Mechanistic insights into zinc oxide nanoparticles induced embryotoxicity via H3K9me3 modulation.

The widespread application of nanoparticles (NPs) in various fields has raised health concerns, especially in reproductive health. Our research has shown zinc oxide nanoparticles (ZnONPs) exhibit the most significant toxicity to pre-implantation embryos in mice compared to other common NPs. In patients undergoing assisted reproduction technology (ART), a significant negative correlation was observed between Zn concentration and clinical outcomes. Therefore, this study explores the impact of ZnONPs exposure on pre-implantation embryonic development and its underlying mechanisms. We revealed that both in vivo and in vitro exposure to ZnONPs impairs pre-implantation embryonic development. Moreover, ZnONPs were found to reduce the pluripotency of mouse embryonic stem cells (mESCs), as evidenced by teratoma and diploid chimera assays. Employing multi-omics approaches, including RNA-Seq, CUT&Tag, and ATAC-seq, the embryotoxicity mechanisms of ZnONPs were elucidated. The findings indicate that ZnONPs elevate H3K9me3 levels, leading to increased heterochromatin and consequent inhibition of gene expression related to development and pluripotency. Notably, Chaetocin, a H3K9me3 inhibitor, sucessfully reversed the embryotoxicity effects induced by ZnONPs. Additionally, the direct interaction between ZnONPs and H3K9me3 was verified through pull-down and immunoprecipitation assays. Collectively, these findings offer new insights into the epigenetic mechanisms of ZnONPs toxicity, enhancing our understanding of their impact on human reproductive health.

Recommendations for the selection of nucleoside analogues as antihuman herpesvirus drugs: a real-world analysis of reported cases from the FDA adverse event reporting system.

OBJECTIVE: The aim of this study is to provide guidance for refining medication protocols, developing alternative strategies, and enhancing protection against herpesvirus infections in personalized clinical settings. METHODS: Adverse drug events (ADEs) data for anti-herpesvirus from the first quarter of 2004 to the fourth quarter of 2022 were collected from the FDA Adverse Event Reporting System (FAERS). Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) methods for data mining. RESULTS: A total of 18,591, 24,206, 6,150, and 419 reports of ADEs associated with acyclovir (ACV), valacyclovir (VACV), ganciclovir (GCV), and famciclovir (FCV) were screened and extracted from the FAERS. In this study, the report summarized the high frequency and strong correlation of ADEs for the four drugs at the Preferred Term (PT) level. Additionally, the analysis also identified the relationship between ADEs and factors such as age, gender, and severity of outcome at the System Organ Class (SOC) level. CONCLUSION: The safety reports for the four-nucleoside analogue anti-herpesvirus drugs are diverse and interconnected. Dosing for patients with herpesvirus infections should be tailored to their specific conditions and the potential risk of disease.

Protein phosphatase SCP4 regulates cartilage development and endochondral osteogenesis via FoxO3a dephosphorylation.

The regulatory mechanisms involved in embryonic development are complex and yet remain unclear. SCP4 represents a novel nucleus-resident phosphatase identified in our previous study. The primary aim of this study was to elucidate the function of SCP4 in the progress of cartilage development and endochondral osteogenesis. SCP4-/- and SCP4Col2ER mice were constructed to assess differences in bone formation using whole skeleton staining. ABH/OG staining was used to compare chondrocyte differentiation and cartilage development. Relevant biological functions were analysed using RNA-sequencing and GO enrichment, further validated by immunohistochemical staining, Co-IP and Western Blot. Global SCP4 knockout led to abnormal embryonic development in SCP4-/- mice, along with delayed endochondral osteogenesis. In parallel, chondrocyte-specific removal of SCP4 yielded more severe embryonic deformities in SCP4Col2ER mice, including limb shortening, reduced chondrocyte number in the growth plate, disorganisation and cell enlargement. Moreover, RNA-sequencing analysis showed an association between SCP4 and chondrocyte apoptosis. Notably, Tunnel-positive cells were indeed increased in the growth plates of SCP4Col2ER mice. The deficiency of SCP4 up-regulated the expression levels of pro-apoptotic proteins both in vivo and in vitro. Additionally, phosphorylation of FoxO3a (pFoxO3a), a substrate of SCP4, was heightened in chondrocytes of SCP4Col2ER mice growth plate, and the direct interaction between SCP4 and pFoxO3a was further validated in chondrocytes. Our findings underscore the critical role of SCP4 in regulating cartilage development and endochondral osteogenesis during embryonic development partially via inhibition of chondrocytes apoptosis regulated by FoxO3a dephosphorylation.

