Vine tea carries out several biological activities including the regulation of plasma lipids and blood glucose, hepato-protective function, and anti-tumor activity and contains the highest content of flavonoids. However, the underlying mechanisms of total flavonoids from vine tea (TF) in the attenuation of NAFLD remain unclear. Therefore, we investigated the interventions and mechanisms of TF in mice with NAFLD using an integrated analysis of network pharmacology, lipidomics, and transcriptomics. Staining and biochemical tests revealed a significant increase in AKT-overexpression-induced (abbreviated as AKT-induced) NAFLD in mice. Lipid accumulation in hepatic intracellular vacuoles was alleviated after TF treatment. In addition, TF reduced the hepatic and serum triglyceride levels in mice with AKT-induced NAFLD. Lipidomics results showed 32 differential lipids in the liver, mainly including triglycerides (TG), diglycerides (DG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Transcriptomic analysis revealed that 314 differentially expressed genes were commonly upregulated in the AKT group and downregulated in the TF group. The differential regulation of lipids by the genes Pparg, Scd1, Chpt1, Dgkz, and Pla2g12b was further revealed by network enrichment analysis and confirmed by RT-qPCR. Furthermore, we used immunohistochemistry (IHC) to detect changes in the protein levels of the key proteins PPARγ and SCD1. In summary, TF can improve hepatic steatosis by targeting the PPAR signaling pathway, thereby reducing de novo fatty acid synthesis and modulating the glycerophospholipid metabolism.

Testosterone does not mediate the correlation between dietary inflammation and serum klotho levels among males: insights from NHANES database.

Introduction: Serum Klotho (S-Klotho) is a transmembrane protein holds pivotal roles in anti-aging. The Dietary Inflammation Index (DII), a meticulously dietary tool, quantifies the inflammatory potential of an individual's diet. The existing research strongly suggests that a low DII diet plays a significant role in delaying aging and reducing aging-related symptoms in males. Testosterone could potentially act as a mediating intermediary between DII and S-Klotho. However, this aspect remains unexplored. This study aims to investigate the potential causal link of testosterone between DII and S-Klotho in males. Methods: We utilized data from National Health and Nutrition Examination Survey (NHANES) which focused on male participants from 2013-2016. Mediation analyses were used to investigate the effects of testosterone (TT), free testosterone (FT), and free androgen index (FAI) on the DII-S-Klotho relationship, using three modes adjusting for covariates. Results: Mediation analysis unveiled a significant inverse correlation between DII and S-Klotho levels (model 1: c = -14.78, p = 0.046). The interaction between DII and S-Klotho was modulated by TT in model 1 (ab = -1.36; 95% CI: -5.59, -0.55; p = 0.008), but lost significance after adjustments (model 2: ab = -0.39; 95% CI: -4.15, 1.66; p = 0.378; model 3: ab = -0.59; 95% CI: -4.08, 2.15; p = 0.442). For FT, the mediating impact was not statistically significant (model 1: ab = 0.43; 95% CI: -0.51, 5.44; p = 0.188; model 2: ab = 0.72; 95% CI: -0.26, 5.91; p = 0.136; model 3: ab = 0.84; 95% CI: -0.02, 8.06; p = 0.056). Conversely, FAI consistently influenced the DII-S-Klotho relationship (model 1: ab = 2.39; 95% CI: 0.69, 9.42; p = 0.002), maintaining significance after adjustments (model 2: ab = 3.2; 95% CI: 0.98, 11.72; p = 0.004; model 3: ab = 3.15; 95% CI: 0.89, 14.51; p = 0.026). Discussion: This study observed no mediating influence of TT or FT on the correlation between DII and S-Klotho after covariate control. Remarkably, FAI continued to significantly mediate the DII-S-Klotho connection even following covariate adjustment, although its significance in males warrants careful consideration.

miR-107-5p ameliorates neurological damage, oxidative stress, and immune responses in mice with Alzheimer's disease by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor-kappaB(NF-κB) pathway.

