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The Varicella zoster virus (VZV), responsible for both varicella (chickenpox) and herpes zoster (shingles), presents significant global health challenges. While primary VZV infection primarily affects children, leading to chickenpox, reactivation in later life can result in herpes zoster and associated post-herpetic neuralgia, among other complications. Vaccination remains the most effective strategy for VZV prevention, with current vaccines largely based on the attenuated vOka strains. Although these vaccines are generally effective, they can induce varicella-like rashes and have sparked concerns regarding cell virulence. As a safer alternative, subunit vaccines circumvent these issues. In this study, we developed a nanoparticle-based vaccine displaying the glycoprotein E (gE) on ferritin particles using the SpyCatcher/SpyTag system, termed FR-gE. This FR-gE nanoparticle antigen elicited substantial gE-specific binding and VZV-neutralizing antibody responses in BALB/c and C57BL/6 mice—responses that were up to 3.2-fold greater than those elicited by the subunit gE while formulated with FH002C, aluminum hydroxide, or a liposome-based XUA01 adjuvant. Antibody subclass analysis revealed that FR-gE produced comparable levels of IgG1 and significantly higher levels of IgG2a compared to subunit gE, indicating a Th1-biased immune response. Notably, XUA01-adjuvanted FR-gE induced a significant increase in neutralizing antibody response compared to the live attenuated varicella vaccine and recombinant vaccine, Shingrix. Furthermore, ELISPOT assays demonstrated that immunization with FR-gE/XUA01 generated IFN-γ and IL-2 levels comparable to those induced by Shingrix. These findings underscore the potential of FR-gE as a promising immunogen for the development of varicella and herpes zoster vaccines.

In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.

Carotenoids are essential nutrients for humans and animals, and carotenoid coloration represents an important meat quality parameter for many farmed animals. Increasingly, studies have demonstrated that vertebrate carotenoid cleavage oxygenases (CCOs) are essential enzymes in carotenoid metabolism and are therefore potential candidate genes for improving carotenoid deposition. However, our understanding of carotenoid bioavailability and CCOs functions in invertebrates, particularly marine species, is currently quite limited. We previously identified that a CCO homolog, PyBCO-like 1, was the causal gene for carotenoid coloration in the ‘Haida golden scallop’, a variety of Yesso scallop (Patinopecten yessoensis) characterized by carotenoid enrichment. Here, we found that another CCO-encoding gene named PyBCO2 (β-carotene oxygenase 2) was widely expressed in P. yessoensis organs/tissues, with the highest expression in striated muscle. Inhibiting BCO2 expression in P. yessoensis through RNA interference led to increased carotenoid (pectenolone and pectenoxanthin) deposition in the striated muscle, and the color of the striated muscle changed from white to light orange. Our results indicate that PyBCO2 might be a candidate gene used for improving carotenoid content in normal Yesso scallops, and also in ‘Haida golden scallops’.

The teat number is a pivotal reproductive trait that significantly influences the survival rate of piglets. A meta-analysis is a robust instrument, enhancing the universality of research findings and improving statistical power by increasing the sample size. This study aimed to identify universal candidate genes associated with teat number traits using a genome-wide association study (GWAS) meta-analysis with three breeds. We identified 21 chromosome threshold significant single-nucleotide polymorphisms (SNPs) associated with five teat number traits in single-breed and cross-breed meta-GWAS analyses. Using a co-localization analysis of expression quantitative trait loci and GWAS loci, we detected four unique genes that were co-localized with cross-breed GWAS loci associated with teat number traits. Through a meta-analysis and integrative analysis, we identified more reliable candidate genes associated with multiple-breed teat number traits. Our research provides new information for exploring the genetic mechanism affecting pig teat number for breeding selection and improvement.

Tumor immune microenvironment constituents, such as CD8+ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8+ T cells. The differentially expressed genes (DEGs) linked to CD8+ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8+ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8+ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8+ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions.

1,2,3-Triazolium salts have demonstrated significant potential in the fields of medicine and agriculture, exhibiting exceptional antibacterial, antifungal, anticancer, and antileishmanial properties. Moreover, these salts can be utilized as additives or components to produce nano- and fiber-based materials with antibacterial properties. In this review, we summarize several synthetic strategies to obtain 1,2,3-triazolium salts and the structures of 1,2,3-triazolium derivatives with biological activities in the domains of pharmaceuticals, pesticides, and functional materials. Additionally, the structure–activity relationship (SAR) of 1,2,3-triazolium salts with different biological activities has been analyzed. Finally, this review presents the potential applications and prospects of 1,2,3-triazolium salts in the fields of agriculture, medicine, and industrial synthesis.