SUMOylation modification of FTO facilitates oxidative damage response of arsenic by IGF2BP3 in an m6A-dependent manner.

N6-methyladenosine (m6A) is the most common form of internal post-transcriptional methylation observed in eukaryotic mRNAs. The abnormally increased level of m6A within the cells can be catalyzed by specific demethylase fat mass and obesity-associated protein (FTO) and stay in a dynamic and reversible state. However, whether and how FTO regulates oxidative damage via m6A modification remain largely unclear. Herein, by using both in vitro and in vivo models of oxidative damage induced by arsenic, we demonstrated for the first time that exposure to arsenic caused a significant increase in SUMOylation of FTO protein, and FTO SUMOylation at lysine (K)- 216 site promoted the down-regulation of FTO expression in arsenic target organ lung, and therefore, remarkably elevating the oxidative damage via an m6A-dependent pathway by its specific m6A reader insulin-like growth factor-2 mRNA-binding protein-3 (IGF2BP3). Consequently, these findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also imply that regulation of FTO SUMOylation may serve as potential approach for treatment of oxidative damage.

New lignans from Phyllanthodendron dunnianum.

A new lignan phyllanins A (1) and a lignan phyllanins B (2) for which the absolute configuration was determined for the first time, along with four known lignans (3-6) were isolated from the branch and leaf extracts of Phyllanthodendron dunnianum. Their planar structures were mainly determined by a combination of 1D and 2D NMR, HRESIMS spectral analyses, and the absolute configurations of the compounds 1 and 2 were established by DFT GIAO 13C NMR and electronic circular dichroism (ECD) calculations. In addition, all these six lignans were firstly tested for the antibacterial activities against MRSA, Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli. Among these compounds, 2 and 5 showed potential antibacterial activities against MRSA and S. aureus with MIC values of 4 and 8 µg/mL, respectively.

Dual engineered bacteria improve inflammatory bowel disease in mice.

Currently, there are many different therapies available for inflammatory bowel disease (IBD), including engineered live bacterial therapeutics. However, most of these studies focus on producing a single therapeutic drug using individual bacteria, which may cause inefficacy. The use of dual drugs can enhance therapeutic effects. However, expressing multiple therapeutic drugs in one bacterial chassis increases the burden on the bacterium and hinders good secretion and expression. Therefore, a dual-bacterial, dual-drug expression system allows for the introduction of two probiotic chassis and enhances both therapeutic and probiotic effects. In this study, we constructed a dual bacterial system to simultaneously neutralize pro-inflammatory factors and enhance the anti-inflammatory pathway. These bacteria for therapy consist of Escherichia coli Nissle 1917 that expressed and secreted anti-TNF-α nanobody and IL-10, respectively. The oral administration of genetically engineered bacteria led to a decrease in inflammatory cell infiltration in colon and a reduction in the levels of pro-inflammatory cytokines. Additionally, the administration of engineered bacteria did not markedly aggravate gut fibrosis and had a moderating effect on intestinal microbes. This system proposes a dual-engineered bacterial drug combination treatment therapy for inflammatory bowel disease, which provides a new approach to intervene and treat IBD. KEY POINTS: • The paper discusses the effects of using dual engineered bacteria on IBD • Prospects of engineered bacteria in the clinical treatment of IBD.

