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Abstract: The genus Flueggea Willd. belongs to the Euphorbiaceae family and is widely distributed in Asia, South America, Oceania, and Europe, with sixteen species. Several species, such as Flueggea suffruticosa and Flueggea virosa, have been used as traditional medicines in Southeast Asia and Africa for a long time for their good medicinal effects in treating rheumatoid arthritis, traumatic injury, gastrointestinal disease etc. The characteristic chemical constituents of this genus are alkaloids and diterpenoids, which show antiviral, anti-inflammatory, analgesic, antitumor, antibacterial, antioxidant, and neuroprotective activities. This review summarizes the traditional medicinal values, chemical constituents, and pharmacological activities of the genus Flueggea to provide a useful reference for the follow-up research and application of the genus.

We investigate the effects of $p$-wave interactions on Efimov trimers in systems comprising two identical heavy fermions and a light particle, with mass ratios larger than $13.6$. Our focus lies on the borromean regime where the ground-state trimer exists in the absence of dimers. Using pair-wise Lennard-Jones potentials and concentrating on the $L^{\pi} = 1^{-}$ symmetry, we explore the critical value of the interspecies $s$-wave scattering length $a_{c}$ at which the borromean state appears in several two-component particle systems. We study the universal properties of $a_{c}$ and the influence of $p$-wave fermion-fermion interactions on its value. Our findings show that, in the absence of $p$-wave fermion-fermion interactions, $a_{c}$ is universally determined by the van der Waals radius and mass ratio. However, when attractive interactions between the two fermions are introduced, the formation of the borromean state becomes favored over the absence of $p$-wave fermion-fermion interaction. Furthermore, we demonstrate that the $p$-wave Efimov effects persist even when the fermion-fermion interaction is taken to the $p$-wave unitary limit.

As a new generation of photovoltaic devices, organic polymer solar cell (Organic Solar Cell, OSC) have attracted wide attention of researchers in recent years because of their unique advantages such as simple process, low energy consumption, low cost and large area preparation. However, the development of OSC has encountered bottlenecks: the low carrier mobility of photovoltaic materials forces the thickness of the active layer of OSC to be reduced as much as possible to meet the requirements of effective collection of photogenerated carriers, while the thinner absorption layer will lead to serious optical absorption loss and device performance degradation. Therefore, how to enhance the optical absorptivity of OSC on the premise of effective carrier collection has become a research hot-spot. Based on this characteristic, with the help of finite element method, the structure model of OSC with multi-tip metal nanoparticles is established, and the effects of metal nanospheres and star particles on OSC light absorption factors are studied systematically. Firstly, the effects of introducing metal nanoparticles into different functional layers of OSC (active layer and buffer layer) are compared and analyzed to determine the introduction location of metal nanoparticles in OSC. Secondly, the localized resonance enhancement rules of spherical and cubic metal nanoparticles in the functional layer are discussed. Combined with the theoretical model, the optimal design method of metal nanoparticles structure parameters (size and period) is established. The results show that the absorption enhancement of metal nanoparticles in the active layer of OSC is higher than that in the buffer layer. On the one hand, it can stimulate more electron hole pair separation, improve the separation rate of electron hole pair, on the other hand, it can also make the separated electron hole to obtain more energy, recombination becomes relatively difficult, and the arrival rate of the battery electrode is improved.

Photo composition is one of the most important factors in the aesthetics of photographs. As a popular application, composition recommendation for a photo focusing on a specific subject has been ignored by recent deep-learning-based composition recommendation approaches. In this paper, we propose a subject-aware image composition recommendation method, SAC-Net, which takes an RGB image and a binary subject window mask as input, and returns good compositions as crops containing the subject. Our model first determines candidate scores for all possible coarse cropping windows. The crops with high candidate scores are selected and further refined by regressing their corner points to generate the output recommended cropping windows. The final scores of the refined crops are predicted by a final score regression module. Unlike existing methods that need to preset several cropping windows, our network is able to automatically regress cropping windows with arbitrary aspect ratios and sizes. We propose novel stability losses for maximizing smoothness when changing cropping windows along with view changes. Experimental results show that our method outperforms state-of-the-art methods not only on the subject-aware image composition recommendation task, but also for general purpose composition recommendation. We also have designed a multistage labeling scheme so that a large amount of ranked pairs can be produced economically. We use this scheme to propose the first subject-aware composition dataset SACD, which contains 2777 images, and more than 5 million composition ranked pairs. The SACD dataset is publicly available at https://cg.cs.tsinghua.edu.cn/SACD/.

