Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways.

Crosstalk-oriented chemical evolution of natural products (NPs) is an efficacious strategy for generating novel skeletons through coupling reactions between NP fragments. In this study, two NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, sorbremnoids A and B (1 and 2), with unprecedented chemical architectures were identified from a fungus Penicillium citrinum. Compounds 1 and 2 exemplify rare instances of hybrid NPs formed via a major facilitator superfamily (MFS)-like enzyme by coupling reactive intermediates from two separate biosynthetic gene clusters (BGCs), pcisor and pci56. Both sorbremnoids A and B are NLRP3 inflammasome inhibitors. Sorbremnoid A demonstrated strong inhibition of IL-1ß by directly binding to the NLRP3 protein, inhibiting the assembly and activation of the NLRP3 inflammasome in vitro, with potential application in diabetic refractory wound healing through the suppression of excessive inflammatory responses. This research will inspire the development of anti-NLRP3 inflammasome agents as lead treatments and enhance knowledge pertaining to NPs derived from biosynthetic crosstalk.

Discovery, Total Synthesis, and Anti-inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A-C (1-3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17-895, which represent the first naturally occurring naphthopyrone-macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro-inflammatory cytokine IL-1ß release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.

Robotic dental implant placement workflow for edentulous jaws.

Yakebot, the first autonomous robotic dental implant system, provides a 1-stop solution for implant design, robot operation, real-time navigation, and precision analysis. This report describes the composition, principles, and implant operation procedures of the Yakebot dental implant robotic system in a patient for whom the robotic workflow procedure was used to place implants in the edentulous maxilla. The results showed that this workflow was more precise and predictable than traditional methods.

Corporate social responsibility, political connections, and barrier industry diversification: Evidence from China.

In this paper, using the data of private sector enterprises listed in China from 2009 to 2014, we study the relationships between corporate social responsibility, political connections, and barrier industry diversification among Chinese public-listed private-sector enterprises. The empirical test results reveal that establishing political connections can contribute to diversification of these firms, while engaging in corporate social responsibility helps to promote their barrier industry diversification. More engagement in corporate social responsibility makes it easier for them to establish political connections and strengthen the association between political connections and barrier industry diversification. This study provides new empirical evidence for not only understanding the relationship between political connections of these firms and access to economic resources but also a new perspective regarding their conduct related to corporate social responsibility (CSR).

The power of implicit political capital on companies' entry barriers.

The paper distinguishes the political capital of private enterprises into three types, in terms of the political identity of entrepreneurs, partial state ownership, and government background of entrepreneurship. The first two are classified as explicit political capital, while the third is called implicit political capital. We investigated how political capital, the institutional environment, and access to protected industries intersect within private sector enterprises (PSEs). The data sample from 2011 to 2018 of listed private companies in China is employed. Firstly, the findings indicate political capital significantly enhances access to protected industries for PSEs. Second, implicit political capital shows a strong impact, while the effects of partial state ownership and entrepreneurs' political identity are weak. Third, explicit political capital weakens the effect on access to protected industries, while implicit political capital still holds significant influence under the improvement of institutional environments. It reveals the situation under the imperfect environment of the market economic system and legal system in China. To be explicit, the concept of ruling by man or power is deeply rooted in the traditional Chinese social governance and social structure model. Therefore, there is enormous room for implicit political capital to function.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

From theory to practice: Monetary policy transmission and bank risk dynamics.

This paper investigates the relationship between monetary policy and bank risk-taking by introducing a model wherein banks expend a level of costly monitoring effort to select low-risk projects, thereby reducing the risk associated with the loans they grant. The impact of monetary policy on bank risk-taking is examined through both theoretical models and empirical analysis. The paper compares theoretical models with different assumptions, revealing an unambiguous negative effect without the assumption of limited liability for banks, and an ambiguous effect with the assumption of limited liability for banks, influenced by the equity ratio. The empirical model employs unique quarterly data comprising balance sheet information for top-listed banks in the U.S. banking system from 2000 to 2017. The findings indicate that low-interest rates contribute to an increase in bank risk-taking. Moreover, this effect is more pronounced after the financial crisis and weaker before the crisis. Additionally, the impact is evident for undercapitalized banks and more substantial for those financed with a higher proportion of equity.