NBR1-mediated autophagic degradation of caspase 8 protects vascular endothelial cells against arsenite-induced apoptotic cell death.

Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

The A subunit of vacuolar H+-ATPase gene (CmVHA-A) plays opposite roles in plant growth and drought tolerance of chrysanthemum under different growing conditions.

As the most prominent proton pumps in plants, vacuolar H+-ATPases (VHAs) comprise multiple subunits that are important for physiological processes and stress tolerance in plants. However, few studies on the roles of subunit genes of VHAs in chrysanthemum have been reported to date. In this study, the gene of A subunit of V-ATPase in chrysanthemum (CmVHA-A) was cloned and identified. CmVHA-A was conserved with VHA-A proteins from other plants. Expression analysis showed that CmVHA-A was highly expressed in most tissues of chrysanthemum except for the flower bud, and was readily induced by polyethylene glycol (PEG) treatment. Functional analysis demonstrated that CmVHA-A exerted a negative influence on the growth and development of shoot and root of chrysanthemum under normal conditions. RNA-sequencing (RNA-seq) analysis revealed the possible explanations for phenotypic differences between transgenic and wild-type (WT) plants. Under drought conditions, CmVHA-A positively affected the drought tolerance of chrysanthemum by enhancing antioxidase activity and alleviating photosynthetic disruption. Overall, CmVHA-A plays opposite roles in plant growth and drought tolerance of chrysanthemums under different growing conditions.

Universal crRNA Acylation Strategy for Robust Photo-Initiated One-Pot CRISPR-Cas12a Nucleic Acid Diagnostics.

Spatiotemporal regulation of clustered regularly interspaced short palindromic repeats (CRISPR) system is attractive for precise gene editing and accurate molecular diagnosis. Although many efforts have been made, versatile and efficient strategies to control CRISPR system are still desirable. Here, we proposed a universal and accessible acylation strategy to regulate the CRISPR-Cas12a system by efficient acylation of 2'-hydroxyls (2'-OH) on crRNA strand with photolabile agents (PLGs). The introduction of PLGs confers efficient suppression of crRNA function and rapid restoration of CRISPR-Cas12a reaction upon short light exposure regardless of crRNA sequences. Based on this strategy, we constructed a universal PhotO-Initiated CRISPR-Cas12a system for Robust One-pot Testing (POIROT) platform integrated with recombinase polymerase amplification (RPA), which showed two orders of magnitude more sensitive than the conventional one-step assay and comparable to the two-step assay. For clinical sample testing, POIROT achieved high-efficiency detection performance comparable to the gold-standard quantitative PCR (qPCR) in sensitivity and specificity, but faster than the qPCR method. Overall, we believe the proposed strategy will promote the development of many other universal photo-controlled CRISPR technologies for one-pot assay, and even expand applications in the fields of controllable CRISPR-based genomic editing, disease therapy, and cell imaging.

Ecdysone-controlled nuclear receptor ERR regulates metabolic homeostasis in the disease vector mosquito Aedes aegypti.

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)-glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)-was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control.

Pt-Decorated Gold Nanoflares for High-Fidelity Phototheranostics: Reducing Side-Effects and Enhancing Cytotoxicity toward Target Cells.

Functionalized with the Au-S bond, gold nanoflares have emerged as promising candidates for theranostics. However, the presence of intracellular abundantly biothiols compromises the conventional Au-S bond, leading to the unintended release of cargoes and associated side-effects on non-target cells. Additionally, the hypoxic microenvironment in diseased regions limits treatment efficacy, especially in photodynamic therapy. To address these challenges, high-fidelity photodynamic nanoflares constructed on Pt-coated gold nanoparticles (Au@Pt PDNF) were communicated to avoid false-positive therapeutic signals and side-effects caused by biothiol perturbation. Compared with conventional photodynamic gold nanoflares (AuNP PDNF), the Au@Pt PDNF were selectively activated by cancer biomarkers and exhibited high-fidelity phototheranostics while reducing side-effects. Furthermore, the ultrathin Pt-shell catalysis was confirmed to generate oxygen which alleviated hypoxia-related photodynamic resistance and enhanced the antitumor effect. This design might open a new venue to advance theranostics performance and is adaptable to other theranostic nanomaterials by simply adding a Pt shell.

