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Flowering time is an important agronomic trait of Chinese cabbage with late flowering being a primary breeding objective. In our previous work, we obtained Chinese cabbage-cabbage translocation lines that contained several beneficial cabbage genes. Cabbage-specific molecular markers show that these genes were coming from chromosome C01 of cabbage. In this study, we investigated the inheritance of flowering time in a couple of translocation lines and analyzed the transmission rate of molecular markers in the offspring. Consequently, we obtained the late flowering Chinese cabbage-cabbage translocation line ‘AT7-4’ in which the flowering time was later than that of ‘85-1’ by about 7 days under 4-week vernalization. Based on previous studies of the genomes of Chinese cabbage and cabbage, we located the cabbage-specific molecular markers that were closely linked at the top of the chromosome A01 in the F2 mapping population generated by self-crossing F1s derived from a cross between the translocation line ‘AT7-4’ and Chinese cabbage ‘14-36’. Five flowering-related genes in the alien fragment were found by functional annotation and their molecular markers were developed. This study lays the foundation for the future improvement of Chinese cabbage varieties using A-C translocation lines.

Background/aims Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis. Methods To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs). Results Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36. Conclusions HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.

Eukaryotic translation initiation factor 2 subunit 3 and structural gene Y-linked (Eif2s3y) gene, the gene encoding eIF2γ protein, is located on the mouse Y chromosome short arm. The Eif2s3y gene is globally expressed in all tissues and plays an important role in regulating global and gene-specific mRNA translation initiation. During the process of protein translation initiation, Eif2s3x (its homolog) and Eif2s3y encoded eIF2γ perform similar functions. However, it has been noticed that Eif2s3y plays a crucial role in spermatogenesis, including spermatogonia mitosis, meiosis, and spermiogenesis of spermatids, which may account for infertility. In the period of spermatogenesis, the role of Eif2s3x and Eif2s3y are not equivalent. Importance of Eif2s3y has been observed in ESC and implicated in several aspects, including the pluripotency state and the proliferation rate. Here, we discuss the functional significance of Eif2s3y in mouse spermatogenesis and self-renewal of ESCs.

Nano-selenium (Se) has attracted growing attention due to its high bioavailability, low toxicity and its possible applications in the prevention of oxidative damage in animal tissues. Recent research works have conveyed that the use of nano-seleniumas food additive could have positive effects on the nutrition of aquatic animals.In this study, the intestinal bacterial communities associated with low and high concentrations of nano-selenium in the diet of Chinese tongue sole were characterized, through 16S rRNA V3–V4 sequencing.Samples were derived from fish fed with diet containing different nano-selenium level, 0 mg/kg for the control group, 1.6 mg/kg for low dose group, and 2.4 mg/kg for high dose group The intestinal microbial community structure showed a low overall diversity, among which the vibro genus occupied the most important position with more than 90% relative abundance in all three group. Significant differences in specie diversity occurred between the nano-selenium treated (both low dose [IL] and high dose [LH]) groups and the control group(IC). Acinetobacter, Arthrobacter, and Streptophytes were the top three enriched genera after the treatment with nano-selenium compared to IC. Meantime, the weight gain rate of the LH group was 9% higher than control. The results revealed the effect of nano-selenium on microbial community structure of gut and growth performance of C.semilaevis, Future research exploring the interaction mechanism between micronutrients and the microbial communities would increase our understanding of the fish nutrition.

Metal–organic framework (MOF) nanoparticles are promising carriers for the internal delivery of therapeutics to the cells; however, the effects of their shape on cellular uptake have not yet been clearly evaluated. Therefore, we synthesized biocompatible Fe-based MOF nanoparticles of two distinct shapes—rods and octahedrons (NH2-MIL-88B(Fe)-ROD and NH2-MIL-88B(Fe)-OCTA, respectively)—and evaluated their cellular uptake kinetics and mechanisms using three different cell lines (HeLa, MDA-MB-231, and L929). Although both nanoparticles possessed the same constituent metal, organic linkers, and thus, crystalline structures, a more rapid uptake was observed with NH2-MIL-88B(Fe)-OCTA, whereas NH2-MIL-88B(Fe)-ROD were endocytosed in a more sustained manner. This could be ascribed to the large number of sharp edges available in NH2-MIL-88B(Fe)-OCTA particles; hence, there were more points of expedited entry into the cells via a clathrin-mediated pathway. The findings herein provide important information for the application of the MOF nanoparticles as intracellular drug delivery carriers, especially when they can be prepared in different shapes with the same composition.