Genome Mining Reveals a UbiA-Type Prenyltransferase Access to Farnesylation of Diketopiperazines.

UbiA-type prenyltransferases (PTases) are significant enzymes that lead to structurally diverse meroterpenoids. Herein, we report the identification and characterization of an undescribed UbiA-type PTase, FtaB, that is responsible for the farnesylation of indole-containing diketopiperazines (DKPs) through genome mining. Heterologous expression of the fta gene cluster and non-native pathways result in the production of a series of new C2-farnesylated DKPs. This study broadens the reaction scope of UbiA-type PTases and expands the chemical diversity of meroterpenoids.

Exploring the Diverse Landscape of Fungal Cytochrome P450-Catalyzed Regio- and Stereoselective Dimerization of Diketopiperazines.

Dimeric indole-containing diketopiperazines (di-DKPs) are a diverse group of natural products produced through cytochrome P450-catalyzed C-C or C-N coupling reactions. The regio- and stereoselectivity of these reactions plays a significant role in the structural diversity of di-DKPs. Despite their pivotal role, the mechanisms governing the selectivity in fungi are not fully understood. Employing bioinformatics analysis and heterologous expression experiments, five undescribed P450 enzymes (AmiP450, AcrP450, AtP450, AcP450, and AtuP450) responsible for the regio- and stereoselective dimerization of diketopiperazines (DKPs) in fungi are identified. The function of these P450s is consistent with phylogenetic analysis, highlighting their dominant role in controlling the dimerization modes. Combinatorial biosynthesis-based pathway reconstitution of non-native gene clusters expands the chemical space of fungal di-DKPs and reveals that the regioselectivity is influenced by the substrate. Furthermore, multiple sequence alignment and molecular docking of these enzymes demonstrate a C-terminal variable region near the substrate tunnel entrance in AtuP450 that is crucial for its regioselectivity. These findings not only reveal the secret of fungal di-DKPs diversity but also deepen understanding of the mechanisms and catalytic specificity involved in P450-catalyzed dimerization reactions.

Phenylhydrazone Alkaloids from the Deep-Sea Cold Seep Derived Fungus Talaromyces amestolkiae HDN21-0307.

Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A-D (1-4) were isolated from the deep-sea cold seep derived fungus Talaromyces amestolkiae HDN21-0307 using the one strain-many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Talarohydrazone A (1) possessed an unusual skeleton combining 2,4-pyridinedione and phenylhydrazone. Talarohydrazone B (2) represents the first natural phenylhydrazone-bearing azadophilone. Bioactivity evaluation revealed that compound 1 exhibited cytotoxic activity against NCI-H446 cells with an IC50 value of 4.1 µM. In addition, compound 1 displayed weak antibacterial activity toward Staphylococcus aureus with an MIC value of 32 µg/mL.

Evolution-Based Discovery of Polyketide Acylated Valine from a Cytochalasin-Like Gene Cluster in Simplicillium lamelliciola HDN13430.

Utilizing a gene evolution-oriented approach for gene cluster mining, a cryptic cytochalasin-like gene cluster (sla) in Antarctic-derived Simplicillium lamelliciola HDN13430 was identified. Compared with the canonical cytochalasin biosynthetic gene clusters (BGCs), the sla gene cluster lacks the key α,ß-hydrolase gene. Heterologous expression of the sla gene cluster led to the discovery of a new compound, slamysin (1), characterized by an N-acylated amino acid structure and demonstrating weak anti-Bacillus cereus activity. These findings underscore the potential of genetic evolution in uncovering novel compounds and indicating specific adaptive evolution within specialized habitats.

