DFT Study of Functional Reduction of CO2 with BH3NMe3: The Real Role of Organic Catalyst TBD.

The detailed mechanism of transition metal-free-catalyzed monomethylation of 2-naphthyl acetonitrile (1a) with CO2 in the presence of triazabicyclodecene (TBD) and BH3NMe3 was investigated using density functional theory. The C-methylation process proved to generate formaldehyde followed by the formation of the product via an alcohol rather than a methoxyborane intermediate. During the reaction, CO2 is activated to form the TBD-CO2 adduct and BH3NMe3 is changed into TBD-BH2 (IM2) in the presence of TBD. IM2 plays a real reducing role within the system due to the unique coordination capability of the B atom. In addition to enhancing the nucleophilicity of 1a through deprotonation by tBuOK, our research also indicates that the generated tBuOH not only assists in proton transfer to generate an alcohol intermediate but also promotes the regeneration of TBD.

HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma.

BACKGROUND: In HBV-associated HCC, T cells often exhibit a state of functional exhaustion, which prevents the immune response from rejecting the tumor and allows HCC to progress. Moreover, polymerase-specific T cells exhibit more severe T-cell exhaustion compared to core-specific T cells. However, whether HBV DNA polymerase drives HBV-specific CD8+ T cell exhaustion in HBV-related HCC remains unclear. METHODS: We constructed a Huh7 cell line stably expressing HA-HBV-DNA-Pol and applied co-culture systems to clarify its effect on immune cell function. We also examined how HBV-DNA-Pol modulated PD-L1 expression in HCC cells. In addition, HBV-DNA-Pol transgenic mice were used to elucidate the underlying mechanism of HBV-DNA-Pol/PD-L1 axis-induced T cell exhaustion. RESULTS: Biochemical analysis showed that Huh7 cells overexpressing HBV-DNA-Pol inhibited the proliferation, activation, and cytokine secretion of Jurkat cells and that this effect was dependent on their direct contact. A similar inhibitory effect was observed in an HCC mouse model. PD-L1 was brought to our attention during screening. Our results showed that the overexpression of HBV-DNA-Pol upregulated PD-L1 mRNA and protein expression. PD-L1 antibody blockade reversed the inhibitory effect of Huh7 cells overexpressing HBV-DNA-Pol on Jurkat cells. Mechanistically, HBV-DNA-Pol interacts with PARP1, thereby inhibiting the nuclear translocation of PARP1 and further upregulating PD-L1 expression. CONCLUSIONS: Our findings suggest that HBV-DNA-Pol can act as a regulator of PD-L1 in HCC, thereby directing anti-cancer immune evasion, which further provides a new idea for the clinical treatment of liver cancer.

Experimental Investigation of Reflectarray Antennas for High-Power Microwave Applications.

The power capacity of reflectarray antennas (RAs) is investigated through full-wave simulations and high-power microwave (HPM) experiments in this paper. In order to illustrate the results in detail, two RA elements are designed. The simulated power handling capacity of two RA elements are 7.17 MW/m2 and 2.3 GW/m2, respectively. To further study the HPM RA, two RA prototypes operating at 2.8 GHz are constructed with the aperture size of 1 m × 1 m. Simulations and experimental measurements are conducted for the two prototypes. The experimental results demonstrate that, even when subjected to 1 GW of power, the radiation beam of the RA with the second elements can still propagate in the intended direction. This research will establish a basis for advancing the practicality of RAs in HPM applications.

Spatiotemporally sequential delivery of biomimetic liposomes potentiates glioma chemotherapy.

