Pediatric Extrapolation Approach for U.S. Food and Drug Administration Approval of Brexpiprazole in Patients Aged 13 to 17 Years with Schizophrenia.

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia.

Unveiling the Diversity and Modifications of Short Peptides in Buthus martensii Scorpion Venom through Liquid Chromatography-High Resolution Mass Spectrometry.

More recently, short peptides in scorpion venom have received much attention because of their potential for drug discovery. Although various biological effects of these short peptides have been found, their studies have been hindered by the lack of structural information especially in modifications. In this study, small peptides from scorpion venom were investigated using high-performance liquid chromatography high-resolution mass spectrometry followed by de novo sequencing. A total of 156 sequences consisting of 2~12 amino acids were temporarily identified from Buthus martensii scorpion venom. The identified peptides exhibited various post-translational modifications including N-terminal and C-terminal modifications, in which the N-benzoyl modification was first found in scorpion venom. Moreover, a short peptide Bz-ARF-NH2 demonstrated both N-terminal and C-terminal modifications simultaneously, which is extremely rare in natural peptides. In conclusion, this study provides a comprehensive insight into the diversity, modifications, and potential bioactivities of short peptides in scorpion venom.

Accelerating therapeutics development during a pandemic: population pharmacokinetics of the long-acting antibody combination AZD7442 (tixagevimab/cilgavimab) in the prophylaxis and treatment of COVID-19.

AZD7442 is a combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies, tixagevimab and cilgavimab, developed for pre-exposure prophylaxis (PrEP) and treatment of coronavirus disease 2019 (COVID-19). Using data from eight clinical trials, we describe a population pharmacokinetic (popPK) model of AZD7442 and show how modeling of "interim" data accelerated decision-making during the COVID-19 pandemic. The final model was a two-compartmental distribution model with first-order absorption and elimination, including standard allometric exponents for the effect of body weight on clearance and volume. Other covariates included were as follows: sex, age >65 years, body mass index ≥30 kg/m2, and diabetes on absorption rate; diabetes on clearance; Black race on central volume; and intramuscular (IM) injection site on bioavailability. Simulations indicated that IM injection site and body weight had > 20% effects on AZD7442 exposure, but no covariates were considered to have a clinically relevant impact requiring dose adjustment. The pharmacokinetics of AZD7442, cilgavimab, and tixagevimab were comparable and followed linear kinetics with extended half-lives (median 78.6 days for AZD7442), affording prolonged protection against susceptible SARS-CoV-2 variants. Comparison of popPK simulations based on "interim data" with a target concentration based on 80% viral inhibition and assuming 1.81% partitioning into the nasal lining fluid supported a decision to double the PrEP dosage from 300 mg to 600 mg to prolong protection against Omicron variants. Serum AZD7442 concentrations in adolescents weighing 40-95 kg were predicted to be only marginally different from those observed in adults, supporting authorization for use in adolescents before clinical data were available. In these cases, popPK modeling enabled accelerated clinical decision-making.

Identification of toxic Gelsemium elegans in processed food and honey based on real-time PCR analysis.

Gelsemium elegans (GE) is a widely distributed hypertoxic plant that has caused many food poisoning incidents. Its pollen can also be collected by bees to produce toxic honey, posing a great threat to the health and safety of consumers. However, for the complex matrices such as cooked food and honey, it is challenging to perform composition analysis. It is necessary to establish more effective strategies for investigating GE contamination. In this study, the real-time PCR (qPCR) analysis combined with DNA barcode matK was proposed for the identification and detection of GE. Fifteen honey samples along with twenty-eight individuals of GE and the common confusable objects Lonicera japonica, Ficus hirta, Stellera chamaejasme and Chelidonium majus were gathered. Additionally, the food mixtures treated with 20-min boiling and 30-min digestion were prepared. Specific primers were designed, and the detection capability and sensitivity of qPCR in honey and boiled and digested food matrices were tested. The results demonstrated that the matK sequence with sufficient mutation sites was an effective molecular marker for species differentiation. GE and the confusable species could be clearly classified by the fluorescence signal of qPCR assay with a high sensitivity of 0.001 ng/µl. In addition, this method was successfully employed for the detection of deeply processed food materials and honey containing GE plants which even accounted for only 0.1 %. The sequencing-free qPCR approach undoubtedly can serve as a robust support for the quality supervision of honey industry and the prevention and diagnosis of food poisoning.