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR-107-5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR-107-5p (to overexpress miR-107-5p) or BAY11-7082 (an NF-κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin-eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid-Aß (Aß1-40/42) contents, and inflammatory factors (TNF-α, IL-6, IL-1ß) in hippocampal tissues were measured using ROS kits and enzyme-linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR-107-5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual-luciferase assay. miR-107-5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF-κB p65 protein expression in the nucleus and cytoplasm were assessed via RT-qPCR and Western blot. Overexpression of miR-107-5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aß1-40 and Aß1-42 levels, diminished neuronal injuries, decreased ROS and TNF-α, IL-6, and IL-1ß levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR-107-5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF-κB p65 in the NF-κB pathway. Inhibition of the NF-κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR-107-5p exerts its beneficial effects by suppressing the TLR4/NF-κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.

Melatonin in cancer biology: pathways, derivatives, and the promise of targeted delivery.

Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we delved into how melatonin interacts with key signaling pathways, such as the Wnt/ß-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity. Additionally, a comprehensive review of current clinical studies provides a dual perspective. These studies confirm melatonin's potential in cancer management but also underscore its inherent limitations, particularly its limited bioavailability, which often relegates it to a supplementary role in treatments. Despite this limitation, there is an ongoing quest for innovative solutions and current advancements include the development of melatonin derivatives and cutting-edge delivery systems. By synthesizing the past, present, and future, this review provides a detailed overview of melatonin's evolving role in oncology, positioning it as a potential cornerstone in future cancer therapeutics.

SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease.

Neuroinflammation plays a crucial role in the pathogenesis and progression of Alzheimer's disease (AD). The Sterile Alpha and Toll Interleukin Receptor Motif-containing protein 1 (SARM1) has been shown to promote axonal degeneration and is involved in neuroinflammation. However, the role of SARM1 in AD remains unclear. In this study, we found that SARM1 was reduced in hippocampal neurons of AD model mice. Interestingly, conditional knockout (CKO) of SARM1 in the central nervous system (CNS, SARM1Nestin-CKO mice) delayed the cognitive decline in APP/PS1 AD model mice. Furthermore, SARM1 deletion reduced the Aß deposition and inflammatory infiltration in the hippocampus and inhibited neurodegeneration in APP/PS1 AD model mice. Further investigation into the underlying mechanisms revealed that the signaling of tumor necrosis factor-α (TNF-α) was downregulated in the hippocampus tissues of APP/PS1;SARM1Nestin-CKO mice, thereby alleviating the cognitive decline, Aß deposition and inflammatory infiltration. These findings identify unrecognized functions of SARM1 in promoting AD and reveal the SARM1-TNF-α pathway in AD model mice.

Development and validation of a fully automatic tissue delineation model for brain metastasis using a deep neural network.

Background: Stereotactic radiosurgery (SRS) treatment planning requires accurate delineation of brain metastases, a task that can be tedious and time-consuming. Although studies have explored the use of convolutional neural networks (CNNs) in magnetic resonance imaging (MRI) for automatic brain metastases delineation, none of these studies have performed clinical evaluation, raising concerns about clinical applicability. This study aimed to develop an artificial intelligence (AI) tool for the automatic delineation of single brain metastasis that could be integrated into clinical practice. Methods: Data from 426 patients with postcontrast T1-weighted MRIs who underwent SRS between March 2007 and August 2019 were retrospectively collected and divided into training, validation, and testing cohorts of 299, 42, and 85 patients, respectively. Two Gamma Knife (GK) surgeons contoured the brain metastases as the ground truth. A novel 2.5D CNN network was developed for single brain metastasis delineation. The mean Dice similarity coefficient (DSC) and average surface distance (ASD) were used to assess the performance of this method. Results: The mean DSC and ASD values were 88.34%±5.00% and 0.35±0.21 mm, respectively, for the contours generated with the AI tool based on the testing set. The DSC measure of the AI tool's performance was dependent on metastatic shape, reinforcement shape, and the existence of peritumoral edema (all P values <0.05). The clinical experts' subjective assessments showed that 415 out of 572 slices (72.6%) in the testing cohort were acceptable for clinical usage without revision. The average time spent editing an AI-generated contour compared with time spent with manual contouring was 74 vs. 196 seconds, respectively (P<0.01). Conclusions: The contours delineated with the AI tool for single brain metastasis were in close agreement with the ground truth. The developed AI tool can effectively reduce contouring time and aid in GK treatment planning of single brain metastasis in clinical practice.

Effect of oligonucleotide MT01 delivered by N-isopropylacrylamide modified polyethyleneimine for bone regeneration.