Aim and Objective: We investigated the inhibitory effects of fractions from Lycopus lucidus Turcz. leaves on genomic DNA oxidation, Nitric Oxide (NO) production, and Matrix Metalloproteinase (MMP) activity. Material and Methods: Oxidative damage of genomic DNA was detected after Fenton reaction with H2O2 using DNA electrophoresis. Western blotting was performed to compare the expression levels of MMP-2 in phorbol 12-myristate 13-acetate (PMA)-induced HT-1080 cells. Lipopolysacchride (LPS)-induced NO production in RAW 264.7 cells was measured using Griess reagent. Results: All fractions (n-Hexane, 85% aq. MeOH, n-BuOH, and water fractions) from the leaves of L. lucidus Turcz. significantly inhibited intracellular production of reactive oxygen species (ROS) (p Conclusion: Overall, these results indicated that L. lucidus Turcz. leaves can be exploited as plant based sources of antioxidants in the pharmaceutical, cosmetic, nutraceutical, and food industries.

Objective The objective of this study was to evaluate the influence of ACE I/D gene polymorphisms on diabetic kidney disease (DKD) risk. Methods All eligible investigations were identified, the number of various genotype in the case and control group were reviewed. The pooled analysis was performed using Stata software. Results In overall subjects, 24,321 participants with 12,961 cases and 11,360 controls were included. the pooled analysis showed a significant link between D allele, DD or II genotype and DKD risk (D versus I: OR = 1.316, 95% CI: 1.213–1.427, P = 0.000; DD versus ID + II: OR = 1.414, 95% CI: 1.253–1.595, P = 0.000; II versus DD + ID: OR = 0.750, 95% CI: 0.647–0.869, P = 0.000). The subgroup pooled analysis showed that ACE I/D gene polymorphism was correlated with DKD both in Asian and in Chinese population. In addition, ACE I/D gene polymorphism was correlated with type 2 DKD (D versus I: OR = 1.361, 95% CI: 1.243–1.490, P = 0.000; DD versus ID + II: OR = 1.503, 95% CI: 1.310–1.726, P = 0.000; II versus DD + ID: OR = 0.738, 95% CI: 0.626 –0.870, P = 0.000). However, there was no obvious correlation in Caucasian subjects and type 1 diabetic patients. Conclusion ACE I/D polymorphisms were correlated with DKD in Asian and type 2 diabetic populations. ACE D allele/DD genotype might be a risk factor, while ACE II genotype might be a protective factor for DKD.

ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v - Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.

Ricin toxin (RT) is a ribosome-inactivating protein derived from the beans of the castor oil plant. Our previous studies have reported that RT can induce the production of inflammatory cytokines and cause inflammatory injury in RAW264.7 cells. In order to explore the various biological processes that long noncoding RNA (lncRNA), circular RNA (circRNA) and micro RNA (miRNA) as endogenous non-coding RNAs (ceRNAs) may participate in the pro-inflammatory mechanism, RT (20 ng/mL) treated and normal RAW264.7 cells were firstly sequenced by RNA-seq. By comparing the differentially expressed genes, we obtained 10 hub genes and enriched the inflammatory-related signaling pathways. Based on our results, we concluded a lncRNA/circRNA-miRNA-mRNA network. Finally, we verified the key genes and pathways by qRT-PCR, WB and ELISA. From the experiment results, an opening MAPK signaling pathway in TNF signaling pathway via TNFR2 was found involved in RT-induced inflammation. This work provides a reference for searching for ceRNA targets or therapeutic drugs in RT-induced inflammatory injury in the future.