As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not only the limited permeability of the blood-brain barrier (BBB) but also the deficiency of targeting tumor lesions. Thus, spatiotemporally sequential delivery of therapeutics from BBB-crossing to glioma accumulation is considered a strategy to obtain better outcomes. Here, we developed a biomimetic chemotherapy nanodrug composed of the hybrid membrane envelope of U87 cell membranes and RAW264.7 cell membranes, and the core of paclitaxel (PTX)-loaded liposome (PTX@C-MMCL). In the research, PTX@C-MMCL showed superior ability to cross the BBB via RAW264.7 cell membranes and accurate targeting to the brain tumor lesions relying on the homotypic targeting capacity of U87 cell membranes. Furthermore, PTX@C-MMCL can maintain a prolonged circulation in vivo. Importantly, PTX@C-MMCL effectively inhibited the development of glioma. Conclusively, our biomimetic nanodrug holds great potential for brain tumor targeting therapy.

Epidemiological analysis of drinking water-type fluorosis areas and the impact of fluorosis on children's health in the past 40 years in China.

This study analyzed the effect of China's fluorosis prevention and control program, which has been in effect for more than 40 years, and the impact of fluorosis on children's health. Relevant research studies were retrieved from the following online databases from the time of their inception to May 2022: PubMed, ScienceDirect, Embase, Cochrane, China National Knowledge Infrastructure, and Wanfang. The Review Manager 5.3 software was used in statistical analyses. This article included seventy studies: Thirty-eight studies reported the effect of improving water quality and reducing fluoride content, the incidence rate of dental fluorosis in children, and the level of urinary fluoride, and thirty-two studies reported the intelligence quotient (IQ) and health status of children. Following water improvement strategies, the fluoride levels in drinking water decreased significantly; urinary fluoride levels and dental fluorosis decreased significantly in children. With regard to the effect of fluorosis on the IQ of children, the results showed that the IQ of children in areas with a high fluoride of fluorosis was lesser than that in areas with a low fluoride, and this difference was significant. Based on the prevalence of dental fluorosis and its effect on the intelligence of children, it appears that reducing fluoride levels in drinking water and monitoring water quality are important strategies for the prevention and treatment of fluorosis.

Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5.

The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts.

High Hepcidin Levels Promote Abnormal Iron Metabolism and Ferroptosis in Chronic Atrophic Gastritis.

BACKGROUND: Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and premalignant lesion of gastric cancer. As an antimicrobial peptide, hepcidin can maintain iron metabolic balance and is susceptible to inflammation. OBJECTIVES: The objective of this study was to clarify whether hepcidin is involved in abnormal iron metabolism and ferroptosis during CAG pathogenesis. METHODS: Non-atrophic gastritis (NAG) and chronic atrophic gastritis (CAG) patient pathology slides were collected, and related protein expression was detected by immunohistochemical staining. The CAG rat model was established using MNNG combined with an irregular diet. RESULTS: CAG patients and rats exhibited iron deposition in gastric tissue. CAG-induced ferroptosis in the stomach was characterized by decreased GPX4 and FTH levels and increased 4-HNE levels. Hepcidin, which is mainly located in parietal cells, was elevated in CAG gastric tissue. The high gastric level of hepcidin inhibited iron absorption in the duodenum by decreasing the protein expression of DMT1 and FPN1. In addition, the IL-6/STAT3 signaling pathway induced hepcidin production in gastric tissue. CONCLUSION: Our results showed that the high level of gastric hepcidin induced ferroptosis in the stomach but also inhibited iron absorption in the intestines. Inhibiting hepcidin might be a new strategy for the prevention of CAG in the future.

Effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells.