Objective: This study aimed to investigate the regulatory effect of N-isopropylacrylamide-modified polyethyleneimine (PEN)-delivered oligodeoxynucleotide (ODN) MT01 on bone regeneration in vitro and in vivo. Methods: A polyethylenimine (PEI) derivative, PEN, was constructed through Michael addition and employed as a carrier for ODN MT01 transfection. PEN/MT01 nanocomposites were characterized using agarose gel retardation assay, size distribution, zeta potential and transmission electron microscopy. The Cell Counting Kit-8 (CCK-8) assay was used to detect the effect of PEN on cell viability. Alkaline phosphatase (ALP) staining was used to detect the osteogenic differentiation ability of PEN/MT01 nanocomposite. Real-time quantitative PCR (q RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the regulatory effects of PEN/MT01 nanocomposite on osteogenic differentiation gene expression. Rat model was observed using the skull defect method and verified using micro-computed tomography (CT), serum biochemical indices, hematoxylin and eosin (H&E) staining and Immunohistochemistry (IHC). Results: PEN had good biological properties and could deliver MT01 well to achieve efficient transmission of MT01. PEN/MT01 nanocomposites were effectively transfected into MC3T3-E1 cells at a ratio of 6.0. CCK-8 assay displayed that PEN had no cytotoxicity to MC3T3-E1 cells. Additionally, PEN/MT01 nanocomposites could promote the expression of osteogenic genes. In vivo results revealed that PEN/MT01 nanocomposites could promote bone regeneration more effectively than the other groups. Conclusion: PEN has good biocompatibility and low toxicity, which is a good carrier for ODN MT01. PEN-delivered MT01 can be potentially employed as a useful approach to achieving bone regeneration.

Role of Berberine Thermosensitive Hydrogel in Periodontitis via PI3K/AKT Pathway In Vitro.

Periodontitis is a long-term inflammatory illness and a leading contributor to tooth loss in humans. Due to the influence of the anatomic parameters of teeth, such as root bifurcation lesions and the depth of the periodontal pocket, basic periodontal treatment on its own often does not completely obliterate flora microorganisms. As a consequence, topical medication has become a significant supplement in the treatment of chronic periodontitis. Berberine (BBR) has various pharmacological effects, such as hypoglycemic, antitumor, antiarrhythmic, anti-inflammatory, etc. The target of our project is to develop a safe and non-toxic carrier that can effectively release berberine, which can significantly reduce periodontal tissue inflammation, and to investigate whether berberine thermosensitive hydrogel can exert anti-inflammatory and osteogenic effects by modulating phosphatifylinositol-3-kinase/Protein Kinase B (PI3K/AKT) signaling pathway. Consequently, firstly berberine temperature-sensitive hydrogel was prepared, and its characterizations showed that the mixed solution gelated within 3 min under 37 °C with a hole diameter of 10-130 µm, and the accumulation of berberine release amounted to 89.99% at 21 days. CCK-8 and live-dead cell staining results indicated that this hydrogel was not biotoxic, and it is also presumed that the optimum concentration of berberine is 5 µM, which was selected for subsequent experiments. Real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB)results demonstrated that inflammatory factors, as well as protein levels, were significantly reduced in the berberine-loaded hydrogel group, and LY294002 (PI3K inhibitor) could enhance this effect (p < 0.05). In the berberine-loaded hydrogel group, osteogenesis-related factor levels and protein profiles were visibly increased, along with an increase in alkaline phosphatase expression, which was inhibited by LY294002 (p < 0.05). Therefore, berberine thermosensitive hydrogel may be an effective treatment for periodontitis, and it may exert anti-inflammatory and osteogenic effects through the PI3K/AKT signaling pathway.

New monoterpenoid indole alkaloids from the stems of Tabernaemontana bovina Lour (Apocynaceae).

Two new monoterpenoid indole alkaloids, named taberibogines E and F (1 and 2), together with three known ones (3-5) were isolated from the stems of Tabernaemontana bovina Lour (Apocynaceae). Their structures including absolute configurations were elucidated from a combination of NMR and HRESIMS data and NMR calculations as well as DP4+ probability analyses. Compounds 1 and 2 exhibited inhibitory effects on LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages.

Yes-associated protein regulates glutamate homeostasis through promoting the expression of excitatory amino acid transporter-2 in astrocytes via ß-catenin signaling.