Many integral membrane proteins might act as indispensable coordinators in specific functional microdomains to maintain the normal operation of known receptors, such as Notch. Gm364 is a multi-pass transmembrane protein that has been screened as a potential female fertility factor. However, there have been no reports to date about its function in female fertility. Here, we found that global knockout of Gm364 decreased the numbers of primordial follicles and growing follicles, impaired oocyte quality as indicated by increased ROS and γ-H2AX, decreased mitochondrial membrane potential, decreased oocyte maturation, and increased aneuploidy. Mechanistically, Gm364 directly binds and anchors MIB2, a ubiquitin ligase, on the membrane. Subsequently, membrane MIB2 ubiquitinates and activates DLL3. Next, the activated DLL3 binds and activates Notch2, which is subsequently cleaved within the cytoplasm to produce NICD2, the intracellular active domain of Notch2. Finally, NICD2 can directly activate AKT within the cytoplasm to regulate oocyte meiosis and quality.

There is increasing evidence that cancer stem cells (CSC) are more radioresistant than differentiated cancer cells (DCC). Radiation treatment of solid tumors can induce long-term enrichment of CSC, which can lead to resistance and a loss of sensitivity to radiotherapy. At the same time, radiation-induced reprogramming of DCCs into CSCs has also been observed. Using a mathematical model, we study the dynamics of CSCs and DCCs with reprogramming induced by radiation therapy. We also investigate the effect of feedback on cell division rates together with reprogramming, and renewal probability. We observe that feedback on cell division rates results in long-term enrichment of CSC whereas the effect of feedback on self-renewal probabilities results only in short-term CSC enrichment even when there is reprogramming. In the context of glioblastoma, we find there is an optimal choice of dose fractionation to reduce CSC percentages and tumor sizes.

A number of studies have focused on the effects of rare earth elements (REEs) on crop plants, while little attention has been paid on how tolerant plant species respond to increasing mixed REE concentrations. In this study, ramie (Boehmeria nivea L.) was exposed to a series of REE concentrations prepared with equimolar mixtures of 16 REEs (i.e. 0, 1.6, 8, 16, 80, 160, 400, 800 μmol/L) in order to explore REE accumulation and fractionation characteristics in ramie and the responses of this plant to mixed REEs. Results show that ramie root and shoot biomasses are unaffected under lower REE concentrations (1.6–80 μmol/L), while the growth of ramie and the uptake of nutrients especially Ca and Mn are largely inhibited under higher REE concentrations (160–800 μmol/L). The P and Mo concentrations in the roots increase with the increasing REE concentrations in the solution, suggestive of an involvement of P and Mo in dealing with the high concentrations of REEs in this plant. The preferential uptake of Ce and heavy REEs (HREEs) and the preferential transport of HREEs within the plant lead to a positive Ce anomaly and a HREE enrichment in ramie leaves. Our study suggests that ramie could be a good candidate for the phytoremediation of heavily REE-contaminated soils (e.g., REE mine tailings in southern China). Our results also shed light on points of taking into account phytoremediation management strategies of REE-contaminated soils (e.g., P and Mo fertilization).

Cronobacter species are a group of Gram-negative opportunistic pathogens, which cause meningitis, septicemia, and necrotizing enterocolitis in neonates and infants, with neurological sequelae in severe cases. Interest in Cronobacter has increased significantly in recent years due to its high virulence in children. In this review, we summarize the current understanding of the prevalence of Cronobacter species in several important food types. We discuss the response mechanisms enabling persistence in adverse growth conditions, as well as its pathogenicity. We emphasize the food safety concerns caused by Cronobacter and subsequent control methods, and clinical treatments.

Intra-articular injection of mesenchymal stem cells (MSCs) is a promising strategy for osteoarthritis (OA) treatment. However, more and more studies reveal that the injected MSCs have poor adhesion, migration, and survival in the joint cavity. A recent study shows that tropoelastin (TE) regulates adhesion, proliferation and phenotypic maintenance of MSCs as a soluble additive, indicating that TE could promote MSCs-homing in regenerative medicine. In this study, we used TE as injection medium, and compared it with classic media in MSCs intra-articular injection such as normal saline (NS), hyaluronic acid (HA), and platelet-rich plasma (PRP). We found that TE could effectively improve adhesion, migration, chondrogenic differentiation of infrapatellar fat pad MSCs (IPFP-MSCs) and enhance matrix synthesis of osteoarthritic chondrocytes (OACs) in indirect-coculture system. Moreover, TE could significantly enhance IPFP-MSCs adhesion via activation of integrin β1, ERK1/2 and vinculin (VCL) in vitro. In addition, intra-articular injection of TE-IPFP MSCs suspension resulted in a short-term increase in survival rate of IPFP-MSCs and better histology scores of rat joint tissues. Inhibition of integrin β1 or ERK1/2 attenuated the protective effect of TE-IPFP MSCs suspension in vivo. In conclusion, TE promotes performance of IPFP-MSCs and protects knee cartilage from damage in OA through enhancement of cell adhesion and activation of integrin β1/ERK/VCL pathway. Our findings may provide new insights in MSCs intra-articular injection for OA treatment., Graphical abstract Image 1, Highlights • Tropoelastin promotes adhesion and migration of IPFP MSCs. • Tropoelastin promotes IPFP MSCs survival and adhesion in joint cavity. • Injection of IPFP MSCs in tropoelastin reduces OA progression.