Institutional gap and enterprise behavior: Evidence from China.

Alternative institutions have played a significant role in the difficult and tenacious development process of private enterprises in recent decades. the paper applied 306 listed companies' data from January 2012 to December 2022 to investigate the relationship between institutional gap and enterprise behavior. Based on the identified, classified, and explained formal and alternative institutions, it proposed the concept of 'institutional gap' to infer the overlapped content of these two states. Concluding from the empirical results, Chinese private enterprises that introduced state-owned equity outperformance in management, financing and entering industries with high barriers. Moreover, the channel of state-owned equity introduction is compared with entrepreneurs' political participation. Although introducing state-owned equity is a crucial approach, the establishment and improvement of relevant legal systems is suggested, such as formal regulations and laws. The government should deepen the reform of the economic system to improve the business environment, so private enterprises consciously rely on market mechanisms to allocate resources efficiently and rationally, instead of actively seeking connections with the government to obtain benefits. The supervisory role of checks and balances shareholders should be exerted to the greatest extent to maintain and increase the value of state-owned assets, rather than allowing the controlling private shareholders to use them as resources acquired political capital.

Steering Muscle-Based Bio-Syncretic Robot Through Bionic Optimized Biped Mechanical Design.

Bio-syncretic robots consisting of artificial structures and living muscle cells have attracted much attention owing to their potential advantages, such as high drive efficiency, miniaturization, and compatibility. Motion controllability, as an important factor related to the main performance of bio-syncretic robots, has been explored in numerous studies. However, most of the existing bio-syncretic robots still face challenges related to the further development of steerable kinematic dexterity. In this study, a bionic optimized biped fully soft bio-syncretic robot actuated by two muscle tissues and steered with a direction-controllable electric field generated by external circularly distributed multiple electrodes has been developed. The developed bio-syncretic robot could realize wirelessly steerable motion and effective transportation of microparticle cargo on artificial polystyrene and biological pork tripe surfaces. This study may provide an effective strategy for the development of bio-syncretic robots and other related studies, such as nonliving soft robot design and muscle tissue engineering.

Design of Light-Driven Biocompatible and Biodegradable Microrobots Containing Mg-Based Metallic Glass Nanowires.

Light-driven microrobots capable of moving rapidly on water surfaces in response to external stimuli are widely used in a variety of fields, such as drug delivery, remote sampling, and biosensors. However, most light-driven microrobots use graphene and carbon nanotubes as photothermal materials, resulting in poor biocompatibility and degradability, which greatly limits their practical bioapplications. To address this challenge, a composition and microstructure design strategy with excellent photothermal properties suitable for the fabrication of light-driven microrobots was proposed in this work. The Mg-based metallic glass nanowires (Mg-MGNWs) were embedded with polyhydroxyalkanoates (PHA) to fabricate biocompatible and degradable microrobots with excellent photothermal effect and complex shapes. Consequently, the microrobot can be precisely driven by a near-infrared laser to achieve high efficiency and remote manipulation on the water surface for a long period of time, with a velocity of 9.91 mm/s at a power density of 2.0 W/cm2. Due to the Marangoni effect, programmable and complex motions of the microrobot such as linear, clockwise, counterclockwise, and obstacle avoidance motions can be achieved. The biocompatible and degradable microrobot fabrication strategy could have great potential in the fields of environmental detection, targeted drug delivery, disease diagnosis, and detection.

Deciphering the potential role of quorum quenching in efficient aerobic denitrification driven by a synthetic microbial community.