The homeostasis of glutamate is mainly regulated by the excitatory amino acid transporters (EAATs), especially by EAAT2 in astrocytes. Excessive glutamate in the synaptic cleft caused by dysfunction or dysregulation of EAAT2 can lead to excitotoxicity, neuronal death and cognitive dysfunction. However, it remains unclear about the detailed regulation mechanism of expression and function of astrocytic EAAT2. In this study, first, we found increased neuronal death and impairment of cognitive function in YAPGFAP -CKO mice (conditionally knock out Yes-associated protein [YAP] in astrocytes), and identified EAAT2 as a downstream target of YAP through RNA sequencing. Second, the expression of EAAT2 was decreased in cultured YAP-/- astrocytes and the hippocampus of YAPGFAP -CKO mice, and glutamate uptake was reduced in YAP-/- astrocytes, but increased in YAP-upregulated astrocytes. Third, further investigation of the mechanism showed that the mRNA and protein levels of ß-catenin were decreased in YAP-/- astrocytes and increased in YAP-upregulated astrocytes. Wnt3a activated YAP signaling and up-regulated EAAT2 through ß-catenin. Furthermore, over-expression or activation of ß-catenin partially restored the downregulation of EAAT2, the impairment of glutamate uptake, neuronal death and cognitive decline that caused by YAP deletion. Finally, activation of EAAT2 also rescued neuronal death and cognitive decline in YAPGFAP -CKO mice. Taken together, our study identifies an unrecognized role of YAP signaling in the regulation of glutamate homeostasis through the ß-catenin/EAAT2 pathway in astrocytes, which may provide novel insights into the pathogenesis of brain diseases that closely related to the dysfunction or dysregulation of EAAT2, and promote the development of clinical strategy.

Discovery of a Unique Flavonoid Biosynthesis Mechanism in Fungi by Genome Mining.

Flavonoids are important plant natural products with variable structures and bioactivities. All known plant flavonoids are generated under the catalysis of a type III polyketide synthase (PKS) followed by a chalcone isomerase (CHI) and a flavone synthase (FNS). In this study, the biosynthetic gene cluster of chlorflavonin, a fungal flavonoid with acetolactate synthase inhibitory activity, was discovered using a self-resistance-gene-directed strategy. A novel flavonoid biosynthetic pathway in fungi was revealed. A core nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS) is responsible for the generation of the key precursor chalcone. Then, a new type of CHI catalyzes the conversion of a chalcone into a flavanone by a histidine-mediated oxa-Michael addition mechanism. Finally, the desaturation of flavanone to flavone is catalyzed by a new type of FNS, a flavin mononucleotide (FMN)-dependent oxidoreductase.

Biosynthesis mechanism, genome mining and artificial construction of echinocandin O-sulfonation.

Micafungin, a semisynthetic derivative of the cyclic hexapeptide FR901379 produced by Coleophoma empetri fermentation, is the only O-sulfonated echinocandin-type antifungal drug. However, the detailed formation mechanism of O-sulfonate group, whether before or after the assembly of hexapeptide, remains elusive. Here, we confirmed that O-sulfonylation occurs after hexapeptide assembly as a kind of postmodification in the biosynthesis of FR901379. The released cyclic hexapeptide was hydroxylated by cytochrome P450 McfP and successively sulfonated by sulfotransferase McfS. And other three echinocandin sulfotransferases were identified through genome mining by using McfS as a sequence probe. Moreover, pneumocandin B0, the precursor of caspofungin, could be O-sulfonated by heterologously introducing the McfP-McfS into the pneumocandin B0-producing species Glarea lozoyensis. The water-solubility of sulfonated pneumocandin B0 is 4000 times higher than that of pneumocandin B0. The revealed O-sulfonation mechanism will provide new insights into the design and production of novel sulfonated echinocandins by metabolic engineering.

SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice.

Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1PV-CKO) mice. SARM1PV-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1PV-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1PV-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1PV-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.

HIF1α is dispensable for oocyte development and female fertility in mice.