Fecal microbiota transplantation (FMT) of human fecal samples into germ-free (GF) mice is useful for establishing causal relationships between the gut microbiota and human phenotypes. However, due to the intrinsic differences between human and mouse intestines and the different diets of the two organisms, it may not be possible to replicate human phenotypes in mice through FMT; similarly, treatments that are effective in mouse models may not be effective in humans. In this study, we aimed to identify human gut microbes that undergo significant and consistent changes (i.e., in relative abundances) after transplantation into GF mice in multiple experimental settings. We collected 16S rDNA-seq data from four published studies and analyzed the gut microbiota profiles from 1713 human-mouse pairs. Strikingly, on average, we found that only 47% of the human gut microbes could be re-established in mice at the species level, among which more than 1/3 underwent significant changes (referred to as "variable taxa"). Most of the human gut microbes that underwent significant changes were consistent across multiple human-mouse pairs and experimental settings. Consequently, about 1/3 of human samples changed their enterotypes, i.e., significant changes in their leading species after FMT. Mice fed with a controlled diet showed a lower enterotype change rate (23.5%) than those fed with a noncontrolled diet (49.0%), suggesting a possible solution for rescue. Most of the variable taxa have been reported to be implicated in human diseases, with some recognized as the causative species. Our results highlight the challenges of using a mouse model to replicate human gut microbiota-associated phenotypes, provide useful information for researchers using mice in gut microbiota studies, and call for additional validations after FMT. An online database named FMT-DB is publicly available at http://fmt2mice.humangut.info/#/.

Foodborne pathogenic bacteria have been considered as a major risk factor for food safety. It is of great significance to carry out in-field screening of pathogenic bacteria to prevent the outbreaks of foodborne diseases. In this study, a portable lab-on-a-disc platform with a microfluidic disc was developed for rapid and automatic detection of Salmonella typhimurium using a nickel nanowire (NiNW) net for effective separation of target bacteria, horseradish peroxidase nanoflowers (HRP NFs) for efficient amplification of biological signals, and a self-developed smartphone APP for accurate analysis of colorimetric images. First, the microfluidic disc was preloaded with reagents and samples and centrifuged to form one bacterial sample column, one immune NiNW column, one HRP NF column, two washing buffer columns and one tetramethylbenzidine (TMB) column, which were separated by air gaps. Then, a rotatable magnetic field was specifically developed to assemble the NiNWs into a net, which was automatically controlled by a stepped motor to successively pass through the sample column for specific capture of target bacteria, the HRP NF column for specific label of target bacteria, the washing columns for effective removal of sample background and non-specific binding NFs, and the TMB column for colorimetric determination of target bacteria. The color change of TMB from colorless to blue was finally analyzed using the smartphone APP to quantitatively determine the target bacteria. This lab-on-a-disc platform could detect Salmonella typhimurium from 5.6 × 101 CFU/20 μL to 5.6 × 105 CFU/20 μL in 1 h with a lower detection limit of 56 CFU/20 μL. The recovery of target bacteria in spiked chicken samples ranged from 97.5% to 101.8%. This portable platform integrating separation, labeling, washing, catalysis and detection onto a single disc is featured with automatic operation, fast reaction, and small size and has shown its potential for in-field detection of foodborne pathogens.