The herbaceous peony (Paeonia lactiflora Pall.) is widely cultivated as an ornamental, medicinal and edible plant in China. Drought stress can seriously affect the growth of herbaceous peony and reduce its quality. In our previous research, a significantly differentially expressed gene, PM19L, was obtained in herbaceous peony under drought stress based on transcriptome analysis, but little is known about its function. In this study, the first PM19L that was isolated in herbaceous peony was comprised of 910 bp, and was designated as PlPM19L (OP480984). It had a complete open reading frame of 537 bp and encoded a 178-amino acid protein with a molecular weight of 18.95 kDa, which was located in the membrane. When PlPM19L was transferred into tobacco, the transgenic plants had enhanced tolerance to drought stress, potentially due to the increase in the abscisic acid (ABA) content and the reduction in the level of hydrogen peroxide (H2O2). In addition, the enhanced ability to scavenge H2O2 under drought stress led to improvements in the enzyme activity and the potential photosynthetic capacity. These results combined suggest that PlPM19L is a key factor to conferring drought stress tolerance in herbaceous peony and provide a scientific theoretical basis for the following improvement in the drought resistance of herbaceous peony and other plants through genetic engineering technology.

12-oxo-phytodienoic acid (OPDA) is a biosynthetic precursor of jasmonic acid and triggers multiple biological processes from plant development to stress responses. However, the OPDA signaling and relevant regulatory networks were largely unknown in basal land plants. Using an integrated multi-omics technique, we investigated the global features in metabolites and transcriptional profiles of an Antarctic moss (Pohlia nutans) in response to OPDA treatment. We detected 676 metabolites based on the widely targeted metabolomics approach. A total of 82 significantly changed metabolites were observed, including fatty acids, flavonoids, phenolic acids, amino acids and derivatives, and alkaloids. In addition, the transcriptome sequencing was conducted to uncover the global transcriptional profiles. The representative differentially expressed genes were summarized into functions including Ca2+ signaling, abscisic acid signaling, jasmonate signaling, lipid and fatty acid biosynthesis, transcription factors, antioxidant enzymes, and detoxification proteins. The integrated multi-omics analysis revealed that the pathways of jasmonate and ABA signaling, lipid and fatty acid biosynthesis, and flavonoid biosynthesis might dominate the molecular responses to OPDA. Taken together, these observations provide insights into the molecular evolution of jasmonate signaling and the adaptation mechanisms of Antarctic moss to terrestrial habitats.

Chlorimuron-ethyl is a widely used herbicide in agriculture. However, uncontrolled chlorimuron-ethyl application causes serious environmental problems. Chlorimuron-ethyl can be effectively degraded by microbes, but the underlying molecular mechanisms are not fully understood. In this study, we identified the possible pathways and key genes involved in chlorimuron-ethyl degradation by the Chenggangzhangella methanolivorans strain CHL1, a Methylocystaceae strain with the ability to degrade sulfonylurea herbicides. Using a metabolomics method, eight intermediate degradation products were identified, and three pathways, including a novel pyrimidine-ring-opening pathway, were found to be involved in chlorimuron-ethyl degradation by strain CHL1. Transcriptome sequencing indicated that three genes (atzF, atzD, and cysJ) are involved in chlorimuron-ethyl degradation by strain CHL1. The gene knock-out and complementation techniques allowed for the functions of the three genes to be identified, and the enzymes involved in the different steps of chlorimuron-ethyl degradation pathways were preliminary predicted. The results reveal a previously unreported pathway and the key genes of chlorimuron-ethyl degradation by strain CHL1, which have implications for attempts to enrich the biodegradation mechanism of sulfonylurea herbicides and to construct engineered bacteria in order to remove sulfonylurea herbicide residues from environmental media.