Patients with obstructive sleep apnoea (OSA) have a high incidence of vascular endothelial injury. The most important pathophysiological feature of OSA is chronic intermittent hypoxia (CIH). This study aimed to investigate the mechanisms of CIH-related vascular endothelial injury.IH exposure was applied to human umbilical vein endothelial cells (HUVECs). After modeling, cell viability, the expression levels of peroxisome proliferator activated receptor γ (PPARγ), apoptosis-associated proteins and mitochondrial division fusion proteins, and the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were assessed via Cell Counting Kit-8 (CCK-8), western blotting, fluorescent microscope, and flow cytometry, respectively. Rosiglitazone (PPARγ agonist), tempo (the mitochondrial-specific antioxidant), and tempo combined with PPARγ interfering RNA were used to treat HUVECs, respectively.After IH exposure, cell viability and levels of MMP decreased, cell apoptosis and ROS levels increased, and the expression levels of PPARγ decreased. Both tempo and rosiglitazone pretreatment ameliorated cell apoptosis and improved cell viability. In addition, mitochondrial function became better after tempo pretreatment. PPARγ interference reversed the protective effects of tempo on IH-related mitochondrial function injury and cell injury.PPARγ regulated the apoptosis and cell viability of IH-treated HUVECs by altering mitochondrial function. This finding clarifies the mechanism of CIH-related vascular endothelial injury.

This article focuses on global finite-time output feedback stabilization for uncertain nonlinear systems with unknown measurement sensitivity. The existence of the continuous measurement error resulting from limited accuracy of sensors invalidates the existing design strategies depending on the use of the precise output in the construction of an observer, which highlights the contribution of this article. Essentially, different from related works, we propose a new finite-time convergent observer by avoiding the use of the information on nonlinearities. By combining the homogeneous domination with the addition of a power integrator method, an output feedback controller composed of multiple nested sign functions is successfully developed. Finally, the effectiveness of the presented scheme is exhibited by a numerical example.

Radix Astragali is one of the most famous and frequently used health food supplements and herbal medicines. Among more than 227 components of Radix Astragali, Astragaloside IV (AG IV) is famous functional compound and is commonly used as a quality marker for Radix Astragali. However, the relatively low content of AG IV in Radix Astragali (Poria cocos solid fermenting Radix Astragali. The optimum fermentation conditions were as follows: Inoculation amount 8 mL; fermentation time 10 d; fermentation humidity 90%. Through fermentation, the content of AG IV was increased from 384.73 to 1986.49 μg/g by 5.16-fold. After in vitro digestion, the contents of genistin, calycosin, formononetin, AG IV, Astragaloside II (AG II) and total flavonoids in fermented Radix Astragali (FRA) of enteric phase II (ENTII) were 34.52 μg/g, 207.32 μg/g, 56.76 μg/g, 2331.46 μg/g, 788.31 μg/g, 3.37 mg/g, which were 2.08-fold, 2.51-fold, 1.05-fold, 8.62-fold, 3.22-fold and 1.50-fold higher than those of control, respectively. The Scanning electron microscopy (SEM) of FRA showed rough surface and porous structure. The DPPH and ABTS radical scavenging rate of FRA were higher than those of control. These results showed that the Poria cocos solid fermentation could increase the content of the AG IV in Radix Astragali and improve the bioaccessibility and antioxidant activity of Radix Astragali, which is providing new ideas for future development and utilization of Radix Astragali.

Here, we demonstrate the development and the synthetic applications of a novel class of diphosphine ligands (SPSiP) based on chiral spirosilabiindane diol (SPSiOL). Starting from SPSiOL, the biphosphine ligands could be readily prepared in three steps with high efficiency. This novel class of biphosphine ligands features rigid configuration, a large dihedral angle, a large P–M–P angle, and a long P–P distance, which might possess unique catalytic reactivities. The potentials of SPSiPs in asymmetric catalysis have also been preliminary disclosed by Rh-catalyzed asymmetric hydrogenation, Rh-catalyzed tandem hydrosilylation, and Pd-catalyzed asymmetric allylic alkylation.

STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-α promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-α, and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation assay. We also found that ERR-α was the key target gene regulated by STAT3 in promoting epithelial–mesenchymal transition (EMT), migration, and invasion. ERR-α upregulated the expression of ZEB1, N-cadherin, and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-α could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-α was a direct regulatory gene target of p-STAT3, which was enriched for processes involving invasion and metastasis in TNBC and provided insight into TNBC pathogenesis, as well as a potential therapeutic option against TNBC metastasis.Implications:Our research first showed that p-STAT3 (Tyr 705) could bind to the promotor region of ERR-α and promote EMT in TNBC by ZEB1 pathways, thus providing a potential clinical target for TNBC.

Supplementary Materials and Methods

Primers of Ch-IP (P1-P11)

Supplementary Figure 1. Time-course analysis of the development of lung tumors induced by urethane in BALB/C mice and MS/MS analysis of destrin identified. Supplementary Figure 2. Validation of targeted proteins chosen by immunohistochemistry analysis. Supplementary Figure 3. Protein expression levels of Prdx5, Ctsd, Ctsh, Ctnna1, and Jup with reference to GAPDH (internal control), examined by immunoblot in the lung tissues of normal control mice and the mice at week 16 and 32 after Urethane treatment. Supplementary Figure 4. The effect of DSTN knockdown or overexpression on colony formation and migration in BEAS-2B cells. Supplementary Figure 5. Representative images of IHC staining using Ki67. Supplementary Figure 6. DSTN knockdown induces G2/M phase arrest in A549 and H1299 cells. Supplementary Figure 7. DSTN knockdown promotes apoptosis in A549 and H1299 cells. Supplementary Figure 8. The effect of DSTN knockdown or overexpression on the migration of A549 and H1299 in vitro. Supplementary figure 9. The effect of DSTN knockdown or overexpression on anchorage-independent growth of A549 and H1299 in vitro. Supplementary figure 10. The effect of DSTN knockdown or overexpression on EMT marker expression. Supplementary Figure 11. The effect of DSTN knockdown or overexpression on the adhesive ability of the A549 and H1299 cells. Supplementary Figure 12. DSTN knockdown or overexpression affects the sub-cellular localization of β-catenin in A549 and H1299 cells. Supplementary figure 13. The interaction between DSTN and β-catenin was assessed by Co-immunoprecipitation.

Supplementary Table 1. The differentially expressed proteins of normal and early - stage lung cancer tissues identified by LC-MS/MS analysis (N: normal; T: tumor).

The whole data of Ch-IP (P1-P11).

The illustration of STAT3/ERR-α signaling pathway.

Supplementary Table 2.Proteins chosen for immunohistochemistry and Western blot validation. Supplementary Table 3. Correlations between clinicopathologic factors and destrin expression. Supplementary Table 4. Multivariate Cox regression analysis of survival rate in 86 lung. Supplementary Table 5. The primers used in this study for plasmid construction. Supplementary Table 6. The primers used in this study for reverse transcription-quantitative polymerasechain reaction analysis.

Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of β-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma.Implications:This finding indicates that DSTN facilitates β-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.

Heparinase I (Hep I), which specifically degrades heparin to oligosaccharide or unsaturated disaccharide, has an important role in the production of low molecular weight heparin (LMWH). However, low productivity and stability of heparinase I hinders its applications. Here, a novel heparinase I (BxHep-I) was cloned from Bacteroides xylanisolvens and overexpressed in soluble form in Escherichia coli. The expression conditions of BxHep-I were optimized for an activity of 7144 U/L. BxHep-I had a specific activity of 57.6 U/mg at the optimal temperature and pH of 30 °C and pH 7.5, with the Km and Vmax of 0.79 mg/mL and 124.58 U/mg, respectively. BxHep-I catalytic activity could be enhanced by Ca2+ and Mg2+, while strongly inhibited by Zn2+ and Co2+. Purified BxHep-I displayed an outstanding thermostability with half-lives of 597 and 158 min at 30 and 37 °C, respectively, which are the highest half-lives ever reported for heparinases I. After storage at 4 °C for one week, BxHep-I retained 73% of its initial activity. Molecular docking revealed that the amino acids Asn25, Gln27, Arg88, Lys116, His156, Arg161, Gln228, Tyr356, Lys358, and Tyr362 form 13 hydrogen bonds with the substrate heparin disaccharides in the substrate binding domain and are mainly involved in the substrate binding of BxHep-I. These results suggest that the BxHep-I with high stability could be a candidate catalyst for the industrial production of LMWH.