Leptomeningeal metastasis (LM) is associated with poor prognosis and represents a terminal event of non-small cell lung cancers (NSCLC). In previous studies, most of LM-patients have detected epidermal growth factor receptor (EGFR) mutation and responded to the third generation of EGFR-tyrosine kinase inhibitor (TKI). This study aimed to report a case of ERBB2 (HER2) exon 20 insertion mutations in the cerebrospinal fluid (CSF) of LM-patient which response to poziotinib. At the beginning, postoperative pathology showed a primary invasive adenocarcinoma with no mutations in EGFR and ROS-1. Pemetrexed plus carboplatin combined with bevacizumab was administered as the first-line followed by bevacizumab alone for continuation maintenance therapy. Targeted therapy and immunotherapy were given after the disease progressed in two months. Subsequently, the patient developed mental symptoms and adenocarcinoma cells were found in the CSF. Next-generation sequencing (NGS) results showed HER2 exon 20 insertion mutations in the primary tissue, CSF and plasma samples. Then, poziotinib was administered and the symptoms improved significantly after 3 days and the progress free survival was nearly 2 months. Therefore, we speculate that the CSF concentration and penetration rate of poziotinib may significantly higher than of other TKIs so that it achieves a higher CSF concentration than standard dosing, and successfully controlled LM. It may provide a new therapeutic option for LM-patient and may be especially who are lung adenocarcinoma with HER2 exon 20 insertion.

The spatial organization of immune cells within the tumor microenvironment (TME) largely determines the anti-tumor immunity and also highly predicts tumor progression and therapeutic response. Tim-3 is a well-accepted immune checkpoint and plays multifaceted immunoregulatory roles via interaction with distinct Tim-3 ligands (Tim-3L), showing great potential as an immunotherapy target. However, the cell sociology mediated by Tim-3/Tim-3L and their contribution to tumor development remains elusive. Here, we analyzed the spatial distribution of Tim-3/Tim-3L in TME using multiplex fluorescence staining and revealed that despite the increased Tim-3 expression in various tumor-infiltrated lymphocytes, Tim-3(+)CD4(+) cells were more accumulated in parenchymal/tumor region compared with stromal region and exhibited more close association with patient survival. Strikingly, CD4 T cells surrounding Tim-3L(+) cells expressed higher Tim-3 than other cells in cancerous tissues. In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings unravel the importance of CD4 T cells in Tim-3/Tim-3L-mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.

Rice-acid, a Chinese traditional acidic rice soup (rice-acid), is widely accepted by consumers due to its unique flavor and anti-oxidation, anti-aging and immunity enhancement functions. This study confirmed that L-lactic acid and malic acid were the main organic acids in rice-acid. Low-temperature rice-acid samples produced by enterprises had the highest signal intensity of sour taste. The total content of free amino acids in different fermented rice-acid samples were in the range of 0.003–0.468 mg/g. 42 key volatile flavor compounds were identified in rice-acid. 8 volatile compounds with a higher contribution to the aroma of rice-acid were respectively acetic acid, 1-octen-3-ol, 2-heptanol, ethyl acetate, propyl propionate, hexanal, nonanal, and 2,3-butanedione. The interaction between lactic acid bacteria (3.00 × 103–7.02 × 106 CFU/mL) and yeasts (5.04 × 104–2.25 × 108 CFU/mL) affected the formation of taste and aroma components in rice-acid. The physicochemical characteristics including titratable acidity, pH, reducing sugars, amino acid nitrogen, gamma-aminobutyric acid showed significant differences between low-temperature fermentation samples and high-temperature fermentation samples. In addition, relationships linking all data through Pearson coefficient correlation were also reported. In summary, the study can be used to improve the quality of rice-acid products.

This study reports four species belonging to two genera of clathrodictyid stromatoporoids from the Sanqushan Formation (Katian, Upper Ordovician), Changshan County, Zhejiang Province, East China: Clathrodictyon cf. mammillatum (Schmidt), C. plicatum Webby and Banks, C. cf. microundulatum Nestor and Labyrinthodictyon cascum (Webby and Morris). Of these, three species (C. cf. mammillatum, C. plicatum and L. cascum) show a wide range of skeletal variation, representing the variation from the normal skeletal phase to abnormal Ecclimadictyon-like crumpled skeletal phase, especially in the axial part of the columnar growth forms. It is uncertain whether the skeletal variation in early clathrodictyids was the result of environmental stress (such as abrupt sediment influxes that often cause growth interruptions of the stromatoporoids) or genetic inheritance. These characteristics suggest that this group had greater environmental tolerance than the earlier labechiids and increased ecological complexity during Late Ordovician by providing a stable, solid and elevated substrate for the other benthic organisms. This may imply that the labechiids and clathrodictyids are quite different groups, probably independently derived during the early evolution of stromatoporoids.

