Bacterial pathogens deliver water- and solute-permeable channels to plant cells.

Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells1,2. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and plants3-5. The widely conserved AvrE-family effectors, including DspE in Erwinia amylovora and AvrE in Pseudomonas syringae, have a central role in the pathogenesis of diverse phytopathogenic bacteria6. These conserved effectors are involved in the induction of 'water soaking' and host cell death that are conducive to bacterial multiplication in infected tissues. However, the exact biochemical functions of AvrE-family effectors have been recalcitrant to mechanistic understanding for three decades. Here we show that AvrE-family effectors fold into a ß-barrel structure that resembles bacterial porins. Expression of AvrE and DspE in Xenopus oocytes results in inward and outward currents, permeability to water and osmolarity-dependent oocyte swelling and bursting. Liposome reconstitution confirmed that the DspE channel alone is sufficient to allow the passage of small molecules such as fluorescein dye. Targeted screening of chemical blockers based on the predicted pore size (15-20 Å) of the DspE channel identified polyamidoamine dendrimers as inhibitors of the DspE/AvrE channels. Notably, polyamidoamines broadly inhibit AvrE and DspE virulence activities in Xenopus oocytes and during E. amylovora and P. syringae infections. Thus, we have unravelled the biochemical function of a centrally important family of bacterial effectors with broad conceptual and practical implications in the study of bacterial pathogenesis.

A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.

A new anti-CRISPR gene promotes the spread of drug-resistance plasmids in Klebsiella pneumoniae.

The Klebsiella pneumoniae (K. pneumoniae, Kp) populations carrying both resistance-encoding and virulence-encoding mobile genetic elements (MGEs) significantly threaten global health. In this study, we identified a new anti-CRISPR gene (acrIE10) on a conjugative plasmid with self-target sequence in K. pneumoniae with type I-E* CRISPR-Cas system. AcrIE10 interacts with the Cas7* subunit of K. pneumoniae I-E* CRISPR-Cas system. The crystal structure of the AcrIE10-KpCas7* complex suggests that AcrIE10 suppresses the I-E* CRISPR-Cas by binding directly to Cas7 to prevent its hexamerization, thereby preventing the surveillance complex assembly and crRNA loading. Bioinformatic and functional analyses revealed that AcrIE10 is functionally widespread across diverse species. Our study reports a novel anti-CRISPR and highlights its potential role in spreading resistance and virulence among pathogens.

NKAIN1, as an oncogene, promotes the proliferation and metastasis of breast cancer, affecting its prognosis.

Na, K-ATPase interaction (NKAIN) is a transmembrane protein family, which can interact with Na, K-ATPase ß1 subunit. NKAIN1 plays an important role in alcohol-dependent diseases such as endometrial and prostate cancers. However, the relationship between NKAIN1 and human breast cancer has not been studied. Hence, this study aimed to explore the relationship between NKAIN1 expression and breast cancer. Data used in this study were mainly from the Cancer Genome Atlas, including differential expression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, multiple Cox regression analysis, co-expression gene analysis, and gene set enrichment analysis. Analyses were performed using reverse transcription-quantitative polymerase chain reaction, western blot analysis, and immunohistochemistry on 46 collected samples. The knockdown or overexpression of NKAIN1 in vitro in MCF-7 and MDA-MB-231 cell lines altered the proliferation and migration abilities of tumor cells. In vivo experiments further confirmed that NKAIN1 knockdown effectively inhibited the proliferation and migration of cancer cells. Therefore, our study identified NKAIN1 as an oncogene that is highly expressed in breast cancer tissues. The findings highlight the potential of NKAIN1 as a molecular biomarker of breast cancer.

Generalized modulation for distance-aware optical camera communication beyond oversampled and undersampled schemes.

Oversampled modulation (OM) and undersampled modulation (UM) are two commonly used optical camera communication (OCC) modulation schemes for high-speed communication in short-range and reliable communication at long distances, respectively. However, the relationship between these two schemes and the tradeoff in performance for arbitrary communication distances have not been thoroughly investigated. In this study, we analyze the impact of distance and modulation parameters on pixel efficiency and packet delivery rate performance, demonstrating the underlying unity of traditional OM and UM schemes. Furthermore, we propose a generalized modulation scheme that allows for achieving predefined link performance at a given distance by adjusting the modulation parameters, such as packet length and repetition counts. Simulation and experimental results show that the proposed generalized modulation scheme provides OCC with a unique distance-aware capability other than the traditional OM and UM schemes, which are two special cases focusing on effectiveness and reliability, respectively. This research enhances our understanding of OCC data modulation and establishes a theoretical foundation for achieving efficient and reliable OCC transmission in complex environments.