The objective of this study was to investigate the protective effects and potential molecular mechanisms of procyanidin B2 (PB2) in MAC-T (mammary alveolar cells-large T antigen) cells during heat stress (HS). The MAC-T cells were divided into three treatment groups: control (37 °C), HS (42 °C), and PB2 + HS (42 °C). Compared with MAC-T cells that were consistently cultured at 37 °C, acute HS treatment remarkably decreased cell viability, reduced activities of catalase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and elevated intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2) was activated and translocated to the nucleus, in accompaniment with upregulation of Nrf2, heme oxygenase 1 (HO-1), thioredoxin reductase 1 (Txnrd1), and heat shock protein 70 (HSP70). In parallel, both mRNA transcript and actual protein secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were increased by heat stress. Pretreatment of MAC-T cells with 0~25 μM PB2 alleviated the decline of cell viability by HS in a dose-dependent fashion and protected cells against HS-induced oxidative stress, as evidenced by significantly improved CAT, SOD, and T-AOC activity, as well as with decreased MDA and ROS generation. Furthermore, PB2 further activated the Nrf2 signaling pathway and reversed the inflammatory response induced by HS. Silencing of Nrf2 by si-Nrf2 transfection not only exacerbated HS-induced cell death and provoked oxidative stress and the inflammatory response, but also greatly abolished the cytoprotective effects under HS of PB2. In summary, PB2 protected MAC-T cells against HS-induced cell death, oxidative stress, and inflammatory response, partially by operating at the Nrf2 signal pathway.

UV-B radiation, sensed by the photoreceptor UVR8, induces signal transduction for plant photomorphogenesis. UV-B radiation affects the concentration of the endogenous plant hormone gibberellin (GA), which in turn triggers DELLA protein degradation through the 26S proteasome pathway. DELLA is a negative regulator in GA signaling, partially relieving the inhibition of hypocotyl growth induced by UV-B in Arabidopsis thaliana. However, GAs do usually not work independently but integrate in complex networks linking to other plant hormones and responses to external environmental signals. Until now, our understanding of the regulatory network underlying GA-involved UV-B photomorphogenesis had remained elusive. In the present research, we investigate the crosstalk between the GA and UV-B signaling pathways in UV-B-induced photomorphogenesis of Arabidopsis thaliana. Compared with wild type Landsberg erecta (Ler), the abundance of HY5, CHS, FLS, and UF3GT were found to be down-regulated in rga-24 and gai-t6 mutants under UV-B radiation, indicating that DELLA is a positive regulator in UV-B-induced photomorphogenesis. Our results indicate that BBX24 interacts with RGA (one of the functional DELLA family members). Furthermore, we also found that RGA interacts with HY5 (the master regulator in plant photomorphogenesis). Collectively, our findings suggest that the HY5–BBX24–DELLA module serves as an important signal regulating network, in which GA is involved in UV-B signaling to regulate hypocotyl inhibition.

The MYB transcription factor (TF) is crucial for plant growth, development, and response to abiotic stress, but it is rarely reported in the herbaceous peony (Paeonia lactiflora Pall.). Here, an MYB TF gene was isolated, and based on our prior mRNA data from P. lactiflora samples, it was treated with drought stress (DS). Its complete cDNA structure was 1314 bp, which encoded 291 amino acids (aa). Furthermore, using sequence alignment analysis, we demonstrated that PlMYB108 was an R2R3-MYB TF. We also revealed that PlMYB108 was primarily localized in the nucleus. Its levels rose during DS, and it was positively correlated with drought tolerance (DT) in P. lactiflora. In addition, when PlMYB108 was overexpressed in tobacco plants, the flavonoid content, antioxidant enzyme activities, and photosynthesis were markedly elevated. Hence, the transgenic plants had stronger DT with a higher leaf water content and lower H2O2 accumulation compared to the wild-type (WT) plants. Based on these results, PlMYB108 is a vital gene that serves to increase flavonoid accumulation, reactive oxygen species (ROS), scavenging capacity, and photosynthesis to confer DT. The results would provide a genetic resource for molecular breeding to enhance plant DT.

Cardiovascular drug research and development (R&D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I−III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.

Since they can provide a natural and flexible description of nonlinear dynamic behavior of complex system, Agent-based models (ABM) have been commonly used for immune system simulation. However, it is crucial for ABM to obtain an appropriate estimation for the key parameters of the model by incorporating experimental data. In this paper, a systematic procedure for immune system simulation by integrating the ABM and regression method under the framework of history matching is developed. A novel parameter estimation method by incorporating the experiment data for the simulator ABM during the procedure is proposed. First, we employ ABM as simulator to simulate the immune system. Then, the dimension-reduced type generalized additive model (GAM) is employed to train a statistical regression model by using the input and output data of ABM and play a role as an emulator during history matching. Next, we reduce the input space of parameters by introducing an implausible measure to discard the implausible input values. At last, the estimation of model parameters is obtained using the particle swarm optimization algorithm (PSO) by fitting the experiment data among the non-implausible input values. The real Influeza A Virus (IAV) data set is employed to demonstrate the performance of our proposed method, and the results show that the proposed method not only has good fitting and predicting accuracy, but it also owns favorable computational efficiency.