[Efficacy and Mechanism of Tetracycline Adsorption by Boron-doped Mesoporous Carbon].

Using coconut shell and boric acid as raw materials， a new boron-doped coconut shell mesoporous carbon material （B-CSC） was prepared using a simple one-step pyrolysis method for efficient adsorption and removal of tetracycline pollutants in water. The effects of pyrolysis temperature and boron-carbon mass ratio on the adsorption performance under key preparation conditions were systematically studied， and their microstructure and physicochemical properties were characterized using a specific surface area and pore size analyzer （BET）， field emission scanning electron microscopy （SEM）， X-ray photon spectroscopy （XPS）， Raman spectrometer （Raman）， and Zeta potentiometer （Zeta）. The effects of initial pH， different metal cations， and different background water quality conditions on the adsorption effect were systematically investigated. Combined with material characterization and correlation analysis， the enhanced adsorption mechanism was discussed and analyzed in depth. The results showed that one-step pyrolysis could incorporate boron into the surface and crystal lattice of coconut shell charcoal， resulting in a larger specific surface area and pore volume， and the main forms of boron introduced were H3BO3， B2O3， B， and B4C. The adsorption capacity of B-CSC to tetracycline reached 297.65 mg·g-1， which was 8.9 times that of the original coconut shell mesoporous carbon （CSC）. At the same time， the adsorption capacity of B-CSC for rhodamine B （RhB）， bisphenol A（BPA）， and methylene blue （MB）， common pollutants in aquatic environments， was as high as 372.65， 255.24， and 147.82 mg·g-1， respectively. The adsorption process of B-CSC to tetracycline was dominated by physicochemical interaction， mainly involving liquid film diffusion， surface adsorption， mesoporous and microporous diffusion， and active site adsorption， and H3BO3 was the main adsorption site. The adsorption strengthening mechanism mainly reduced the chemical inertness of the carbon network and enhanced its π-π interaction and hydrogen bonding with tetracycline molecules.

Strong Linearly Polarized Light Emission by Coupling Out-of-Plane Exciton to Anisotropic Gap Plasmon Nanocavity.

With exceptional quantum confinement, 2D monolayer semiconductors support a strong excitonic effect, making them an ideal platform for exploring light-matter interactions and as building blocks for novel optoelectronic devices. Different from the well-known in-plane excitons in transition metal dichalcogenides (TMD), the out-of-plane excitons in indium selenide (InSe) usually show weak emission, which limits their applications as light sources. Here, by embedding InSe in an anisotropic gap plasmon nanocavity, we have realized plasmon-enhanced linearly polarized photoluminescence with an anisotropic ratio up to ∼140, corresponding to degree of polarization (DoP) of ∼98.6%. Such polarization selectivity, originating from the polarization-dependent plasmonic enhancement supported by the "nanowire-on-mirror" nanocavity, can be well tuned by the InSe thickness. Moreover, we have also realized an InSe-based light-emitting diode with polarized electroluminescence. Our research highlights the role of excitonic dipole orientation in designing nanophotonic devices and paves the way for developing InSe-based optoelectronic devices with polarization control.

Intact lung tissue and bronchoalveolar lavage fluid are both suitable for the evaluation of murine lung microbiome in acute lung injury.