Discovery of N-benzyl-6-methylpicolinamide as a potential scaffold for bleaching herbicides.

BACKGROUND: In pesticide research, bleaching herbicides have always been a hot topic. Our previous research showed that N-(4-fluorobenzyl)-2-methoxybenzamide is an innovative lead compound for bleaching herbicides. RESULTS: A total of 40 derivatives of picolinamides were prepared and evaluated for their herbicidal activity by Petri dish tests and postemergence trials. The structure-activity relationship (SAR) revealed that introducing electron-withdrawing groups at the 3- or 4-positions of the benzyl significantly enhances herbicidal activity. Furthermore, ZI-04 induced similar symptoms such as bleaching effect in treated weeds and accumulation of biosynthetic precursors for carotenoids as observed with diflufenican. ZI-04 also exhibited significant cross-resistance to diflufenican and had a lower resistance risk than diflufenican. CONCLUSION: N-benzyl-6-methylpicolinamides were discovered as a novel scaffold for bleaching herbicides. The accumulation of phytoene, phytofluene and ζ-Carotene in radish cotyledons, and cross-resistance observed with diflufenican, showed that title compounds can interfere with carotenoid biosynthesis. © 2024 Society of Chemical Industry.

Fe3 O4 -Incorporated Metal-Organic Framework for Chemo/Ferroptosis Synergistic Anti-Tumor via the Enhanced Chemodynamic Therapy.

Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe3 O4 as a therapeutic platform is proposed. Carboxymethyl cellulose (CMC) is used as a stabilizer of Fe3 O4 , which is then decorated on the surface of ZIF-8 via the electrostatic interaction and serves as an efficient Fenton reaction trigger. Meanwhile, the pH-responsive ZIF-8 scaffold acts as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX-ZIF-8@Fe3 O4 /CMC (DZFC) nanoparticles concomitantly accelerate DOX release and generate more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger glutathione peroxidase 4 (GPX4)-dependent ferroptosis via the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti-tumor efficacy. No marked toxic effects are detected during DZFC treatment in a tumor-bearing mouse model. This composite nanoparticle remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines.

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Chromatin accessibility complex subunit 1 enhances tumor growth by regulating the oncogenic transcription of YAP in breast and cervical cancer.

Background: As a component of chromatin remodeling complex, chromatin accessibility complex subunit 1 (CHRAC1) is critical in transcription and DNA replication. However, the significance of CHRAC1 in cancer progression has not been investigated extensively. This research aimed to determine the function of CHRAC1 in breast and cervical cancer and elucidate the molecular mechanism. Methods: The Bio-ID method was used to identify the interactome of transcriptional activator Yes-associated protein (YAP) and the binding between YAP and CHRAC1 was verified by immunofluorescence. CCK8, colony formation and subcutaneous xenograft assays were conducted to explore the function of CHRAC1 in cancer cell proliferation. RNA-seq analysis and RT-PCR were used to analyze the transcription program change after CHRAC1 ablation. The diagnostic value of CHRAC1 was analyzed by TCGA database and further validated by immunohistochemistry staining. Results: In the current study, we found that the chromatin remodeler CHRAC1 was a potential YAP interactor. CHRAC1 depletion suppressed breast and cervical cancer cell proliferation and tumor growth. The potential mechanism may be that CHRAC1 interacts with YAP to facilitate oncogenic transcription of YAP target genes in Hippo pathway, thereby promoting tumorigenesis. CHRAC1 was elevated in cervical and breast cancer biopsies and the upregulation correlated with shorter survival, poor pathological stages and metastasis of cancer patients. Moreover, CHRAC1 expression was statistically associated with YAP in breast and cervical cancer biopsies. Conclusions: These findings highlight that CHRAC1 contributes to cancer progression through regulating the oncogenic transcription of YAP, which makes it a potential therapeutic target for cancer treatment.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.

EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway.

The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment.

Application of flipped classroom combined with case-based learning in Introduction to Environmental Health Science.