BACKGROUND: 3D cancer stem cell (CSC) cultures are widely used as in vitro tumor models. In this study, we determined the effects of enriching HCT116 tumor spheres initially cultured in serum-free medium with different concentrations of serum, focusing on the effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells (CCSCs). METHODS: CCSCs were enriched in standard serum-free medium and serum-free medium with different concentrations of serum for 1 week. The expression of CSC-associated markers in CCSCs, and the presence and relative proportion of CSCs (CD133/CD44 cell sorting) were then determined to elucidate the effect of the microserum environment on the preservation of CSC-related features. Further, the tumorigenic capacity of CCSCs was evaluated in an immunodeficiency mouse model. RESULTS: Our data indicated that a significantly greater number of spheres with a greater size range and high viability without drastic alteration in biological and structural features, which maintained self-renewal potential after sequential passages were formed after serum supplementation. Real-time analysis showed that both serum spheres and serum-free spheres displayed similar expression patterns for key stemness genes. Serum spheres showed higher expression of the CSC surface markers CD133 and CD44 than did CSCs spheres cultured in serum-free medium. Adherent cultures in complete medium could adapt to the serum-containing microenvironment faster and showed higher proliferation ability. The addition of serum induced EMT and promoted the migration and invasion of serum globular cells. Compared with serum-free cells and adherent cells, serum spheres showed higher tumor initiation ability. CONCLUSIONS: Microserum environment stimulation could be an effective strategy for reliable enrichment of intact CCSCs, and a more efficient CSC enrichment method.

Nano-vaccines combining customized in situ anti-PD-L1 depot for enhanced tumor immunotherapy.

Low response rate of immune checkpoint blockade (ICB) has limited its clinical application. A promising strategy to overcome this limitation is the use of therapeutic cancer vaccines, which aim to induce robust immune responses that synergize with ICB through immune enhancement and immune normalization strategies. Herein, we developed a combination immunotherapy by combining nano-vaccines consisting of whole tumor cell lysates/CpG liposomes (LCLs) with an anti-PD-L1 loaded lipid gel (aPD-L1@LG). The LCLs were fabricated using cationic liposomes, while the lipid gels (LGs) were prepared by using soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO). Subcutaneous administration of LCLs successfully activated dendritic cells (DCs), and intratumoral administration of anti-PD-L1@LG ensured sustained ICB activity. These results demonstrated that this combination immunotherapy enhanced anti-tumor efficacy and prolonged the survival time in melanoma by activating systemic anti-tumor immune responses. These findings highlight the potential of this rational design as a promising strategy for tumor treatment.

Pyridine-appended disulfidephospholipids enable exceptionally high drug loading and stability as a robust liposomal platform.

Low drug loading and instability of liposomes are two main challenges in the clinic. Herein, a liposomal platform from alternative pyridine-appended disulfidephospholipid (Pyr-SS-PC) was developed for delivering camptothecin (CPT) with high loading and stability. These Pyr-SS-PC lipids with π-π stacking open a general gate in the delivery of aromatic ring-containing drugs.

Mechanism of action of Asparagus officinalis extract against multiple myeloma using bioinformatics tools, in silico and in vitro study.

Introduction: Asparagus (Asparagus officinalis) is a perennial flowering plant species. Its main components have tumor-prevention, immune system-enhancement, and anti-inflammation effects. Network pharmacology is a powerful approach that is being applied increasingly to research of herbal medicines. Herb identification, study of compound targets, network construction, and network analysis have been used to elucidate how herbal medicines work. However, the interaction of bioactive substances from asparagus with the targets involved in multiple myeloma (MM) has not been elucidated. We explored the mechanism of action of asparagus in MM through network pharmacology and experimental verification. Methods: The active ingredients and corresponding targets of asparagus were acquired from the Traditional Chinese Medicine System Pharmacology database, followed by identification of MM-related target genes using GeneCards and Online Mendelian Inheritance in Man databases, which were matched with the potential targets of asparagus. Potential targets were identified and a target network of traditional Chinese medicine was constructed. The STRING database and Cytoscape were utilized to create protein-protein interaction (PPI) networks and further screening of core targets. Results: The intersection of target genes and core target genes of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was enriched, the top-five core target genes were selected, and the binding affinity of corresponding compounds to the top-five core targets was analyzed using molecular docking. Network pharmacology identified nine active components of asparagus from databases based on oral bioavailability and drug similarity, and predicted 157 potential targets related to asparagus. Enrichment analyses showed that "steroid receptor activity" and the "PI3K/AKT signaling pathway" were the most enriched biological process and signaling pathway, respectively. According to the top-10 core genes and targets of the PPI pathway, AKT1, interleukin (IL)-6, vascular endothelial growth factor (VEGF)A, MYC, and epidermal growth factor receptor (EGFR) were selected for molecular docking. The latter showed that five core targets of the PI3K/AKT signaling pathway could bind to quercetin, among which EGFR, IL-6, and MYC showed strong docking, and the diosgenin ligand could bind to VEGFA. Cell experiments showed that asparagus, through the PI3K/AKT/NF-κB pathway, inhibited the proliferation and migration of MM cells, and caused retardation and apoptosis of MM cells in the G0/G1 phase. Discussion: In this study, the anti-cancer activity of asparagus against MM was demonstrated using network pharmacology, and potential pharmacological mechanisms were inferred using in vitro experimental data.