S670, an amide derivative of 3-O-acetyl-11-keto-ß-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

Identification of multiple odorant receptors essential for pyrethrum repellency in Drosophila melanogaster.

Pyrethrum extract from dry flowers of Tanacetum cinerariifolium (formally Chrysanthemum cinerariifolium) has been used globally as a popular insect repellent against arthropod pests for thousands of years. However, the mechanistic basis of pyrethrum repellency remains unknown. In this study, we found that pyrethrum spatially repels and activates olfactory responses in Drosophila melanogaster, a genetically tractable model insect, and the closely-related D. suzukii which is a serious invasive fruit crop pest. The discovery of spatial pyrethrum repellency and olfactory response to pyrethrum in D. melanogaster facilitated our identification of four odorant receptors, Or7a, Or42b, Or59b and Or98a that are responsive to pyrethrum. Further analysis showed that the first three Ors are activated by pyrethrins, the major insecticidal components in pyrethrum, whereas Or98a is activated by (E)-ß-farnesene (EBF), a sesquiterpene and a minor component in pyrethrum. Importantly, knockout of Or7a, Or59b or Or98a individually abolished fly avoidance to pyrethrum, while knockout of Or42b had no effect, demonstrating that simultaneous activation of Or7a, Or59b and Or98a is required for pyrethrum repellency in D. melanogaster. Our study provides insights into the molecular basis of repellency of one of the most ancient and globally used insect repellents. Identification of pyrethrum-responsive Ors opens the door to develop new synthetic insect repellent mixtures that are highly effective and broad-spectrum.

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice.

SIGNIFICANCE STATEMENT: Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were recently described. Our in vitro and mouse model studies investigate the proposed disease mechanism as an overlap of autosomal-dominant polycystic kidney disease and autosomal-dominant tubulointerstitial kidney disease pathogenesis. We find that DNAJB11 loss impairs cleavage and maturation of the autosomal-dominant polycystic kidney disease protein polycystin-1 (PC1) and results in dosage-dependent cyst formation in mice. We find that Dnajb11 loss does not activate the unfolded protein response, drawing a fundamental contrast with the pathogenesis of autosomal-dominant tubulointerstitial kidney disease. We instead propose that fibrosis in DNAJB11 -kidney disease may represent an exaggerated response to polycystin-dependent cysts. BACKGROUND: Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases. METHODS: We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments, we generated two novel Dnajb11-/- cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein. RESULTS: Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11-/- mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. CONCLUSIONS: DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.

XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1 α -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1 . METHODS: We engineered a Pkd1 REJ domain missense murine model, Pkd1 R2216W , on the basis of the orthologous human hypomorphic allele Pkd1 R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression. RESULTS: Expression of active XBP1 in cultured cells bearing PC1 R2216W mutations increased levels and ciliary trafficking of PC1 R2216W . Mice homozygous for Pkd1 R2216W or heterozygous for Pkd1 R2216Win trans with a conditional Pkd1 fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters. CONCLUSIONS: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.

CD5L aggravates rheumatoid arthritis progression via promoting synovial fibroblasts proliferation and activity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive cartilage erosion and joint destruction. Synovial fibroblasts (SFs) play a crucial role in the pathogenesis of RA. This study aims to explore the function and mechanism of CD5L during RA progression. We examined the levels of CD5L in synovial tissues and SFs. The collagen-induced arthritis (CIA) rat models were used to investigate the effect of CD5L on RA progression. We also investigated the effects of exogenous CD5L on the behavior and activity of RA synovial fibroblasts (RASFs). Our results showed that CD5L expression was significantly upregulated in synovium of RA patients and CIA-rats. Histology and Micro-CT analysis showed that synovial inflammation and bone destruction were more severe in CD5L-treated CIA rats compared with control rats. Correspondingly, CD5L blockade alleviated bone damage and synovial inflammation in CIA-rats. The exogenous CD5L treatment promoted RASFs proliferation invasion and proinflammatory cytokine production. Knockdown of CD5L receptor by siRNA significantly reversed the effect of CD5L treatment on RASFs. Moreover, we observed that CD5L treatment potentiated PI3K/Akt signaling in the RASFs. The promoted effects of CD5L on IL-6 and IL-8 expression were significantly reversed by PI3K/Akt signaling inhibitor. In conclusion, CD5L promote RA disease progression via activating RASFs. CD5L blocking is a potential therapeutic approach for RA patients.