Objectives: To explore the effect of flipped classroom combined with case-based learning in Introduction to Environmental Health Science for the Master of Public Health (MPH). Methods: The MPH Master's class of 2022 was selected as the experimental group at Guilin Medical University from September to December 2022, and the flipped classroom combined with the case-based learning was adopted. The class of 2021 was the control group, and we taught them with the traditional teaching method. A self-designed questionnaire and academic performance were used to evaluate the teaching effects of the two groups. Results: There was no difference in the paper score between grades 2022 and 2021, and the design question score of grade 2022 was higher than that of grade 2021. The difference was statistically significant (p < 0.05). The students in grade 2022 had a high overall recognition of the teaching effect of the flipped classroom combined with case-based learning in Introduction to Environmental Health Science. Conclusion: The teaching method of the flipped classroom combined with case-based learning is more suitable than the traditional teaching method in the Introduction to Environmental Health Science for MPH. It can stimulate the independent learning ability of MPH students and improve their ability to use knowledge and an innovative spirit.

Myc-Associated Zinc Finger Protein Promotes Metastasis of Papillary Thyroid Cancer.

BACKGROUND: Myc-associated zinc finger protein (MAZ) plays a role in cancer progression and metastasis. However, the role and underlying molecular mechanism of MAZ in thyroid cancer have not yet been fully elucidated. This study aimed to explore the clinical significance of MAZ in thyroid cancer tissues, and clarify its mechanism in the occurrence and development of thyroid cancer. METHODS: The expression level of MAZ protein in thyroid cancer tissues was detected by bioinformatics analysis and immunohistochemistry (IHC). The relationship between the expression level of MAZ and clinicopathological characteristics of thyroid cancer patients was analyzed by multivariate logistic regression analysis. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression level of MAZ in thyroid cancer cell lines. After MAZ knockdown cell lines were constructed, wound healing and Transwell assays were used to detect the migratory and invasive abilities of cancer cells. RESULTS: The results of IHC showed that the expression level of MAZ protein in thyroid cancer tissues was higher than that in normal adjacent thyroid tissues (p < 0.05), which was consistent with the high expression level of MAZ in thyroid cancer tissues found in The Cancer Genome Atlas (TCGA) database. The results of multivariate logistic regression analysis indicated that the expression level of MAZ was correlated with tumor diameter and tumor capsule of thyroid cancer patients. Moreover, patients with the high MAZ expression level had shorter overall and disease-free survival compared with thyroid cancer patients with the low MAZ expression level (p < 0.05). Further cell function assays indicated that downregulation of MAZ expression level could inhibit the migration and invasion of thyroid cancer cell lines. Moreover, the expression level of epithelial-mesenchymal transition (EMT)-related factor fibronectin 1 (FN1) was obtained from the RNA-seq of MAZ knockdown in thyroid cancer cells. RT-qPCR confirmed that the expression level of FN1 was elevated in MAZ knockdown cell lines (p < 0.05). Bioinformatics analysis indicated that the expression level of FN1 was upregulated in thyroid cancer tissues and had a negative relationship with the expression level of MAZ, as evidenced by correlation analysis. CONCLUSIONS: A high expression level of MAZ in thyroid cancer tissues was associated with a poor prognosis of patients. MAZ could affect the progression of thyroid cancer by inducing the EMT process.

The mechanisms of microcystin-LR-induced genotoxicity and neurotoxicity in fish and mammals: Bibliometric analysis and meta-analysis.

Microcystin-leucine arginine (MC-LR) is a typical cyanobacterial toxin, and the threat of this toxin is increasing among organisms. Despite extensive toxicological studies on MC-LR, there is no comprehensive analysis based on previously published data. Therefore, we conducted bibliometric analysis and meta-analysis to identify research hotspots and to elucidate the key mechanism of the relationship between MC-LR and genotoxicity and neurotoxicity among fish and mammals. One of the hotspots is toxic mechanisms (indicated by the frequent appearance of oxidative stress, DNA damage, apoptosis, neurotoxicity, genotoxicity, ROS, comet assay, signalling pathway, and gene expression indicate as keywords). The density visualization shows a high frequency of "microcystin-LR" and "toxicology," and the overlay visualization emphasizes the prominence of "neurotoxicity" in recent years. These findings confirm the importance of studying MC-LR toxicity. Meta-analysis indicated that in both fish and mammals, MC-LR exposure increased ROS levels by 294 % and increased DNA damage biomarkers by 174 % but decreased neurotoxicity biomarkers by 9 %. Intergroup comparisons revealed that the exposure concentration of MC-LR was significantly correlated with genotoxicity and neurotoxicity levels in both fish and mammals (p < 0.05). Furthermore, the random forest (RF) model revealed that exposure concentration was the primary determinant associated with the induction of ROS, genotoxicity, and neurotoxicity induced by MC-LR. This is likely the dominant mechanism by which excessive ROS production induced by MC-LR causes oxidative stress, ultimately leading to genotoxicity and neurotoxicity in both fish and mammals.