The Tarim craton in modern Central Asia was an important component of the supercontinent Rodinia in the Neoproterozoic, although its paleogeography in Rodinia during that era is still controversial. Here, we present new stratigraphic, geochemical, and geochronological data from the Neoproterozoic sedimentary and volcanic rock successions along the northwestern margin of the Tarim craton and discuss the significance of these data and our interpretations for its tectonic evolution and paleogeographic position within Rodinia. The Lower Ediacaran sedimentary sequence (Sugetbrak Formation) in northwest Tarim includes terrestrial and shallow-marine clastic rocks intercalated with two discrete basaltic lava flows near the top. The Upper Ediacaran sedimentary sequence conformably overlying the volcanic and clastic rocks consists mainly of stromatolitic dolomite (Chigebrak Formation), representing a transgressive shallow-marine environment. Previous U-Pb zircon dating of the basaltic lava flows has constrained the timing of their eruption in the early Ediacaran (615 Ma). Detrital zircon U-Pb dating of a feldspar-quartz-sandstone unit situated between the two lava flows revealed an oldest age of 2517 ± 18 Ma and a youngest age of 612 ± 6 Ma, with a majority of zircon grains (n = 42) dated at 891–754 Ma (Tonian). A quartz-sandstone unit above the upper lava flow revealed an oldest age of 2724 ± 15 Ma and a youngest age of 607 ± 8 Ma, with a missing age group of 891–800 Ma. These data and observations indicate: (1) a major switch in the depositional setting from a terrestrial (synrifting) to shallow-marine environment following the eruption of the upper lava unit; and (2) an abrupt disappearance of the source rocks of the 891–800 Ma zircons and sediments from the provenance of the post-615 Ma (postrifting) sedimentary sequence. The basaltic rocks have low SiO2 and MgO but high total Fe2O3 and TiO2 contents (2.34–3.19 wt%), analogous to high-Ti basalts and continental flood basalts. Their Ti/V ratios (65–88), low Th/Nb ratios (~0.1), and high TiO2/Yb ratios (~1.1) are similar to those of ocean-island basalt (OIB). Combined with their Sm/Yb and La/Sm ratios and Sr-Nd-Pb-Hf isotope values, we infer that magmas of the Sugetbrak basalts were likely derived from partial melting of an enriched mantle source (EM I) in a transitional spinel-garnet lherzolite field. This petrogenetic evolution was a result of mantle plume–influenced rift magmatism during the Ediacaran breakup of Rodinia. The Central Tianshan terrane, which was attached to the northern Tarim craton until the Ediacaran Period, was the provenance of 891–800 Ma (Tonian) zircons in the synrift sedimentary succession. As the Central Tianshan terrane broke away from the Tarim craton after ca. 615 Ma, Tonianaged zircons were no longer available to the depocenter of the postrift sedimentary sequence. The transition from rifting to drifting between the Tarim craton and the Central Tianshan terrane marked the final breakup of Rodinia, a global event that was possibly driven by mantle plume activities coeval with the development of the Central Iapetus magmatic province in Laurentia during the Ediacaran.

The synthesis of the originally proposed structure of (±)-nicotlactone A, a potent antiviral lignan with three continuous chiral centers, is reported in 5 steps from methyl acrylate. The key steps of the synthesis included an In-catalyzed regioselective allylation and a Mn-catalyzed Mukaiyama hydration reaction. Our synthetic strategy also enabled us to get the other three epimers and investigate the structure–activity relationship. The NMR data of the synthesized compounds do not match that of the isolated sample, indicating that the structure of nicotlactone A remains to be reassigned. All the synthetic target compounds were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. Bioassay results indicated that (±)-8-demethylnicotlactone A displayed similar anti-TMV activity to the commercial agent ningnanmycin, thus being a promising candidate or lead compound for developing novel antiviral agents in crop protection.

Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases.