A multifunctional fluorescent probe based on Schiff base with AIE and ESIPT characteristics for effective detections of Pb2+, Ag+ and Fe3.

In this work, three Schiff-based fluorescent probes with aggregation-induced emission (AIE) and excited intramolecular proton transfer (ESIPT) characters were synthesized by grafting 2-aminobenzothiazole group onto 4-substituted salicylaldehydes. More important, a rare tri-responsive fluorescent probe (SN-Cl) was developed by purposeful variation of substituents in the molecule. It could selectively identify Pb2+, Ag+ and Fe3+ in different solvent systems or with the help of masking agent and show complete fluorescence enhancement without interference of other ions. Meanwhile, the other two probes (SN-ON and SN-N) could only recognize Pb2+ in DMSO/Tris-HCl buffer (3: 7, v/v, pH = 7.4). According to Job's plot, density functional theory (DFT) calculations and NMR analysis, coordination between SN-Cl and Pb2+/Ag+/Fe3+ was determined. The LOD values for three ions were as low as 0.059 µM, 0.012 µM and 8.92 µM, respectively. Ideally, SN-Cl showed satisfactory performance in real water samples detection and test paper experiments for three ions. Also, SN-Cl could be used as an excellent imaging agent for Fe3+ in HeLa cells. Therefore, SN-Cl has the ability to be a "single fluorescent probe for three targets".

[Corrigendum] Long non­coding RNA AC245100.4 promotes prostate cancer tumorigenesis via the microRNA­145­5p/RBBP5 axis.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, concerning the cell proliferation and migration assay data shown in Figs. 6D and 7B, there were a pair of panels showing overlapping data, such that the same data had apparently been selected to show the results from different experiments. Subsequently, the authors referred back to their original data, and identified further incorrectly assembled data panels in Figs. 3B and 7B. The corrected versions of Fig. 3B (showing the correct data for the 'AC245100.4 / PC3 / 0 h' scratch­wound assay data panel), Fig. 6D (showing the correct data for the 'PC3 / NC­mimic' and 'DU­145 / NC­inhibitor' data panels) and Fig. 7D (showing the correct data for the 'PC3 / 24 h / Inhibitor­miR­145­5p + siAC245100.4' data panel) are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not grossly affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 45: 619­629, 2021; DOI: 10.3892/or.2020.7894].

A Broadband Vortex Beam Generator Based on Single-Layer Hybrid Phase-Turning Metasurface.

Vortex beams carrying orbital angular momentum (OAM) have become a research frontier due to the prospect of improving spectral efficiency and transmission capacity in communication systems. In this work, a hybrid phase-turning meta-atom that combines resonance and geometric (Pancharatnam-Berry) phase modulation is used to form a single-layer metasurface. A linearly polarized broadband vortex beam of mode l = -1 is obtained by the metasurface. An experimental prototype of the vortex beam generator has been fabricated and measured. The simulated and measured results demonstrate that the whole vortex beam generator exhibits over 70% mode purity from 26.5 GHz to 40 GHz (the relative bandwidth is 38.57%). In addition, a wide 3 dB gain bandwidth and low crosstalk are also provided by the proposed generator. This indicates that the proposed generator has important application value for vortex beam communication and its related applications.