Exploring the correlation of metabolites changes and microbial succession in solid-state fermentation of Sichuan Sun-dried vinegar.

BACKGROUND: The traditional Sichuan Sun-dried vinegar (SSV) with unique flavor and taste is believed to be generated by the solid-state fermentation craft. However, how microorganisms and their metabolites change along with fermentation has not yet been explored. RESULTS: In this study, our results demonstrated that the middle and late stages of SSV fermentation were the periods showing the largest accumulation of organic acids and amino acids. Furthermore, in the bacterial community, the highest average relative abundance was Lactobacillus (ranging from 37.55 to 92.50%) in all fermentation stages, while Acetobacters ranked second position (ranging from 20.15 to 0.55%). The number of culturable lactic acid bacteria is also increased during fermentation process (ranging from 3.93 to 8.31 CFU/g). In fungal community, Alternaria (29.42%), Issatchenkia (37.56%) and Zygosaccharomyces (69.24%) were most abundant in different fermentation stages, respectively. Interestingly, Zygosaccharomyces, Schwanniomyces and Issatchenkia were first noticed as the dominant yeast genera in vinegar fermentation process. Additionally, spearman correlation coefficients exhibited that Lactobacillus, Zygosaccharomyces and Schwanniomyces were significant correlation with most metabolites during the fermentation, implying that these microorganisms might make a significant contribution to the flavor formation of SSV. CONCLUSION: The unique flavor of SSV is mainly produced by the core microorganisms (Lactobacillus, Zygosaccharomyces and Schwanniomyces) during fermentation. This study will provide detailed information related to the structure of microorganism and correlation between changes in metabolites and microbial succession in SSV. And it will be very helpful for proposing a potential approach to monitor the traditional fermentation process.

BER analysis on exposure effect for optical camera communication.

The exposure effect of cameras in optical camera communication (OCC) distorts the received light pulses and generates inter-symbol interference (ISI), which adversely affects the bit error rate (BER) performance. In this Letter, we derive an analytical expression of BER based on the pulse response model of the camera-based OCC channel and analyze the impact of exposure time on BER performance considering asynchronous transmission characteristics. Numerical simulations and experimental results demonstrate that a long exposure time is beneficial in a noise-dominant communication scenario, while a short exposure time is preferable when ISI is dominant. This Letter provides a comprehensive analysis of the influence of exposure time on BER performance, offering a theoretical foundation for the design and optimization of OCC systems.

Disentangling the Ecological Processes and Driving Forces Shaping the Seasonal Pattern of Halobacteriovorax Communities in a Subtropical Estuary.

Halobacteriovorax are predatory bacteria that have a significant ecological role in marine environments. However, understanding of dynamics of populations, driving forces, and community composition of Halobacteriovorax groups in natural marine environments is still limited. Here, we used high-throughput sequencing to study the underlying mechanisms governing the diversity and assembly of the Halobacteriovorax community at spatiotemporal scales in a subtropical estuary. Phylogenetic analysis showed that 10 of 15 known Halobacteriovorax clusters were found in the studied estuary. Halobacteriovorax α-diversity and ß-diversity exhibited significant seasonal variation. Variation partitioning analysis showed that the effect of nutrients was greater than that of other measured water properties on Halobacteriovorax community distribution. The results of Spearman's and Mantel's tests indicated that the trophic pollutants dissolved inorganic phosphorus (DIP) and NH4+-N in the estuary were the key factors that significantly affected Halobacteriovorax species and community diversity. In addition, this work indicated that the biological stoichiometry (especially N/P) of nutrients exerted a significant influence on the Halobacteriovorax community. Furthermore, we found that both deterministic and stochastic processes contributed to the turnover of Halobacteriovorax communities, and environmental filtering dominated the assembly of estuarine Halobacteriovorax communities. Overall, we provide new insights into the mechanisms in the generation and maintenance of the Halobacteriovorax community in marine environments.