Angiotensin-converting enzyme 2 (ACE2) has become a hot topic in neuroscience research in recent years, especially in the context of the global COVID-19 pandemic, where its role in neurological diseases has received widespread attention. ACE2, as a multifunctional metalloprotease, not only plays a critical role in the cardiovascular system but also plays an important role in the protection, development, and inflammation regulation of the nervous system. The COVID-19 pandemic further highlights the importance of ACE2 in the nervous system. SARS-CoV-2 enters host cells by binding to ACE2, which may directly or indirectly affect the nervous system, leading to a range of neurological symptoms. This review aims to explore the function of ACE2 in the nervous system as well as its potential impact and therapeutic potential in various neurological diseases, providing a new perspective for the treatment of neurological disorders.

Proteomics offers a robust method for quantifying proteins and elucidating their roles in cellular functions, surpassing the insights provided by transcriptomics. The Clinical Proteomic Tumor Analysis Consortium database, enriched with comprehensive cancer proteomics data including phosphorylation and ubiquitination profiles, alongside transcriptomics data from the Genomic Data Commons, allow for integrative molecular studies of cancer. The ProteoCancer Analysis Suite (PCAS), our newly developed R package and Shinyapp, leverages these resources to facilitate in-depth analyses of proteomics, phosphoproteomics, and transcriptomics, enhancing our understanding of the tumor microenvironment through features like immune infiltration and drug sensitivity analysis. This tool aids in identifying critical signaling pathways and therapeutic targets, particularly through its detailed phosphoproteomic analysis. To demonstrate the functionality of the PCAS, we conducted an analysis of GAPDH across multiple cancer types, revealing a significant upregulation of protein levels, which is consistent with its important biological and clinical significance in tumors, as indicated in our prior research. Further experiments were used to validate the findings performed using the tool. In conclusion, the PCAS is a powerful and valuable tool for conducting comprehensive proteomic analyses, significantly enhancing our ability to uncover oncogenic mechanisms and identify potential therapeutic targets in cancer research.

As a newly discovered regulated cell death mode, ferroptosis is associated with the development of Parkinson’s disease (PD) and has attracted much attention. Nonetheless, the relationship between ferroptosis and PD pathogenesis remains unclear. The GSE8397 dataset includes GPL96 and GPL97 platforms. The differential genes were analyzed by immune infiltration and Gene Set Enrichment Analysis (GSEA) (p < 0.05), and differential multiple |logFC| > 1 and weighted gene coexpression network analysis (WGCNA) were used to screen differential expression genes (DEGs). The intersection with 368 ferroptosis-related genes (FRGs) was conducted for gene ontology/Kyoto encyclopedia of gene and genome (GO/KEGG) enrichment analysis, gene expression analysis, correlation analysis, single-cell sequencing analysis, and prognosis analysis (area under the curve, AUC) and to predict relevant miRNAs and construct network diagrams using Cytoscape. The intersection genes of differentially expressed ferroptosis-related genes (DEFRGs) and mitochondrial dysfunction genes were validated in the substantia nigra of MPTP-induced PD mice models by Western blotting and immunohistochemistry, and the protein-binding pocket was predicted using the DoGSiteScorer database. According to the results, the estimated scores were positively correlated with the stromal scores or immune scores in the GPL96 and GPL97 platforms. In the GPL96 platform, the GSEA showed that differential genes were mainly involved in the GnRH signaling pathway, B cell receptor signaling pathway, inositol phosphate metabolism, etc. In the GPL97 platform, the GSEA showed that differential genes were mainly involved in the ubiquitin-mediated proteolysis, axon guidance, Wnt signaling pathway, MAPK signaling pathway, etc. We obtained 26 DEFRGs, including 12 up-regulated genes and 14 down-regulated genes, with good correlation. The area under the prognostic analysis curve (AUC > 0.700) showed a good prognostic ability. We found that they were enriched in different neuronal cells, oligodendrocytes, astrocytes, oligodendrocyte precursor cells, and microglial cells, and their expression scores were positively correlated, and selected genes with an AUC curve ≥0.9 were used to predict miRNA, including miR-214/761/3619-5p, miR-203, miR-204/204b/211, miR-128/128ab, miR-199ab-5p, etc. For the differentially expressed ferroptosis–mitochondrial dysfunction-related genes (DEF-MDRGs) (AR, ISCU, SNCA, and PDK4), in the substantia nigra of mice, compared with the Saline group, the expression of AR and ISCU was decreased (p < 0.05), and the expression of α-Syn and PDK4 was increased (p < 0.05) in the MPTP group. Therapeutic drugs that target SNCA include ABBV-0805, Prasinezumab, Cinpanemab, and Gardenin A. The results of this study suggest that cellular DEF-MDRGs might play an important role in PD. AR, ISCU, SNCA, and PDK4 have the potential to be specific biomarkers for the early diagnosis of PD.