The innate cytokine IL-33 is increasingly recognised to possess biological effects on various immune cells. We have previously demonstrated elevated serum level of soluble ST2 in patients with active systemic lupus erythematosus suggesting involvement of IL-33 and its receptor in the lupus pathogenesis. This study sought to examine the effect of exogenous IL-33 on disease activity of pre-disease lupus-prone mice and the underlying cellular mechanisms. Recombinant IL-33 was administered to MRL/lpr mice for 6 weeks whereas control group received phosphate-buffered saline. IL-33-treated mice displayed less proteinuria, renal histological inflammatory changes and had lower serum levels of pro-inflammatory cytokines including IL-6 and TNF-α. Renal tissue and splenic CD11b+ extracts showed features of M2 polarisation with elevated mRNA expression of Arg1, FIZZI and reduced iNOS. These mice also had increased IL-13, ST2, Gata3 and Foxp3 mRNA expression in renal and splenic tissues. Kidneys of these mice displayed less CD11b+ infiltration, had downregulated MCP-1 and increased infiltration of Foxp3 expressing cells. Splenic CD4+ T cells showed increased ST2 expressing CD4+Foxp3+ population and reduced IFN-γ+ population. There were no differences in serum anti-dsDNA antibodies and renal C3 and IgG2a deposit in these mice. Exogenous IL-33 was found to ameliorate disease activity in lupus-prone mice with induction of M2 polarisation, Th2 response and expansion of regulatory T cells. IL-33 likely orchestrated autoregulation of these cells through upregulation of ST2 expression.

Background Porcine respiratory and reproductive syndrome(PRRS) is still the most undermine viral disease in hog(Sus scrofa domestica,Sus) farming without effective drug of treatment. This study is aimed to discover its molecular mechanism and provide potential drug targets of LHQW(Lanhua Qingwen) against PRRS. Methods An LHQW target gene set was established from Traditional Chinese Medicine Systems Pharmacology database(TCMSP) and Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP),PRRSV(Porcine respiratory and reproductive syndrome virus)-associated pneumonia–related gene set was obtained from 5 disease-gene databases.,Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Protein-protein interaction (PPI) network were performed to discover the potential proteins.Molecular docking was performed to identify the patterns of interactions between the effective molecules and targeted proteins. Results A total of 509 bioactive ingredients and 255 targets of LHQW as well as 2738 PRRSV-associated pneumonia genes were obtained.The GO and KEGG indicated that LHQW can act by regulating stress response,virus infection and immune response.PPI networks and subnetworks identified 9 core genes.The molecular docking was conducted on the most significant gene MAP kinase-activated protein kinase 3(MAPK3) and other genes of RAC-alpha serine/threonine-protein kinase(AKT1),estrogen receptor 1(ESR1),MAP kinase-activated protein kinase 1(MAPK1),transcription factor p65(RELA) and Heat shock protein HSP 90-alpha(HSP90AA1),which are involved in virus infection,inflammation and oxidative stress pathways.Naringenin can target simultaneously the active pockets of these 6 proteins which exerting potential therapeutic effects in PRRS. Conclusions The network pharmacological strategy integrates molecular docking to unravel the molecular mechanism of LHQW.Naringenin is a promising molecule for target of MAPK3,AKT1,ESR1,MAPK1,RELA and HSP90AA1 involving in oxidative stress,metabolic regulation,anti-inflammatory and immune defence pathways to treat PRRSV-associated pneumonia.

IntroductionMetabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease related to metabolic syndrome. However, ecological shifts in the saliva microbiome in patients with MAFLD remain unknown. This study aimed to investigate the changes to the salivary microbial community in patients with MAFLD and explore the potential function of microbiota.MethodsSalivary microbiomes from ten MAFLD patients and ten healthy participants were analyzed by 16S rRNA amplicon sequencing and bioinformatics analysis. Body composition, plasma enzymes, hormones, and blood lipid profiles were assessed with physical examinations and laboratory tests.ResultsThe salivary microbiome of MAFLD patients was characterized by increased α-diversity and distinct β-diversity clustering compared with control subjects. Linear discriminant analysis effect size analysis showed a total of 44 taxa significantly differed between the two groups. Genera Neisseria, Filifactor, and Capnocytophaga were identified as differentially enriched genera for comparison of the two groups. Co-occurrence networks suggested that the salivary microbiota from MAFLD patients exhibited more intricate and robust interrelationships. The diagnostic model based on the salivary microbiome achieved a good diagnostic power with an area under the curve of 0.82(95% CI: 0.61–1). Redundancy analysis and spearman correlation analysis revealed that clinical variables related to insulin resistance and obesity were strongly associated with the microbial community. Metagenomic predictions based on Phylogenetic Investigation of Communities by Reconstruction of Unobserved States revealed that pathways related to metabolism were more prevalent in the two groups.ConclusionsPatients with MAFLD manifested ecological shifts in the salivary microbiome, and the saliva microbiome-based diagnostic model provides a promising approach for auxiliary MAFLD diagnosis.