Low efficiency is one of the main challenges for the application of aerobic denitrification technology in wastewater treatment. To improve denitrification efficiency, a synthetic microbial community (SMC) composed of denitrifiers Acinetobacter baumannii N1 (AC), Pseudomonas aeruginosa N2 (PA) and Aeromonas hydrophila (AH) were constructed. The nitrate (NO3--N) reduction efficiency of the SMC reached 97 % with little nitrite (NO2--N) accumulation, compared to the single-culture systems and co-culture systems. In the SMC, AH proved to mainly contribute to NO3--N reduction with the assistance of AC, while PA exerted NO2--N reduction. AC and AH secreted N-hexanoyl-DL-homoserine lactone (C6-HSL) to promote the electron transfer from the quinone pool to nitrate reductase. The declined N-(3-oxododecanoyl)-L-homoserine lactone (3OC12-HSL), resulting from quorum quenching (QQ) by AH, stimulated the excretion of pyocyanin, which could improve the electron transfer from complex III to downstream denitrifying enzymes for NO2--N reduction. In addition, C6-HSL mainly secreted by PA led to the up-regulation of TCA cycle-related genes and provided sufficient energy (such as NADH and ATP) for aerobic denitrification. In conclusion, members of the SMC achieved efficient denitrification through the interactions between QQ, electron transfer, and energy metabolism induced by N-acyl-homoserine lactones (AHLs). This study provided a theoretical basis for the engineering application of synthetic microbiome to remove nitrate wastewater.

Sulfur vacancy-rich (α/ß-CdS)/SiO2 photocatalysts for enhanced visible-light-driven photocatalytic degradation of rhodamine B.

The development of highly efficient photocatalysts for visible-light-driven degradation of organic pollution is of great interest for wastewater purification. In this work, a sulfur vacancy-rich (α/ß-CdS)/SiO2 (α: hexagonal & ß: cubic) photocatalyst with a high catalytic activity was novelly synthesized on a nano-SiO2 carrier by the reaction of Cd2+ with a CS2 storage material (CS2SM) as sulfur source and crystalline modifiers. The dispersion of α/ß-CdS on the nano-SiO2 carrier significantly enhanced the visible-light-driven catalytic activity of (α/ß-CdS)/SiO2 photocatalyst, and 93.37 % rhodamine B (RhB) conversion was determined over 50 mg (α/ß-CdS)/SiO2 photocatalyst for 30 mL 400 mg/L RhB solution at light intensity of 150 mW/cm2 and 298.15 K. After five cycle tests, the (α/ß-CdS)/SiO2 photocatalyst still owned excellent visible-light-driven catalytic degradation stability (>90 %). The characterizations of morphology, functional groups, and photo-electrochemistry of (α/ß-CdS)/SiO2 photocatalyst demonstrated that nano-SiO2 as a carrier played meaningful role in dispersing α/ß-CdS and reducing agglomeration, thus increasing the active site of photocatalytic degradation reaction, and the presence of α/ß hetero-phase junctions and sulfur vacancies allows the rapid separation of photo-generated carriers and inhibits photo-generated electron-holes recombination. Meanwhile, the electron paramagnetic resonance (EPR) and free radical masking test have also proved that the main active species is ·O2- for the oxidation of RhB. Therefore, the work is providing a new reference to the visible-light-driven degradation of wastewater with high RhB concentration at room temperature.

Accuracy of the Yakebot dental implant robotic system versus fully guided static computer-assisted implant surgery template in edentulous jaw implantation: A preliminary clinical study.

AIMS: To compare the accuracy of the Yakebot dental implant robotic system with that of fully guided static computer-assisted implant surgery (CAIS) template in edentulous implantation. MATERIALS AND METHODS: Thirteen patients with edentulous were recruited and divided into two groups: the Yake robotic system group (experimental) (n = 5) and the CAIS group (control) (n = 8). Postoperative cone-beam computed tomography (CBCT) was performed immediately, and the 3-dimensional positions of implants were obtained and compared with that in the preoperative design. The comparison showed platform, apical, depth, and angular deviations. A value of p < 0.05 was considered statistically significant. RESULTS: A total of 84 implants (36 in the robotic group and 48 in the CAIS group) were placed. The mean deviation at the implant platform, apex, depth, and angle in the CAIS group was 1.37 ± 0.72 mm, 1.28 ± 0.68 mm, 0.88 ± 0.47 mm, and 3.47 ± 2.02°, respectively. However, the mean deviation at the implant platform, apex, depth, and angle in the robotic group was 0.65 ± 0.25 mm, 0.65 ± 0.22 mm, 0.49 ± 0.24 mm, and 1.43 ± 1.18°, respectively. Significant differences in the four types of deviation (p < 0.05) between the two groups were observed. CONCLUSION: The accuracy of robotic system in edentulous implant placement was superior to that of the CAIS template, suggesting that robotic system is more accurate, safe, and flexible, can be considered a promising treatment in clinical practice.