Chemodynamic therapy (CDT) has attracted tremendous interest in cancer therapy because it is independent of oxygen and photoirradiation. However, the therapeutic efficacy of CDT is restricted by insufficient H2O2 levels in tumor cells. Herein, employing endogenous GSH as a template and cationic polymeric chitosan (CS) as crosslinker and stabilizer exhibiting easy cell uptake, red luminescent gold nanoclusters (denoted CS-GSH@AuNCs) were successfully synthesized in HeLa cells. The in situ synthesized CS-GSH@AuNCs exhibited both superoxidase dismutase (SOD) and peroxidase (POD)-like activity, which could promote the production of H2O2 from superoxide anion radicals (O2•−) and then •OH. The combination of GSH elimination and H2O2 elevation boosted the generation of •OH, which could trigger cancer cell apoptosis and death. The enzyme-like activity of CS-GSH@AuNCs could be effectively activated under acidic conditions, and showed a high killing effect on tumor cells but minimal toxicity to normal cells. The developed GSH consumption and •OH promotion theranostic platform is an innovative route for enhanced CDT by the amplification of oxidative stress.

Recurrent aphthous stomatitis (RAS) is a common recurrent ulcerative disease of the oral mucosa which is closely related to oral microbial composition. However, the specific effect and the mechanism of smoking in RAS are unclear. In this study, 16S rRNA sequencing technology was used to compare the differences in saliva microbial community between 28 non-smoking healthy controls (NSctrl), 31 non-smoking RAS patients (NSras), and 19 smoking RAS patients (Sras). The results showed that the bacterial community diversity in patients with RAS (NSras and Sras) was lower than that of NSctrl. The microbial community in smoking-associated RAS is less diverse and distinct from that of non-smokers. The RAS groups have higher abundance of Veillonella, Rothia, and Sneathia and lower abundance of Bacteroidales, Bacteroides, Wolinella, Moryella, Pyramidobacter, and Christensenellaceae at the genera level. A significantly different abundance of Anaerovorax, Candidatus Endomicrobium, Lactococcus, Sneathia, Veillonella, and Cloacibacterium was observed between the Sras and the NSras group. Notably, there was a significant difference in many species from the genus Prevotella and Treponema between the NSras and the Sras group. Further, the relative abundance of several taxa is correlated with smoking age or frequency, including Megasphaera, Haemophilus, Leptotrichia, and Rothia at the genera level, and Prevotella melaninogenica, Prevotella salivae, Megasphaera micronuciformis, Haemophilus parainfluenzae, Alloprevotella tannerae, Actinomyces naeslundii, Lautropia mirabilis, and Capnocytophaga sputigena at the species level. Among patients with RAS, smoking aggravated the pathways of respiration and human pathogens. Our results suggest that smoking is closely related to changes in the oral microbiota, which may contribute an opposite effect to the pathogenesis of RAS. This study provides new insight and theoretical basis for the cause and pathogenesis of RAS and better prevention and treatment.

Fusarium moniliforme (F. moniliforme) and its secondary metabolite fumonisin pose a severe threat to food safety, and searching for effective antimicrobial agents is a focus of current research. In this study, the secondary structure of Sub3 was analyzed by circular dichroism, meanwhile, the inhibition rate of Sub3 against F. moniliforme infection of maize was studied. To explore the possible inhibition mechanisms, morphological and structural changes of spores treated with Sub3 at 0, 1/2MIC and MIC were observed by scanning electron microscopy and transmission electron microscopy; the cell wall integrity, membrane integrity, reactive oxygen species, mitochondrial membrane potential, ATP synthase activity, redox reactions, and the nuclear damage of F. moniliforme were also investigated. The results showed that Sub3 was mostly in the state of random in deionized water, while mainly showed the β-sheet structure in the hydrophobic environment of 50% TFE solution, indicating that Sub3 might generate partial structure deformation when acting on the cell membrane; and its minimum inhibitory concentration (MIC) on F. moniliforme spores was 0.2 g/L. Under the 1/2MIC and MIC, the inhibition rates of Sub3 against F. moniliforme infected maize were 34.3% and 75.6%, respectively. The results of inhibition mechanisms revealed that the defective pathogenicity of F. moniliforme caused by Sub3 was attributed to damages on both the cell wall and the cell membrane, which might upset balance of intracellular redox system and mitochondrial energy metabolism and trigger nucleus damage, ultimately leading to cell death. The results provided direct evidence for inhibition of F. moniliforme infection of maize by Sub3, and useful knowledge applicable for food preservation.