The tumor and tissue microbiota of human beings have recently been investigated. Gut permeability is known as a possible resource for the positive detection of tissue bacteria. Herein, we report that microbiota were detected in high abundance in the hepatocytes of healthy rats and that they were shared with the gut microbiota to an extent. We assessed male Sprague Dawley (SD) rats for the 16S ribosomal ribonucleic acid (rRNA) gene. After the rats were sacrificed by blood drainage from the portal vein, we extracted total deoxyribonucleic acid (DNA) from their ileal and colonic contents and liver tissues. The V3–V4 region of the 16S rRNA gene was amplified by polymerase chain reaction (PCR) and sequenced using an Illumina HiSeq 2500 platform. Sequences were assigned taxonomically by the SILVA database. We also detected bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA) in situ using immunofluorescence (IF) and western blotting and the 16S rRNA gene using fluorescent in situ hybridization (FISH). In the livers of six rats, we detected 54,867.50 ± 6450.03 effective tags of the 16S rRNA gene and clustered them into 1003 kinds of operational taxonomic units (OTUs; 805.67 ± 70.14 , 729–893). Rats showed conservation of bacterial richness, abundance, and evenness. LPS and the 16S rRNA gene were detected in the nuclei of hepatocytes. The main function composition of the genomes of annotated bacteria was correlated with metabolism ( 79.92 ± 0.24 % ). Gram negativity was about 1.6 times higher than gram positivity. The liver microbiome was shared with both the small and large intestines but showed significantly higher richness and evenness than the gut microbiome, and the β-diversity results showed that the liver microbiome exhibited significantly higher similarity than the small and large intestines ( P < 0.05 ). Our results suggest that the bacteria in the liver microbiome are hidden intracellular inhabitants in healthy rat livers.

To date, the extremely high polarity and poor signal intensity of macromolecular nucleic acids are greatly impeding the progress of mass spectrometry technology in the quality control of nucleic acid drugs and the characterization of DNA oxidation and RNA modifications. We recently described a general

Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j–4 can significantly induce the apoptosis of MDA-MB-231 cells (IC50 = 2.68 ± 0.27 μM). In further studies, 12j–4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j–4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors. 10 novel biphenyl derivatives were designed and synthesised. 12j–4 can cause the apoptosis of MDA-MB-231 cells with an IC50 value of 2.68 ± 0.27 μM in the absence of immune cells. 12j–4 prevents the phosphorylation of AKT by binding to cytoplasmic PD-L1 to induce apoptosis through non-immune pathways.

Fine-root decomposition is a critical process regulating ecosystem carbon cycles and affecting nutrient cycling and soil fertility. However, whether interaction between warming and grazing affects fine-root decomposition is still under-researched in natural grasslands. A two-factorial experiment with asymmetric warming (i.e. daytime vs. nighttime and growing season vs. nongrowing season) and moderate grazing (i.e. about average 50% forage utilization rate) was conducted to explore whether warming and grazing affect fine-root decomposition and loss of nutrients during a 2-year decomposition period in an alpine meadow on the Tibetan Plateau. Both warming and grazing facilitated carbon cycling through increase in fine-root decomposition, and influenced element cycling which varies among elements. The effects of warming and grazing on fine-root decomposition and loss of nutrients were additive. Both warming and grazing significantly increased cumulative percentage mass loss and total organic carbon loss of fine roots during the 2-year experiment. Only warming with grazing treatment reduced percentage nitrogen loss, whereas warming, regardless of grazing, decreased percentage phosphorus loss. Warming and grazing alone increased percentage loss of potassium, sodium, calcium and magnesium compared with control. There were no interactions between warming and grazing on fine-root decomposition and loss of nutrients. There was greater temperature sensitivity of decreased phosphorus loss than that of decreased nitrogen loss. Different temperature sensitivities of percentage loss of nutrients from fine-root decomposition would alter ratios of the available nutrients in soils, and may further affect ecosystem structure and functions in future warming.

An efficient procedure for p-toluenesulfonic acid-catalyzed iodination of isoquinolin-1(2H)-ones with N-iodosuccinimide under mild reaction conditions is reported. This methodology features scalable synthesis, wide substrate scope, and high functional-group tolerance.