Abundant and Rare Taxa of Planktonic Fungal Community Exhibit Distinct Assembly Patterns Along Coastal Eutrophication Gradient.

Revealing planktonic fungal ecology under coastal eutrophication is crucial to our understanding of microbial community shift in marine pollution background. We investigated the diversity, putative interspecies interactions, assembly processes and environmental responses of abundant and rare planktonic fungal communities along a eutrophication gradient present in the Beibu Gulf. The results showed that Dothideomycetes and Agaricomycetes were the predominant classes of abundant and rare fungi, respectively. We found that eutrophication significantly altered the planktonic fungal communities and affected the abundant taxa more than the rare taxa. The abundant and rare taxa were keystone members in the co-occurrence networks, and their interaction was enhanced with increasing nutrient concentrations. Stochastic processes dominated the community assembly of both abundant and rare planktonic fungi across the eutrophication gradient. Heterogeneous selection affected abundant taxa more than rare taxa, whereas homogenizing dispersal had a greater influence on rare taxa. Influences of environmental factors involving selection processes were detected, we found that abundant fungi were mainly influenced by carbon compounds, whereas rare taxa were simultaneously affected by carbon, nitrogen and phosphorus compounds in the Beibu Gulf. Overall, these findings highlight the distinct ecological adaptations of abundant and rare fungal communities to marine eutrophication.

High-resolution magnetic resonance imaging-based radiomic features aid in selecting endovascular candidates among patients with cerebral venous sinus thrombosis.

OBJECTIVES: Cerebral venous sinus thrombosis (CVST) can cause sinus obstruction and stenosis, with potentially fatal consequences. High-resolution magnetic resonance imaging (HRMRI) can diagnose CVST qualitatively, although quantitative screening methods are lacking for patients refractory to anticoagulation therapy and who may benefit from endovascular treatment (EVT). Thus, in this study, we used radiomic features (RFs) extracted from HRMRI to build machine learning models to predict response to drug therapy and determine the appropriateness of EVT. MATERIALS AND METHODS: RFs were extracted from three-dimensional T1-weighted motion-sensitized driven equilibrium (MSDE), T2-weighted MSDE, T1-contrast, and T1-contrast MSDE sequences to build radiomic signatures and support vector machine (SVM) models for predicting the efficacy of standard drug therapy and the necessity of EVT. RESULTS: We retrospectively included 53 patients with CVST in a prospective cohort study, among whom 14 underwent EVT after standard drug therapy failed. Thirteen RFs were selected to construct the RF signature and CVST-SVM models. In the validation dataset, the sensitivity, specificity, and area under the curve performance for the RF signature model were 0.833, 0.937, and 0.977, respectively. The radiomic score was correlated with days from symptom onset, history of dyslipidemia, smoking, fibrin degradation product, and D-dimer levels. The sensitivity, specificity, and area under the curve for the CVST-SVM model in the validation set were 0.917, 0.969, and 0.992, respectively. CONCLUSIONS: The CVST-SVM model trained with RFs extracted from HRMRI outperformed the RF signature model and could aid physicians in predicting patient responses to drug treatment and identifying those who may require EVT.

Interconvertible Pyridone Alkaloids from the Marine-Derived Fungus Penicillium oxalicum QDU1.

Eleven new pyridone alkaloids, penicipyridones A-K (1-11), and three new tetramic acids, tolypocladenols D-F (12-14), were isolated from rice media cultures of the marine-derived fungus Penicillium oxalicum QDU1. Their structures, including absolute configurations, were determined by comprehensive analyses of spectroscopic data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction data. Interestingly, several of the penicipyridones undergo interconversions between hydroxy and methoxy groups at C-4 in acidic MeOH solution. Furthermore, in an acidic aqueous solution, OH-4 could be replaced by diverse substituent groups. Compounds 1, 4, 5, 8, 10, 11, and 14 exhibited moderate inhibitory effects on NO production in the LPS-induced RAW264.7 macrophages, with IC50 values ranging from 9.2 to 19 µM.