The membrane-less organelles in cytoplasm that are presented as cytoplasmic foci were successively identified. Although multiple CCCH zinc-finger proteins have been found to be localized in cytoplasmic foci, the relationship between their specific localization and functions still needs further clarification. Here, we report that the heterologous expression of two Brassica campestris CCCH zinc-finger protein genes (BcMF30a and BcMF30c) in Arabidopsis thaliana can affect microgametogenesis by involving the formation of cytoplasmic foci. By monitoring the distribution of proteins and observing pollen phenotypes, we found that, when these two proteins were moderately expressed in pollen, they were mainly dispersed in the cytoplasm, and the pollen developed normally. However, high expression induced the assembly of cytoplasmic foci, leading to pollen abortion. These findings suggested that the continuous formation of BcMF30a/BcMF30c-associated cytoplasmic foci due to high expression was the inducement of male sterility. A co-localization analysis further showed that these two proteins can be recruited into two well-studied cytoplasmic foci, processing bodies (PBs), and stress granules (SGs), which were confirmed to function in mRNA metabolism. Together, our data suggested that BcMF30a and BcMF30c play component roles in the assembly of pollen cytoplasmic foci. Combined with our previous study on the homologous gene of BcMF30a/c in Arabidopsis, we concluded that the function of these homologous genes is conserved and that cytoplasmic foci containing BcMF30a/c may participate in the regulation of gene expression in pollen by regulating mRNA metabolism.

Parkinson’s disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin–Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and β-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases.

Acute pancreatitis is a common gastrointestinal disease with increasing incidence worldwide. COVID-19 is a potentially life-threatening contagious disease spread throughout the world, caused by severe acute respiratory syndrome coronavirus 2. More severe forms of both diseases exhibit commonalities with dysregulated immune responses resulting in amplified inflammation and susceptibility to infection. Human leucocyte antigen (HLA)-DR, expressed on antigen-presenting cells, acts as an indicator of immune function. Research advances have highlighted the predictive values of monocytic HLA-DR (mHLA-DR) expression for disease severity and infectious complications in both acute pancreatitis and COVID-19 patients. While the regulatory mechanism of altered mHLA-DR expression remains unclear, HLA-DR−/low monocytic myeloid-derived suppressor cells are potent drivers of immunosuppression and poor outcomes in these diseases. Future studies with mHLA-DR-guided enrollment or targeted immunotherapy are warranted in more severe cases of patients with acute pancreatitis and COVID-19.

Starch is one of the main utilization products of sorghum (Sorghum bicolor L.), the fifth largest cereal crop in the world. Up to now, the regulation mechanism of starch biosynthesis is rarely documented in sorghum. In the present study, we identified 30 genes encoding the C2-C2 zinc finger domain (DOF), with one to three exons in the sorghum genome. The DOF proteins of sorghum were divided into two types according to the results of sequence alignment and evolutionary analysis. Based on gene expressions and co-expression analysis, we identified a regulatory factor, SbDof21, that was located on chromosome 5. SbDof21 contained two exons, encoding a 36.122 kD protein composed of 340 amino acids. SbDof21 co-expressed with 15 genes involved in the sorghum starch biosynthesis pathway, and the Pearson correlation coefficients (PCCs) with 11 genes were greater than 0.9. The results of qRT-PCR assays indicated that SbDof21 is highly expressed in sorghum grains, exhibiting low relative expression levels in the tissues of roots, stems and leaves. SbDOF21 presented as a typical DOF transcription factor (TF) that was localized to the nucleus and possessed transcriptional activation activity. Amino acids at positions 182–231 of SbDOF21 formed an important structure in its activation domain. The results of EMSA showed that SbDOF21 could bind to four tandem repeats of P-Box (TGTAAAG) motifs in vitro, such as its homologous proteins of ZmDOF36, OsPBF and TaPBF. Meanwhile, we also discovered that SbDOF21 could bind and transactivate SbGBSSI, a key gene in sorghum amylose biosynthesis. Collectively, the results of the present study suggest that SbDOF21 acts as an important regulator in sorghum starch biosynthesis, exhibiting potential values for the improvement of starch contents in sorghum.