Background: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. Patients and Methods: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. Results: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1–11.1), BRCA2 (OR, 15.3; 95% CI, 10.0–23.2), MSH2 (OR, 15.8; 95% CI, 4.2–59.6), and PALB2 (OR, 5.9; 95% CI, 2.7–13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34–3.58] and 2.47 [95% CI, 1.23–4.96], respectively) but similar benefit from docetaxel. Conclusions: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Sheath blight (ShB) is one of the most common diseases in rice that significantly affects yield production. However, the underlying mechanisms of rice defense remain largely unknown. Our previous transcriptome analysis identified that infection with Rhizoctonia solani significantly induced the expression level of SWEET2a, a member of the SWEET sugar transporter. The sweet2a genome-editing mutants were less susceptible to ShB. Further yeast-one hybrid, ChIP, and transient assays demonstrated that WRKY53 binds to the SWEET2a promoter to activate its expression. WRKY53 is a key brassinosteroid (BR) signaling transcription factor. Similar to the BR receptor gene BRI1 and biosynthetic gene D2 mutants, the WRKY53 mutant and overexpressor were less and more susceptible to ShB compared to wild-type, respectively. Inoculation with R. solani induced expression of BRI1, D2, and WRKY53, but inhibited MPK6 (a BR-signaling regulator) activity. Also, MPK6 is known to phosphorylate WRKY53 to enhance its transcription activation activity. Transient assay results indicated that co-expression of MPK6 and WRKY53 enhanced WRKY53 trans-activation activity to SWEET2a. Furthermore, expression of WRKY53 SD (the active phosphorylated forms of WRKY53) but not WRKY53 SA (the inactive phosphorylated forms of WRKY53), enhanced WRKY53-mediated activation of SWEET2a compared to expression of WRKY53 alone. Taken together, our analyses showed that R. solani infection may activate BR signaling to induce SWEET2a expression via WRKY53 through negative regulation of ShB resistance in rice.

Polynitrogen heterocycles are readily available and have recently arisen as versatile synthons for the formation of various C–C and C–X bonds, and medicinally active nitrogen-containing heterocycles. Several cascade reactions, including annulation, radical cascade, and borylation reactions, have been reported in which polynitrogen heterocycles are applied as arylation reagents. The success of these exceptional reactions illustrates the great synthetic potential of polynitrogen heterocycles, which provides a direct and useful approach to arylation reactions and the synthesis of nitrogen-containing heterocycles. The use of photocatalysts to effectively transfer energy from visible light to non-absorbing compounds has gained increasing attention as this method allows for the mild and efficient generation of radicals in a controlled manner. This approach has thus led to new methods that involve unique bond formation reactions. In addition, the use of free radical intermediates stabilized by transition metal catalysts is a powerful way to construct new chemical bonds. The aim of this review is to highlight the rapidly expanding area of radical-initiated denitrogenative cascade reactions of polynitrogen heterocycles and elaborate on their mechanisms from a new perspective by using photocatalysis and metal-based catalysis.

To investigate clinical outcomes of countertraction method in treating irreducible subcoracoid dislocation of shoulder joint combined with Hill-Sacks injury.A total of 56 patients with irreducible subcoracoid dislocation of the shoulder joint combined with Hill-Sacks injury admitted from December 2013 to June 2020 were retrospectively analyzed. Under the anesthesia of shoulder joint cavity injection, the reduction was performed by using anti-traction method (experimental group) and traditional Hippocrates method (control group), 28 cases in each group. There were 11 males and 17 females in experimental group, with an average age of (61.95±19.32) years old, 9 cases on the left side, and 19 cases on the right side. Twelve males and 16 females in control group, with an average age of (63.13±12.75) years old, 11 cases on the left side, 17 cases on the right side. The curative effects between two groups were evaluated before and after operation, including the success rate of reduction, the duration of reduction, the distance from successful reduction to injury, complications and functional rehabilitation(Constant score of shoulder joint).The success rates of reduction in experimental group and control group were 92.86%(26/28) and 67.86% (19/28), respectively, and the difference was statistically significant (For patients with irreducible subcoracoid dislocation of the shoulder joint with Hill-Sacks injury, the countertraction method under anesthesia of the shoulder joint cavity achieved a higher success rate and few complications.