Root Exudates Mediate the Processes of Soil Organic Carbon Input and Efflux.

Root exudates, as an important form of material input from plants to the soil, regulate the carbon input and efflux of plant rhizosphere soil and play an important role in maintaining the carbon and nutrient balance of the whole ecosystem. Root exudates are notoriously difficult to collect due to their underlying characteristics (e.g., low concentration and fast turnover rate) and the associated methodological challenges of accurately measuring root exudates in native soils. As a result, up until now, it has been difficult to accurately quantify the soil organic carbon input from root exudates to the soil in most studies. In recent years, the contribution and ecological effects of root exudates to soil organic carbon input and efflux have been paid more and more attention. However, the ecological mechanism of soil organic carbon input and efflux mediated by root exudates are rarely analyzed comprehensively. In this review, the main processes and influencing factors of soil organic carbon input and efflux mediated by root exudates are demonstrated. Soil minerals and soil microbes play key roles in the processes. The carbon allocation from plants to soil is influenced by the relationship between root exudates and root functional traits. Compared with the quantity of root exudates, the response of root exudate quality to environmental changes affects soil carbon function more. In the future, the contribution of root exudates in different plants to soil carbon turnover and their relationship with soil nutrient availability will be accurately quantified, which will be helpful to understand the mechanism of soil organic carbon sequestration.

Role of flavonoids in age-related macular degeneration.

A common eye disorder known as age-related macular degeneration (AMD) eventually results in blindness and vision loss. AMD has a complicated and poorly understood aetiology. The main pathological processes associated with AMD include oxidative damage, inflammation, and neovascularization. Flavonoids are naturally occurring bioactive substances with extensive distribution and antioxidant, anti-inflammatory, and neovascularization inhibitory properties. Several in vitro and in vivo AMD-related models pertinent to vision and this ocular ailment have been used to assess the mechanisms of action of various flavonoids. This article will discuss the research progress of flavonoids in AMD, especially the characteristics and mechanism of flavonoids in treating AMD.

New Glycosyltransferases in Panax notoginseng Perfect Main Ginsenosides Biosynthetic Pathways.

Ginsenosides, the main bioactive ingredients of the Panax genus, are dammarane or oleanane triterpenoids with glycosylated modifications at C3/C6/C20 hydroxyls or C28 carboxyl, and their diverse glycosylation pattern has attracted great attention. However, the biosynthesis of some important saponins is still unclear. In this study, six UGTs were characterized, two of which were novel. PnUGT71A3 catalyzes not only the C6 hydroxyl glycosylation of protopanaxatriol (PPT) and F1 to form Rh1 and Rg1, respectively, but also the C20 hydroxyl glycosylation of protopanaxadiol (PPD)-type Rg3 to generate Rd. Especially, PnUGT94M1 is UDP-ß-l-rhamnose (UDP-Rha)-dependent, regioselectively catalyzing the C2' hydroxyl rhamnosylation of C6 glucose of the PPT-type ginsenosides Rg1 and Rh1 to generate ginsenosides Re and Rg2, respectively. Site-directed mutagenesis showed that His21, Asp120, Ser363, and Pro372 are key residues, and the triple mutant (G344S/G345S/L346T) highly improved the activity toward Rg1 and Rh1. The findings in this study, perfect main ginsenosides biosynthetic pathways in the Panax genus, expand the biocatalyst toolbox for ginsenoside production and show that the PSPG motif is one of the options to modify UGTs to improve their activities.

Design and synthesis of hederagenin derivatives modulating STING/NF-κB signaling for the relief of acute liver injury in septic mice.