FKBP3 aggravates the malignant phenotype of diffuse large B-cell lymphoma by PARK7-mediated activation of Wnt/ß-catenin signalling.

Diffuse large B-cell lymphoma (DLBCL) is difficult to treat due to the high recurrence rate and therapy intolerance, so finding potential therapeutic targets for DLBCL is critical. FK506-binding protein 3 (FKBP3) contributes to the progression of various cancers and is highly expressed in DLBCL, but the role of FKBP3 in DLBCL and its mechanism are not clear. Our study demonstrated that FKBP3 aggravated the proliferation and stemness of DLBCL cells, and tumour growth in a xenograft mouse model. The interaction between FKBP3 and parkinsonism associated deglycase (PARK7) in DB cells was found using co-immunoprecipitation assay. Knockdown of FKBP3 enhanced the degradation of PARK7 through increasing its ubiquitination modification. Forkhead Box O3 (FOXO3) belongs to the forkhead family of transcription factors and inhibits DLBCL, but the underlying mechanism has not been reported. We found that FOXO3 bound the promoter of FKBP3 and then suppressed its transcription, eventually weakening DLBCL. Mechanically, FKBP3 activated Wnt/ß-catenin signalling pathway mediated by PARK7. Together, FKBP3 increased PARK7 and then facilitated the malignant phenotype of DLBCL through activating Wnt/ß-catenin pathway. These results indicated that FKBP3 might be a potential therapeutic target for the treatment of DLBCL.

Gut microbe and hepatic macrophage polarization in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder with the potential to progress to hepatic fibrosis, hepatic cirrhosis, and even hepatocellular carcinoma. Activation of hepatic macrophages, important innate immune cells predominantly composed of Kupffer cells, plays a pivotal role in NAFLD initiation and progression. Recent findings have underscored the regulatory role of microbes in both local and distal immune responses, including in the liver, emphasizing their contribution to NAFLD initiation and progression. Key studies have further revealed that gut microbes can penetrate the intestinal mucosa and translocate to the liver, thereby directly influencing hepatic macrophage polarization and NAFLD progression. In this review, we discuss recent evidence regarding the translocation of intestinal microbes into the liver, as well as their impact on hepatic macrophage polarization and associated cellular and molecular signaling pathways. Additionally, we summarize the potential mechanisms by which translocated microbes may activate hepatic macrophages and accelerate NAFLD progression.

Diversity recovery and probiotic shift of gastric microbiota in functional dyspepsia patients after Helicobacter pylori eradication therapy.

The effects of Helicobacter pylori eradication on gastric mucosa-colonizing microbes in patients with functional dyspepsia (FD) remain unclear. Here, we explored microbial variation induced by H. pylori infection and eradication treatment in FD patients. Gastric microbial abundance and diversity were significantly reduced in the H. pylori-infected FD patients. Eradication treatment increased alpha and beta diversity of gastric mucosa-colonizing microbes, and promoted the expansion of several probiotic microbes, such as Leuconostoc mesenteroides, which exhibited a matched antagonistic performance against H. pylori. Significant variation was observed in gastric mucosa-colonizing microbes between H. pylori-positive and H. pylori-negative FD patients. Eradication treatment induced microbial diversity recovery and may provide sufficient nutrition and space for probiotic microbes, such as Leuconostoc mesenteroides.