Background: It has been thought that oocyte may develop in a low oxygen environment, as changes in follicle structure and formation of a fluid-filled antrum. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. HIF1α is expressed in mature mouse oocytes and continues to be expressed after fertilization, from the 2-cell to blastocyst stage. However, the physiological roles of HIF pathway during oogenesis and embryogenesis have still not been elucidated in detail. Methods: Mutant mice with oocyte-specific HIF1α deletion were generated by crossing Hif1α fl/fl mice with transgenic mice expressing Gdf9-promoter-mediated Cre recombinase. Breeding assay was carried out to detect female fertility. In vitro fertilization and embryo culture were used to assess early embryo development. Oocyte meiotic progression was also examined. Quantitative RT-PCR was used for analyzing of candidate genes expression. Results: We successfully generated mutant mice with oocyte-specific deletion of HIF1α. Oocytes loss of HIF1α did not affect female fertility, ovulation and early embryo development. Moreover, oocytes can mature in vitro, and form well-organized spindle in the absence of HIF1α. In addition, pronounced differences in Hif2α and Hif3α mRNA expression were not observed in HIF1α-deleted oocytes. These results revealed that HIF pathway in oocytes is not essential for female fertility.

YAP signaling in horizontal basal cells promotes the regeneration of olfactory epithelium after injury.

The horizontal basal cells (HBCs) of olfactory epithelium (OE) serve as reservoirs for stem cells during OE regeneration, through proliferation and differentiation, which is important in recovery of olfactory function. However, the molecular mechanism of regulation of HBC proliferation and differentiation after injury remains unclear. Here, we found that yes-associated protein (YAP) was upregulated and activated in HBCs after OE injury. Deletion of YAP in HBCs led to impairment in OE regeneration and functional recovery of olfaction after injury. Mechanically, YAP was activated by S1P/S1PR2 signaling, thereby promoting the proliferation of HBCs and OE regeneration after injury. Finally, activation of YAP signaling enhanced the proliferation of HBCs and improved functional recovery of olfaction after OE injury or in Alzheimer's disease model mice. Taken together, these results reveal an S1P/S1PR2/YAP pathway in OE regeneration in response to injury, providing a promising therapeutic strategy for OE injury.

Construction of an efficient Claviceps paspali cell factory for lysergic acid production.

Lysergic acid (LA) is the key precursor of ergot alkaloids, and its derivatives have been used extensively for the treatment of neurological disorders. However, the poor fermentation efficiency limited its industrial application. At the same time, the hardship of genetic manipulation has hindered the metabolic engineering of Claviceps strains to improve the LA titer further. In this study, an efficient genetic manipulation system based on the protoplast-mediated transformation was established in the industrial strain Claviceps paspali. On this basis, the gene lpsB located in the ergot alkaloids biosynthetic gene cluster was deleted to construct the LA-producing cell factory. Plackett-Burman and Box-Behnken designs were used in shaking flasks, achieving an optimal fermentation medium composition. The final titer of LA and iso-lysergic acid (ILA) reached 3.7 g·L-1, which was 4.6 times higher than that in the initial medium. Our work provides an efficient strategy for the biosynthesis of LA and ILA and lays the groundwork for its industrial production.

Research on the Enhanced Oil Recovery Technique of Horizontal Well Volume Fracturing and CO2 Huff-n-Puff in Tight Oil Reservoirs.

The low oil productivity of tight oil reservoirs is mainly caused by poor reservoir physical properties such as low porosity and permeability, a small pore and throat ratio, and bad well connectivity, which lead to bad water injection capability and rapid pressure decline for the reservoir. In this paper, an enhanced oil recovery technique for tight oil reservoirs is proposed by combination of horizontal well volume fracturing and CO2 huff-n-puff to improve the reservoir physical properties and increase the flow capability of crude oil. In the initial reservoir development stage, the precise horizontal well trajectory and reservoir volume fracturing scale are designed by analyzing the distribution of sand body thickness and the oily sedimentary facies. The micro-seismic tracking technique is also used to monitor the fracture elongation. When the reservoir energy cannot satisfy the economic limit of oil productivity, the CO2 huff-n-puff technique is applied to increase the reservoir energy quickly. After the precise fracturing technique is used in tight oil Block X, the average oil production rate of six fractured horizontal wells increases by 5 ton (1 ton = 7.33 bbl) at the initial production stage, and the effective oil production increase life lasts for 32 months. When the reservoir energy is supplemented using the CO2 huff-n-puff technique, the oil production rate of pilot experiment well SP-1 increases from 1.9 to 12.8 ton with a cumulative oil increase of 1333.8 ton.