Arbuscular mycorrhiza (AM) is a mutualistic symbiosis formed between most land plants and Glomeromycotina fungi. During symbiosis, plants provide organic carbon to fungi in exchange for mineral nutrients. Previous legume studies showed that the required for arbuscular mycorrhization2 (RAM2) gene is necessary for transferring lipids from plants to AM fungi (AMF) and is also likely to play a “signaling” role at the root surface. To further explore RAM2 functions in other plant lineages, in this study, two rice (Oryza sativa) genes, OsRAM2 and OsRAM2L, were identified as orthologs of legume RAM2. Examining their expression patterns during symbiosis revealed that only OsRAM2 was strongly upregulated upon AMF inoculation. CRISPR/Cas9 mutagenesis was then performed to obtain three Osram2 mutant lines (-1, -2, and -3). After inoculation by AMF Rhizophagus irregularis or Funneliformis mosseae, all of the mutant lines showed extremely low colonization rates and the rarely observed arbuscules were all defective, thus supporting a conserved “nutritional” role of RAM2 between monocot and dicot lineages. As for the signaling role, although the hyphopodia numbers formed by both AMF on Osram2 mutants were indeed reduced, their morphology showed no abnormality, with fungal hyphae invading roots successfully. Promoter activities further indicated that OsRAM2 was not expressed in epidermal cells below hyphopodia or outer cortical cells enclosing fungal hyphae but instead expressed exclusively in cortical cells containing arbuscules. Therefore, this suggested an indirect role of RAM2 rather than a direct involvement in determining the symbiosis signals at the root surface. [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2022.

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

Unripe banana is rich with resistant starch (RS) and this non-processed food confers many health benefits. However, unripe banana is not consumed directly and when cooked its native RS is rendered digestible. We have developed macaroni from chemically modified unripe banana flour (RS4), which maintains their content of resistant starch after being cooked, with and without the supplementation of turmeric extract. We hypothesized that consuming our banana RS4 macaroni would confer beneficial effects on metabolic profiles. Healthy Wistar rats were fed for 6 weeks with cooked banana RS4 macaroni, with and without the turmeric extract supplementation, and compared to rats fed with standard wheat macaroni. No significant physiological differences between groups were observed except rats that consumed banana RS4 macaroni had significantly smaller stomachs (pLachnospiraceae Erysipelotrichaceae and Clostridiaceae. In conclusion, the consumption of banana RS4 macaroni by healthy rats receiving a regular diet improved their blood chemistry profile associated with metabolic syndrome, and the addition of turmeric extract can significantly alter fecal microbiota.

Marine natural products play critical roles in the chemical defense of many marine organisms and are essential, reputable sources of successful drug leads. Sixty-seven 14-membered resorcylic acid lactone derivatives 3–27 and 30–71 of the natural product zeaenol (1) isolated from the marine-derived fungus Cochliobolus lunatus were semisynthesized by chlorination, acylation, esterification, and acetalization in one to three steps. The structures of these new derivatives were established by HRESIMS and NMR techniques. All the compounds (1–71) were evaluated for their antialgal and antiplasmodial activities. Among them, 14 compounds displayed antifouling activities against adhesion of the fouling diatoms. In particular, 9 and 34 exhibited strong and selective inhibitory effects against the diatoms Navicula laevissima and Navicula exigua (EC50 = 6.67 and 8.55 μmol/L), respectively, which were similar in efficacy to those of the positive control SeaNine 211 (EC50 = 2.90 and 9.74 μmol/L). More importantly, 38, 39, and 69–71 showed potent antiplasmodial activities against Plasmodium falciparum with IC50 values ranging from 3.54 to 9.72 μmol/L. Very interestingly, the five antiplasmodial derivatives displayed non-toxicity in the cytotoxicity assays and the zebrafish embryos model, thus, representing potential promising antiplasmodial drug agents. The preliminary structure–activity relationships indicated that biphenyl substituent at C-2, acetonide at positions C-5′ and C-6′, and tri- or tetra-substituted of acyl groups increased the antiplasmodial activity. Therefore, combining evaluation of chemical ecology with pharmacological models will be implemented as a systematic strategy, not only for environmentally friendly antifoulants but also for structurally novel drugs.