To disclose the effect of crystal plane on the adsorption-photocatalytic activity of MnS, octahedral MnS was prepared via the hydrothermal route to enhance the adsorption and photocatalytic efficiencies of tetracycline hydrochloride (TCH) in visible light region. The optimal MnS treated at 433 K for 16 h could remove 94.83% TCH solution of 260 mg L−1 within 180 min, and its adsorption-photocatalytic efficiency declined to 89.68% after five cycles. Its excellent adsorption-photocatalytic activity and durability were ascribed to the sufficient vacant sites of octahedral structure for TCH adsorption and the feasible band-gap structure for visible-light response. In addition, the band gap structure (1.37 eV) of MnS with a conduction band value of −0.58 eV and a valence band value of 0.79 eV was favorable for the generation of O2−, while unsuitable for the formation of OH. Hence, octahedral MnS was a potential material for the removal of antibiotics from wastewater.

Cystatins, as reversible inhibitors of papain-like and legumain proteases, have been identified in several plant species. Although the cystatin family plays crucial roles in plant development and defense responses to various stresses, this family in wheat (Triticum aestivum L.) is still poorly understood. In this study, 55 wheat cystatins (TaCystatins) were identified. All TaCystatins were divided into three groups and both the conserved gene structures and peptide motifs were relatively conserved within each group. Homoeolog analysis suggested that both homoeolog retention percentage and gene duplications contributed to the abundance of the TaCystatin family. Analysis of duplication events confirmed that segmental duplications played an important role in the duplication patterns. The results of codon usage pattern analysis showed that TaCystatins had evident codon usage bias, which was mainly affected by mutation pressure. TaCystatins may be regulated by cis-acting elements, especially abscisic acid and methyl jasmonate responsive elements. In addition, the expression of all selected TaCystatins was significantly changed following viral infection and cold stress, suggesting potential roles in response to biotic and abiotic challenges. Overall, our work provides new insights into TaCystatins during wheat evolution and will help further research to decipher the roles of TaCystatins under diverse stress conditions.

Chinese cabbage (Brassica campestris) is an economically important leaf vegetable crop worldwide. Mounting studies have shown that cysteine-cysteine-cysteine-histidine (CCCH) zinc-finger protein genes are involved in various plant growth and development processes. However, research on the involvement of these genes in male reproductive development is still in its infancy. Here, we identified 11 male fertility-related CCCH genes in Chinese cabbage. Among them, a pair of paralogs encoding novel non-tandem CCCH zinc-finger proteins, Brassica campestris Male Fertility 30a (BcMF30a) and BcMF30c, were further characterized. They were highly expressed in pollen during microgametogenesis and continued to express in germinated pollen. Further analyses demonstrated that both BcMF30a and BcMF30c may play a dual role as transcription factors and RNA-binding proteins in plant cells. Functional analysis showed that partial bcmf30a bcmf30c pollen grains were aborted due to the degradation of pollen inclusion at the microgametogenesis phase, and the germination rate of viable pollen was also greatly reduced, indicating that BcMF30a and BcMF30c are required for both pollen development and pollen germination. This research provided insights into the function of CCCH proteins in regulating male reproductive development and laid a theoretical basis for hybrid breeding of Chinese cabbage.

Expansins are a kind of structural proteins of the plant cell wall, and they enlarge cells by loosening the cell walls. Therefore, expansins are involved in many growth and development processes. The complete genomic sequences of Brassica rapa, Brassica oleracea and Brassica nigra provide effective platforms for researchers to study expansin genes, and can be compared with analogues in Arabidopsis thaliana. This study identified and characterized expansin families in B. rapa, B. oleracea, and B. nigra. Through the comparative analysis of phylogeny, gene structure, and physicochemical properties, the expansin families were divided into four subfamilies, and then their expansion patterns and evolution details were explored accordingly. Results showed that after the three species underwent independent evolution following their separation from A. thaliana, the expansin families in the three species had increased similarities but fewer divergences. By searching divergences of promoters and coding sequences, significant positive correlations were revealed among orthologs in A. thaliana and the three basic species. Subsequently, differential expressions indicated extensive functional divergences in the expansin families of the three species, especially in reproductive development. Hence, these results support the molecular evolution of basic Brassica species, potential functions of these genes, and genetic improvement of related crops.