N-benzyl-2-methoxy-5-propargyloxybenzoamides, a new type of bleaching herbicides targeting the biosynthesis pathway of plastoquinone.

BACKGROUND: Previously, the herbicidal activity of N-benzyl-2-methoxybenzamides was discovered during a random screening program in our laboratory. The chemicals resulted in bleaching effect of newly grown leaves by interfering with the biosynthesis of ß-carotene in plant. RESULTS: A total of 28 benzamides were synthesized and subjected for the evaluation of herbicidal activity. Structure-activity relationship (SAR) showed that introducing propargyloxy group at 5-position of benzoyl-benzene ring and fluorine or methyl group at 3- or 4-position of benzyl-benzene ring is beneficial for the activity. Post-emergence herbicidal activities of compounds 406 and 412 were comparable to those of mesotrione and diflufenican. Studies on MOA showed that 406 decreased the level of both ß-carotene and plastoquinone (PQ) in treated plants. The bleaching effect in green alga caused by 406 could be reversed by supplying exogenous homogentisic acid (HGA), the precursor of plastoquinone. CONCLUSION: N-benzyl-2-methoxy-5-propargyloxybenzoamides were discovered as new candidates for bleaching herbicides. Preliminary investigation on mechanism of action (MOA) showed that the title compounds might indirectly interfere with carotenoid biosynthesis by blocking the production of PQ. © 2023 Society of Chemical Industry.

Global Path Planning of Unmanned Surface Vehicle Based on Improved A-Star Algorithm.

To make unmanned surface vehicles that are better applied to the field of environmental monitoring in inland rivers, reservoirs, or coasts, we propose a global path-planning algorithm based on the improved A-star algorithm. The path search is carried out using the raster method for environment modeling and the 8-neighborhood search method: a bidirectional search strategy and an evaluation function improvement method are used to reduce the total number of traversing nodes; the planned path is smoothed to remove the inflection points and solve the path folding problem. The simulation results reveal that the improved A-star algorithm is more efficient in path planning, with fewer inflection points and traversing nodes, and the smoothed paths are more to meet the actual navigation demands of unmanned surface vehicles than the conventional A-star algorithm.

Convergence analysis on a tracking differentiator used in active disturbance rejection control.

This paper presents convergence analysis for a tracking differentiator of an active disturbance rejection control method which is widely applied but lacks theoretical analysis. Since a nonlinear piecewise function is used in the tracking differentiator, the convergence analysis is difficult for tracking errors. Convergence proof processes of the tracking differentiator are divided into three situations based on the nonlinear piecewise function. Tracking errors of the tracking differentiator are proved to be uniformly ultimately bounded considering three situations, and relationships between upper bounds of tracking errors and adjustment parameters are founded by a Lyapunov approach, which provides a basis for parameters adjustment. Finally, simulation and experiment results verify the effectiveness of the proposed convergence analysis.

An integrated approach to evaluate acetamiprid-induced oxidative damage to tRNA in human cells based on oxidized nucleotide and tRNA profiling.