BACKGROUND: Accumulating clinical evidence suggests that lung microbiome is closely linked to the progression of pulmonary diseases; however, it is still controversial which specimen type is preferred for the evaluation of lung microbiome. METHODS AND RESULTS: To address this issue, we established a classical acute lung injury (ALI) mice model by intratracheal instillation of lipopolysaccharides (LPS). We found that the bacterial DNA obtained from the bronchoalveolar lavage fluid (BALF), intact lung tissue [Lung(i)], lung tissue after perfused [Lung(p)], and feces of one mouse were enough for 16S rRNA sequencing, except the BALF of mice treated with phosphate buffer saline (PBS), which might be due to the biomass of lung microbiome in the BALF were upregulated in the mice treated with LPS. Although the alpha diversity among the three specimens from lungs had minimal differences, Lung(p) had higher sample-to-sample variation compared with BALF and Lung(i). Consistently, PCoA analysis at phylum level indicated that BALF was similar to Lung(i), but not Lung(p), in the lungs of mice treated with LPS, suggesting that BALF and Lung(i) were suitable for the evaluation of lung microbiome in ALI. Importantly, Actinobacteria and Firmicutes were identified as the mostly changed phyla in the lungs and might be important factors involved in the gut-lung axis in ALI mice. Moreover, Actinobacteria and Proteobacteria might play indicative roles in the severity of lung injury. CONCLUSION: This study shows both Lung(i) and BALF are suitable for the evaluation of murine lung microbiome in ALI, and several bacterial phyla, such as Actinobacteria, may serve as potential biomarkers for the severity of ALI. Video Abstract.

A Very Deep Graph Convolutional Network for 13C NMR Chemical Shift Calculations with Density Functional Theory Level Performance for Structure Assignment.

Nuclear magnetic resonance (NMR) chemical shift calculations are powerful tools for structure elucidation and have been extensively employed in both natural product and synthetic chemistry. However, density functional theory (DFT) NMR chemical shift calculations are usually time-consuming, while fast data-driven methods often lack reliability, making it challenging to apply them to computationally intensive tasks with a high requirement on quality. Herein, we have constructed a 54-layer-deep graph convolutional network for 13C NMR chemical shift calculations, which achieved high accuracy with low time-cost and performed competitively with DFT NMR chemical shift calculations on structure assignment benchmarks. Our model utilizes a semiempirical method, GFN2-xTB, and is compatible with a broad variety of organic systems, including those composed of hundreds of atoms or elements ranging from H to Rn. We used this model to resolve the controversial J/K ring junction problem of maitotoxin, which is the largest whole molecule assigned by NMR calculations to date. This model has been developed into user-friendly software, providing a useful tool for routine rapid structure validation and assignation as well as a new approach to elucidate the large structures that were previously unsuitable for NMR calculations.

Semaglutide alleviates gut microbiota dysbiosis induced by a high-fat diet.

This study investigated the effects of semaglutide (Sema) on the gut microbiota of obese mice induced with high-fat diet (HFD). Male C57BL/6 J mice aged 6 weeks were enrolled and randomly distributed to four groups, which were provided with a normal control diet (NCD,NCD + Sema) and a 60% proportion of a high-fat diet (HFD,HFD + Sema), respectively. HFD was given for 10 weeks to develop an obesity model and the intervention was lasted for 18 days. The results showed semaglutide significantly reduced body weight gain, areas under the curve (AUC) of glucose tolerance test and insulin resistance test, as well as adipose tissue weight in mice. Semaglutide effectively reduced lipid deposition and lipid droplet formation in the liver of obese mice, and regulated the expression of genes related to abnormal blood glucose regulation. Additionally, semaglutide influenced the composition of gut microbiota, mitigating the microbial dysbiosis induced by a high-fat diet by impacting the diversity of the gut microbiota. After the high-fat diet intervention, certain strains such as Akkermansia, Faecalibaculum, and Allobaculum were significantly decreased, while Lachnospiraceae and Bacteroides were significantly increased. However, the application of semaglutide restored the lost flora and suppressed excessive bacterial abundance. Moreover, semaglutide increased the content of tight junction proteins and repaired the damage to intestinal barrier function caused by the high-fat diet intervention. Furthermore, correlation analysis revealed inverse relationship among Akkermansia levels and weight gain, blood glucose levels, and various obesity indicators. Correlation analysis also showed that Akkermansia level was negatively correlated with weight gain, blood glucose levels and a range of obesity indicators. This phenomenon may explain the anti-obesity effect of semaglutide, which is linked to alterations in gut microbiota, specifically an increase in the abundance of Akkermansia. In summary, our findings indicate that semaglutide has the potential to alleviate gut microbiota dysbiosis, and the gut microbiota may contribute to the obesity-related effects of this drug.