Breast cancer is a common malignancy threatening women’s health around the world. Despite improved treatments for different subtypes of breast tumors that have been put forward, there still exists a poor therapeutic response and prognosis. Magnetic fields, as a non-invasive therapy, have shown anti-tumor effects in vitro and in vivo; however, the detailed mechanisms involved are still not clear. In this study, we found that in exposure to low-frequency magnetic fields (LF-MFs) with an intensity of 1 mT and frequencies of 50, 125, 200, and 275 Hz, separately, the proliferation of breast cancer cells was inhibited and LF-MF with 200 Hz reached the optimum inhibition effect, on exposure time-dependently. Notably, we found that exposure to LF-MF led to MCF-7 and ZR-75-1 cell apoptosis and cell cycle arrest. Moreover, we also discovered that LF-MF effectively increased the level of reactive oxygen species (ROS), suppressed the PI3K/AKT signaling pathway, and activated glycogen synthase kinase-3β (GSK-3β). We demonstrated that the GSK3β activity contributed to LF-MF-induced cell proliferation inhibition and apoptosis, while the underlying mechanism was associated with the inhibition of PI3K/AKT through increasing the intracellular ROS accumulation. These results indicate that LF-MF with a specific frequency may be an attractive therapy to treat breast cancers.

The search to date for accurate protein biomarkers in acute ischemic stroke has taken into consideration the stage and/or the size of infarction, but has not accounted for the site of stroke. In the present study, multiple reaction monitoring using labeled reference peptide (LRP) following laser capture microdissection (LCM) is used to identify site-specific protein biomarker candidates. In middle cerebral artery occlusion (MCAO) rat models, both intact and infarcted brain tissue was collected by LCM, followed by on-film digestion and semi-quantification using triple-quadrupole mass spectrometry. Thirty-four unique peptides were detected for the verification of 12 proteins in both tissue homogenates and LCM-captured samples. Six insoluble proteins, including neurofilament light polypeptide (NEFL), alpha-internexin (INA), microtubule-associated protein 2 (MAP2), myelin basic protein (MBP), myelin proteolipid protein (PLP) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), were found to be site-specific. Soluble proteins, such as neuron-specific enolase (NSE) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), and some insoluble proteins, including neurofilament heavy polypeptide (NEFH), glial fibrillary acidic protein (GFAP), microtubule-associated protein tau (MAPT) and tubulin β-3 chain (TUBB3), were found to be evenly distributed in the brain. Therefore, we conclude that some insoluble protein biomarkers for stroke are site-specific, and would make excellent candidates for the design and analysis of relevant clinical studies in the future.

Small-cell lung cancer (SCLC) is characterized as an aggressive tumor with brain metastasis. Although preventing SCLC metastasis to the brain is immensely important for survival, the molecular mechanisms of SCLC cells penetrating the blood–brain barrier (BBB) are largely unknown. Recently, visfatin has been considered as a novel pro-inflammatory adipocytokine involved in various cancers. Herein, we present evidence that elevated levels of visfatin in the serum of SCLC patients were associated with brain metastasis, and visfain was increased in NCI-H446 cells, a SCLC cell line, during interacting with human brain microvascular endothelial cells (HBMEC). Using in vitro BBB model, we found that visfatin could promote NCI-H446 cells migration across HBMEC monolayer, while the effect was inhibited by knockdown of visfatin. Furthermore, our findings indicated that CC chemokine ligand 2 (CCL2) was involved in visfatin-mediated NCI-H446 cells transendothelial migtation. Results also showed that the upregulation of CCL2 in the co-culture system was reversed by blockade of visfatin. In particular, visfatin-induced CCL2 was attenuated by specific inhibitor of PI3K/Akt signaling in NCI-H446 cells. Taken together, we demonstrated that visfatin was a prospective target for SCLC metastasis to brain, and understanding the molecular mediators would lead to effective strategies for inhibition of SCLC brain metastasis.

Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant-induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death and survival pathways during hypoxia/reoxygenation (H/R) injury remains unclear. In the present study, we investigated the role of TRPV1 in H/R induced apoptosis of H9C2 cardiomyocytes. We demonstrated that TRPV1 was indeed expressed in H9C2 cells, and activated by H/R injury. Although neuropeptide release caused by TRPV1 activation on sensory neurons elicits a cardioprotective effect, we found that capsaicin (CAP; a TRPV1 agonist) treatment of H9C2 cells paradoxically enhanced the level of apoptosis by increasing intracellular calcium and mitochondrial superoxide levels, attenuating mitochondrial membrane potential, and inhibiting mitochondrial biogenesis (measured by the expression of ATP synthase β). In contrast, treatment of cells with capsazepine (CPZ; a TRPV1 antagonist) or TRPV1 siRNA attenuated H/R induced-apoptosis. Furthermore, CAP and CPZ treatment revealed a similar effect on cell viability and mitochondrial superoxide production in primary cardiomyocytes. Finally, using both CGRP8–37 (a CGRP receptor antagonist) and RP67580 (a SP receptor antagonist) to exclude the confounding effects of neuropeptides, we confirmed aforementioned detrimental effects as TRPV1−/− mouse hearts exhibited improved cardiac function during ischemia/reperfusion. In summary, direct activation of TRPV1 in myocytes exacerbates H/R-induced apoptosis, likely through calcium overload and associated mitochondrial dysfunction. Our study provides a novel understanding of the role of myocyte TRPV1 channels in ischemia/reperfusion injury that sharply contrasts with its known extracardiac neuronal effects.

Carbon nanotubes are ideal candidates for the mechanical reinforcement of ceramic due to their excellent mechanical properties, high aspect ratio and nanometer scale diameter. In this study, the effects of multi-walled carbon nanotubes (MWCNTs) on the mechanical properties of diopside (Di) scaffolds fabricated by selective laser sintering were investigated. Results showed that compressive strength and fracture toughness improved significantly with increasing MWCNTs from 0.5 to 2 wt %, and then declined with increasing MWCNTs to 5 wt %. Compressive strength and fracture toughness were enhanced by 106% and 21%, respectively. The reinforcing mechanisms were identified as crack deflection, MWCNTs crack bridging and pull-out. Further, the scaffolds exhibited good apatite-formation ability and supported adhesion and proliferation of cells in vitro.

The activities of pectin methylesterases (PMEs) are regulated by pectin methylesterase inhibitors (PMEIs), which consequently control the pectin methylesterification status. However, the role of PMEI genes in Brassica oleracea, an economically important vegetable crop, is poorly understood. In this study, 95 B. oleracea PMEI (BoPMEI) genes were identified. A total of 77 syntenic ortholog pairs and 10 tandemly duplicated clusters were detected, suggesting that the expansion of BoPMEI genes was mainly attributed to whole-genome triplication (WGT) and tandem duplication (TD). During diploidization after WGT, BoPMEI genes were preferentially retained in accordance with the gene balance hypothesis. Most homologous gene pairs experienced purifying selection with ω (Ka/Ks) ratios lower than 1 in evolution. Five stamen-specific BoPMEI genes were identified by expression pattern analysis. By combining the analyses of expression and evolution, we speculated that nonfunctionalization, subfunctionalization, neofunctionalization, and functional conservation can occur in the long evolutionary process. This work provides insights into the characterization of PMEI genes in B. oleracea and contributes to the further functional studies of BoPMEI genes.

Pectin methylesterase inhibitor genes (PMEIs) are a large multigene family and play crucial roles in cell wall modifications in plant growth and development. Here, a comprehensive analysis of the PMEI gene family in Brassica campestris, an important leaf vegetable, was performed. We identified 100 Brassica campestris PMEI genes (BcPMEIs), among which 96 BcPMEIs were unevenly distributed on 10 chromosomes and nine tandem arrays containing 20 BcPMEIs were found. We also detected 80 pairs of syntenic PMEI orthologs. These findings indicated that whole-genome triplication (WGT) and tandem duplication (TD) were the main mechanisms accounting for the current number of BcPMEIs. In evolution, BcPMEIs were retained preferentially and biasedly, consistent with the gene balance hypothesis and two-step theory, respectively. The molecular evolution analysis of BcPMEIs manifested that they evolved through purifying selection and the divergence time is in accordance with the WGT data of B. campestris. To obtain the functional information of BcPMEIs, the expression patterns in five tissues and the cis-elements distributed in promoter regions were investigated. This work can provide a better understanding of the molecular evolution and biological function of PMEIs in B. campestris.

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