Probiotics can effectively modulate host immune responses and prevent gastrointestinal diseases. The objective of this study was to investigate the probiotic characteristics of Lactobacillus brevis KU15152 isolated from kimchi and its protective potential against intestinal inflammation induced by Staphylococcus aureus lipoteichoic acid (aLTA). L. brevis KU15152 exhibited a high survival rate in artificial gastric and bile environments. Additionally, the adhesion capability of the strain to HT-29 cells was higher than that of L. rhamnosus GG. L. brevis KU15152 did not produce harmful enzymes, such as β-glucuronidase, indicating that it could be used as a potential probiotic. The anti-inflammatory potential of L. brevis KU15152 was determined in HT-29 cells. Treatment with L. brevis KU15152 suppressed the production of interleukin-8 without inducing significant cytotoxicity. The downregulatory effects of L. brevis KU15152 were involved in the suppression of nuclear factor-kappa B activation mediated by the extracellular signal-regulated kinase and Akt signaling pathways. Collectively, these data suggest that L. brevis KU15152 can be used in developing therapeutic and prophylactic products to manage and treat aLTA-induced intestinal damage.

Echinococcosis is a zoonotic parasitic disease that is highly endemic to the Qinghai province of China. Limited data are available on the prevalence of the causal pathogen, Echinococcus spp., in definitive hosts in this region. Thus, the aim of this study was to evaluate the prevalence of Echinococcus spp. in wild foxes and stray dogs in Qinghai province. Five hundred and twenty-eight feces from wild foxes and 277 from stray dogs were collected from 11 counties in the Golog, Yushu, and Haixi prefectures and screened for Echinococcus spp. using copro-DNA polymerase chain reaction (PCR). In total, 5.5% of wild foxes and 15.2% of stray dogs tested positive for Echinococcus spp. The prevalence rates of Echinococcus spp. in wild foxes in Golog, Yushu, and Haixi were 7.3%, 5.2%, and 1.9%, respectively. In stray dogs, these rates were 13.3%, 17.3%, and 0%, respectively. Sequencing analysis determined that Echinococcus multilocularis was the most prevalent species, occurring in 4.0% and 12.6% of wild foxes and stray dogs, respectively. Echinococcus shiquicus was observed in 1.5% of wild foxes and 0.7% of stray dogs. Echinococcus granulosus was observed only in wild dogs, with a prevalence rate of 1.8%. To our knowledge, this is the first report on the prevalence of E. shiquicus in dogs in Qinghai province. The current results improve our understanding of the transmission and dissemination of human echinococcosis and suggest that exposure to the eggs of E. multilocularis harbored by wild foxes and stray dogs may pose a great risk of alveolar echinococcosis to humans in Qinghai province.

Objective: Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor (MAPKi) resistance, which is one of the most common forms of resistance that has emerged in many types of cancers. Here, we aimed to systematically identify the genetic interactions underlying MAPKi resistance, and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance. Methods: We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi, and validated 3 genetic combinations through competitive growth, cell viability, and spheroid formation assays. We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations. We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation, Western blot, qRTPCR, and immunofluorescence assays. Results: We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance (ITGB3 + IGF1R, ITGB3 + JNK, and HDGF + LGR5). We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure. Specifically, we discovered a novel protein complex, HDGF-LGR5, that adaptively responded to MAPKi to enhance cancer cell stemness, which was up- or downregulated by the inhibitors of ITGB3 + JNK or ITGB3 + IGF1R. Conclusions: Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells. ITGB3- + IGF1R-targeting drugs (cilengitide + linsitinib) could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex, which enhanced cancer stemness during MAPKi stress.