Immunological evaluation of patients with Alzheimer's disease based on mitogen-stimulated cytokine productions and mitochondrial DNA indicators.

BACKGROUND: Based on its objective characteristics, laboratory markers have always been the research direction of clinical diagnosis and assessment of mental disorders including Alzheimer's disease. METHODS: MTT Colorimetric Assay, ELISA, and quantitative PCR were used to investigate the responsiveness of peripheral blood mononuclear cells (PBMCs) to mitogen Lipopolysaccharides (LPS) and Phytohemagglutinin (PHA), PBMCs genomic methylation and hydroxymethylation levels, nuclear DNA and mitochondrial DNA damage, respiratory chain enzyme activities, and circulating cell-free mitochondrial DNA levels were detected in 90 patients with Alzheimer's disease. RESULTS: In the Alzheimer's disease group, LPS stimulated PBMCs viability, TNF-α secretion, PHA stimulated IL-10 secretion, genomic DNA methylation levels, circulating cell-free mitochondrial DNA copies, citrate synthase activity were reduced compared to the control; while the LPS stimulated PBMCs IL-1α secretion, PHA stimulated IL-1α and IFN-γ secretion, plasma IL-6 and TNF-α, mitochondrial DNA damages were increased compared to the control. CONCLUSIONS: The reactivity of peripheral blood mononuclear cells to mitogens, mitochondrial DNA integrity characteristics, and cell-free mitochondrial DNA copies may be used as candidate laboratory biomarkers to help clinical management of Alzheimer's disease.

Transfluthrin enhances odorant receptor-mediated spatial repellency in Aedes aegypti.

Mosquito-borne diseases are an increasing global health challenge and vector-based interventions remain the most important methods for reducing the public health burden of most mosquito-borne diseases. Transfluthrin, a volatile pyrethroid insecticide, is used widely and effectively as an insecticide and as a repellent. In a recent study, we showed that at very low concentrations transfluthrin repels Aedes aegypti mosquitoes in a hand-in-cage assay without detectable stimulation of antennal olfactory responses. Furthermore, activation of sodium channels by transfluthrin enhances repellency by DEET, which has been reported to repel mosquitoes via odorant receptor (Or)-dependent and Or-independent mechanisms. However, whether activation of sodium channels by transfluthrin can serve as a general mechanism for synergizing the activities of other repellents remain unknown. In this study, we found that, in hand-in-cage assay, transfluthrin enhanced repellency by geranyl acetate and (E)-ß-farnesene, which activate AaOr31. Such enhancement was not observed in AaOr31-knockout mosquitoes and dampened in a pyrethroid-resistant strain carrying two sodium channel mutations, which reduce the action of transfluthrin on sodium channels. In addition, transfluthrin also enhanced repellency by (-)-borneol, (±)-citronellal, camphor, and eucalyptol, which activate Or-mediated repellency. Our study has uncovered the ability of transfluthrin to enhance the repellency to a variety of mosquito repellents, beyond DEET, and provided experimental support for the emerging paradigm of synergistic interactions between repellency mediated by sodium channel activation and Or activation. These findings have potential implications in the development of more effective mosquito repellent mixtures.

Potential Immunoregulatory Mechanism of Plant Saponins: A Review.

Saponins are extracted from different parts of plants such as seeds, roots, stems, and leaves and have a variety of biological activities including immunomodulatory, anti-inflammatory effects, and hypoglycemic properties. They demonstrate inherent low immunogenicity and possess the capacity to effectively regulate both the innate and adaptive immune responses. Plant saponins can promote the growth and development of the body's immune organs through a variety of signaling pathways, regulate the activity of a variety of immune cells, and increase the secretion of immune-related cytokines and antigen-specific antibodies, thereby exerting the role of immune activity. However, the chemical structure of plant saponins determines its certain hemolytic and cytotoxicity. With the development of science and technology, these disadvantages can be avoided or reduced by certain technical means. In recent years, there has been a significant surge in interest surrounding the investigation of plant saponins as immunomodulators. Consequently, the objective of this review is to thoroughly examine the immunomodulatory properties of plant saponins and elucidate their potential mechanisms, with the intention of offering a valuable point of reference for subsequent research and advancement within this domain.