Systemic inflammatory responses often result in sepsis and inhibition of inflammation is one strategy for sepsis treatment. In this study, we designed and synthesized 32 novel hederagenin (HD) derivatives with modifications at the A-ring, C-28, and C-23 positions and screened their anti-inflammatory activities in vitro, finding multiple compounds with potential anti-inflammatory activity. Of these, compound 1 was the most effective and was used for subsequent investigations into its mechanism of action and in vivo activity. In vivo assessments of anti-inflammatory activity showed that compound 1 reduced inflammation in a mouse model of sepsis with acute liver injury caused by lipopolysaccharide (LPS). Compound 1 also inhibited STING, p-IRF3, p-TBK1, p-p65, and p-IκB proteins in cGAS-STING-associated signaling. These findings indicated that compound 1 reduced inflammation through inhibition of STING expression and hence reducing activation of STING and nuclear factor-κB (NF-κB) signaling. Our work demonstrated that compound 1 is a promising lead compound for designing and developing anti-sepsis drugs.

M1/M2 re-polarization of kaempferol biomimetic NPs in anti-inflammatory therapy of atherosclerosis.

Atherosclerosis (AS), a leading cause of death worldwide, involves chronic macrophage inflammation from its initiation to the emergence of complications. Targeting plaque inflammation by re-polarizing pro-inflammatory M1 to anti-inflammatory M2 could therefore provide a promising strategy to treat AS, but currently available anti-inflammatory drugs limit clinical outcomes. In this study, we found that kaempferol (KPF) is capable of potential anti-inflammation as a novel drug candidate, which has been scarcely reported. Building upon these findings, we fabricated a macrophage-biomimetic KPF delivery platform, abbreviated as KPF@MM-NPs to potentiate therapeutic payloads, wherein the designed ROS-responsive Dextran-g-PBMEO NPs with π-π stacking were coated with macrophage membrane (MM) for effective target and accumulation in atherosclerotic lesions. Therapy of KPF@MM-NPs afforded significant decrease in proliferating macrophage inflammation while went with the reduction of key pro-inflammatory cytokines and re-polarization M1 to M2 phenotype, inducing excellent anti-AS responses in ApoE-/- mice after i.p. delivery. The mechanism of KPF@MM-NPs was further investigated and found it related to block the ROS/NF-κB signaling pathways. Together with as well demonstrated biosafety profiles, this proof-of-concept opens an instructive door for the study of KPF-mediated nanodrugs in treatment of AS based on biomimetic NPs.

Single-Layer Wide-Angle Scanning Linear Phased Arrays Based on Multimode Microstrip Patch Elements.

This paper introduces a novel single-layer microstrip patch element designed to achieve a wide beamwidth, in order to address the growing demand for wide-angle scanning capabilities in modern phased array systems. The proposed element, comprising a slot-etched circular patch and an array of metallized holes arranged in square rings, offers a unique approach to beam shaping. By carefully adjusting parameters such as the slot structure and feeding position, our element is engineered to simultaneously excite both the TM01 and TM21 modes, a key feature that contributes to its wide beamwidth characteristics. Through the constructive interference of these modes, our element demonstrates a remarkable 3 dB beamwidth of approximately 150° in both principal planes, showcasing its potential for wide-angle scanning applications. To validate the practical performance of this proposed element, two linear phased arrays are manufactured and experimentally evaluated. The simulation results confirm the wide-angle scanning capability of the antennas in both the E-plane and H-plane. Furthermore, the experimental assessment demonstrates that these linear phased arrays can effectively generate scanning beams within a frequency range of 25 GHz to 28 GHz, covering a wide angular range from -60° to 60°, while maintaining a gain loss within 3 dB. This innovative design approach not only offers a promising solution for achieving a wide beamwidth in microstrip patch elements, but also holds significant potential for the development of cost-effective phased arrays with wide-angle scanning capabilities, making it a valuable contribution to the advancement of phased array technology.