BackgroundEpstein-Barr virus-associated gastric cancer (EBVaGC) exhibits unique histological characteristics within the immune-cell-rich microenvironment, but the role of tertiary lymphoid structure (TLS) in EBVaGC is not yet fully understood.MethodsWe retrospectively identified EBVaGC from 8517 consecutive GC cases from the two top cancer centers in China. Furthermore, we evaluated the prognostic value of TLS in 148 EBVaGC patients from our institute and then validated it in an external cohort (76 patients). TLS was quantified and its relationships with overall survival (OS) and therapeutic response were further analyzed. Multiplex immunofluorescence staining and targeted sequencing were used to characterize the composition of TLS and the genomic landscape, respectively.ResultsIn our study, EBVaGC was observed in 4.3% (190/4436) and 2.6% (109/4081) of GCs in the training and validation cohorts, respectively. TLS was identified in the intratumor (94.6%) and peritumor (77.0%) tissues with lymphoid aggregates, primary and secondary (i.e., mature TLSs) follicles in EBVaGC. Kaplan-Meier analysis showed that mature TLS in intratumoral tissues was associated with a favorable OS in the training and validation cohorts (p < 0.0001; p = 0.0108). Multivariate analyses demonstrated that intratumoral TLS maturation, pTNM, and PD-L1 expression were independent prognostic factors for OS (p < 0.05). Furthermore, the mature TLS was significantly associated with a good response to treatment in EBVaGC patients. Interestingly, the mutation frequency of SMARCA4 was significantly lower in the mature TLS groups.ConclusionsIntratumoral mature TLS was associated with a favorable prognosis and good therapeutic response, suggesting that it is a potential prognostic biomarker and predicts a good therapeutic response in EBVaGC patients.

Bioactive ingredients from natural products have always been an important resource for the discovery of drugs for Alzheimer's disease (AD). Senile plaques, which are formed with amyloid-beta (Aβ) peptides and excess metal ions, are found in AD brains and have been suggested to play an important role in AD pathogenesis. Here, we attempted to design an effective and smart screening method based on cheminformatics approaches to find new ingredients against AD from Vaccinium myrtillus (bilberry) and verified the bioactivity of expected ingredients through experiments. This method integrated advanced artificial intelligence models and target prediction methods to realize the stepwise analysis and filtering of all ingredients. Finally, we obtained the expected new compound malvidin-3-O-galactoside (Ma-3-gal-Cl). The in vitro experiments showed that Ma-3-gal-Cl could reduce the OH· generation and intracellular ROS from the Aβ/Cu2+/AA mixture and maintain the mitochondrial membrane potential of SH-SY5Y cells. Molecular docking and Western blot results indicated that Ma-3-gal-Cl could reduce the amount of activated caspase-3 via binding with unactivated caspase-3 and reduce the expression of phosphorylated p38 via binding with mitogen-activated protein kinase kinases-6 (MKK6). Moreover, Ma-3-gal-Cl could inhibit the Aβ aggregation via binding with Aβ monomer and fibers. Thus, Ma-3-gal-Cl showed significant effects on protecting SH-SY5Y cells from Aβ/Cu2+/AA induced damage via antioxidation effect and inhibition effect to the Aβ aggregation.

The fast reactor is gradually being paid attention to in nuclear power due to a better breeding effect, and its economy is also directly followed. Due to the restriction of the core power density, the core power level is directly related to the volume of the core active area. When the power level and the volume of the core gradually increase, the mass of uranium and 235U in the core at the beginning of life will gradually increase on the basis of a critical uranium inventory. At the same time, due to the gradual increase in the breeding effect, the utilization rate of uranium resources at the end of life will gradually increase. Due to the characteristics of the large critical uranium mass and high breeding effect, the mass of uranium and 235U in the low power level core at the beginning of life cannot be further reduced because of the critical uranium inventory. The lifetime of the high power level core should be extended to use the wealthy reactivity of the core because of the improvement in the breeding effect. However, due to the requirements of the nuclear power refuel time and the limitation to fuel consumption, the breeding effect brought by the improvement in the core power level and the size of the active zone may be less effective. In this article, the power level and economy of lead-based modular nuclear power are analyzed, and the economy of different power level fast reactors with 2,000 EFPD lifetime such as 100 MWt, 300 MWt, 500 MWt, 700 MWt, and 1000 MWt thermal power is designed and analyzed. By analyzing the invention of uranium and 235U and the fuel utilization of different core schemes, the best economic analysis of the single reactor power of the current lead-based modular reactor is proposed and the foundation of the lead-based modular nuclear power is provided.