Sesquiterpenes and α-pyrones from an endophytic fungus Xylaria curta YSJ-5.

Chemical investigation of the culture extract of an endophyte Xylaria curta YSJ-5 from Alpinia zerumbet (Pers.) Burtt. et Smith resulted in the isolation of eight previously undescribed compounds including five eremophilane sesquiterpenes xylarcurenes A-E, one norsesquiterpene xylarcurene F, and two α-pyrone derivatives xylarpyrones A-B together with eight known related derivatives. Their chemical structures were extensively established based on the 1D- and 2D-NMR spectroscopic analysis, modified Mosher's method, electronic circular dichroism calculations, single-crystal X-ray diffraction experiments, and the comparison with previous literature data. All these compounds were tested for in vitro cytotoxic, anti-inflammatory, α-glucosidase inhibitory, and antibacterial activities. As a result, 6-pentyl-4-methoxy-pyran-2-one was disclosed to display significant antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with minimal inhibitory concentration value of 6.3 µg/mL.

The accumulation of modular serine protease mediated by a novel circRNA sponging miRNA increases Aedes aegypti immunity to fungus.

BACKGROUND: Mosquitoes transmit many infectious diseases that affect human health. The fungus Beauveria bassiana is a biological pesticide that is pathogenic to mosquitoes but harmless to the environment. RESULTS: We found a microRNA (miRNA) that can modulate the antifungal immunity of Aedes aegypti by inhibiting its cognate serine protease. Fungal infection can induce the expression of modular serine protease (ModSP), and ModSP knockdown mosquitoes were more sensitive to B. bassiana infection. The novel miRNA-novel-53 is linked to antifungal immune response and was greatly diminished in infected mosquitoes. The miRNA-novel-53 could bind to the coding sequences of ModSP and impede its expression. Double fluorescence in situ hybridization (FISH) showed that this inhibition occurred in the cytoplasm. The amount of miRNA-novel-53 increased after miRNA agomir injection. This resulted in a significant decrease in ModSP transcript and a significant increase in mortality after fungal infection. An opposite effect was produced after antagomir injection. The miRNA-novel-53 was also knocked out using CRISPR-Cas9, which increased mosquito resistance to the fungus B. bassiana. Moreover, mosquito novel-circ-930 can affect ModSP mRNA by interacting with miRNA-novel-53 during transfection with siRNA or overexpression plasmid. CONCLUSIONS: Novel-circ-930 affects the expression level of ModSP by a novel-circ-930/miRNA-novel-53/ModSP mechanism to modulate antifungal immunity, revealing new information on innate immunity in insects.

Leucine aminopeptidase1 controls egg deposition and hatchability in male Aedes aegypti mosquitoes.

Aedes aegypti are vectors for several arboviruses infecting hundreds of millions of people annually. Controlling mosquito populations by regulating their reproduction is a potential strategy to minimize viral transmission in the absence of effective antiviral therapies or vaccines. Here, we demonstrate that leucine aminopeptidase1 (LAP1), detected by a SWATH-MS-based proteomic screen of female spermathecae, is a crucial determinant in mosquito population expansion. Mitochondrial defects and aberrant autophagy of sperm in LAP1 mutant males (LAP1-/-), prepared using CRISPR/Cas9 system, result in a reduction of reproduction in wild-type females that mated with them. The fitness of LAP1-/- males is strong enough to efficiently transmit genetic changes to mosquito populations through a low number of hatchable offspring. Thus, LAP1-/- males represent an opportunity to suppress mosquito populations and further studies should be undertaken to characterize LAP1's suitability for gene drive usage.