Acetamiprid is poisonous to mammals due to severe acetamiprid-induced oxidative stress that could cause mitochondrial dysfunctions, lipid and protein oxidation, inflammation, apoptosis, and DNA damage. Evidence has accumulated for the role of oxidative stress in changing structures and functions of transfer RNAs (tRNAs) by inducing tRNA cleavage, reprogramming tRNA modifications and impairing aminoacyl-tRNA synthetase editing sites. However, the impact of acetamiprid-induced oxidative stress on tRNA is still unknown. Here, we investigated the effects of acetamiprid on cell viability, reactive oxygen species (ROS) levels, DNA damage, cellular oxidized nucleotide concentrations, and oxidative damage to tRNA in HepG2 cells and LO2 cells. Acetamiprid can cause the significant increment of ROS and DNA oxidative damage. In this study, an integrated approach was established to simultaneously study the network of oxidized nucleotides and explore the tRNA oxidative damage after acetamiprid exposure. A simple and high-throughput liquid chromatography with tandem mass spectrometry (LC-MS/MS) method coupled with (trimethylsilyl)diazomethane (TMSD) derivatization was successfully developed to quantify 12 cellular oxidized nucleotides that cannot be detected using traditional detection methods because of the huge interferences from naturally abundant nucleotides. Meanwhile, the accumulation rate and the locating sites of 8-oxo-2, 7-dihydro-guanine (8-oxo-G) in tRNA were inspected using the established N-(tert-Butyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) labeling-based tRNA profiling method. After acetamiprid treatment, the increment of oxidized nucleoside triphosphates is smaller than that of their corresponding mono- and diphosphates, as well as the dephosphorylated nucleosides, on account of the existence of sanitization enzymes. Several tRNA fragments, CUC[m1A]Gp, CACGp, [Cm]C[m2G]p, and DDGp, are significantly downregulated in acetamiprid-treated HepG2 cells, while only [Cm]C[m2G]p in acetamiprid-treated LO2 cells. According to the profiling results, the significantly changed fragment CUC[m1A]Gp might be caused by the oxidation of guanine (G) to form 8-oxo-G at position 15 in human tRNAphe([Gm]AA), providing more information about the effect of oxidized nucleobases on tRNA's functions.

Recombinant hemagglutinin displaying on yeast reshapes congenital lymphocyte subsets to prompt optimized systemic immune protection against avian influenza infection.

Introduction: Prophylactic vaccination is regarded as the most effective means to control avian flu infection. Currently, there is a need for a universal vaccine that provides broad and long-lasting protection against influenza virus. Meanwhile, although yeast-based vaccines have been used in clinic, studies are still required to further understand the molecular mechanism of yeast-based vaccines under physiological conditions. Methods: We generated a yeast-based vaccine against influenza hemagglutinin (HA) of H5, H7 and H9 using surface displaying technology and evaluated the protective efficacy of chickens after exposure to H9N2 influenza virus. Results: Oral yeast vaccine provided less clinical syndrome, reduced viral loading and alleviated airway damage significantly. Compared to the commercial inactivated vaccine, yeast vaccine stimulated the activation of splenic NK and APCs cells and boosted TLR7-IRF7-IFN signaling in spleen. Meanwhile, γδ T cells in the bursa of Fabricius were activated and the innate lymphoid cells (ILCs) in the bursa of Fabricius promoted the CILPs to differentiate to ILC3 cells in oral yeast birds. Moreover, the reshaped gut microbiota and a suppressed Th17-IL17-mediated inflammation in intestine was observed in oral yeast chickens, which might facilitate the recovery of intestinal mucosal immunity upon virus infection. Collectively, our findings suggest that oral yeast based multivalent bird flu vaccines provide an attractive strategy to update host defense function via reshapes of multi-systemic immune homeostasis.

A meta-analysis on the toxicity of microcystin-LR to fish and mammals.

Microcystin-leucine arginine (MC-LR), the most prevalent and dangerous microcystin, poses high risks to living organisms, especially fish and mammals. Although many studies have focused on the toxic effect on fish and mammals exposed to MC-LR, works that incorporate published data into a comprehensive comparison and analysis are still limited. Here, the adverse effects of oxidative stress markers, health, functional traits, and performance traits in fish and mammals were systematically verified by collecting data from 67 studies for the first time. Notably, we first found that the activities of malondialdehyde (MDA) (p < 0.05) and lactoperoxidase (LPO) always showed increases, whereas the growth (performance traits) always had a significant decrease (p < 0.001) under all variables of MC-LR exposure, i.e., exposure time, exposure concentration, exposure route, and even life stage. Additionally, our study first verified that the activities of MDA and LPO can be employed as oxidative stress indicators of MC-LR effects in fish and mammals instead of other biomarkers of oxidative stress, such as superoxide dismutase (SOD) and catalase (CAT), considered by previous studies. Growth may be regarded as a highly sensitive indicator of MC-LR toxicity in mammals and fish. At the same time, we first found that the impact of MC-LR exposure concentration on LPO, MDA, and growth is higher than that of exposure time, exposure route, and different life stages using the random forest (RF) model. In short, this work sheds light on the potential biochemical and individual toxicity of MC-LR exposure in fish and mammals.