HLA-B*35:01-mediated activation of emodin-specific T cells contributes to Polygonum multiflorum thunb. -induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: HLA-B*35:01 has been identified as a risk allele for Polygonum multiflorum Thunb.-induced liver injury (PMLI). However, the immune mechanism underlying HLA-B*35:01-mediated PMLI remains unknown. AIM OF THE STUDY: To characterize the immune mechanism of HLA-B*35:01-mediated PMLI. MATERIALS AND METHODS: Components of P. multiflorum (PM) bound to the HLA-B*35:01 molecule was screened by immunoaffinity chromatography. Both wild-type mice and HLA-B*35:01 transgenic (TG) mice were treated with emodin. The levels of transaminases, histological changes and T-cell response were assessed. Splenocytes from emodin-treated mice were isolated and cultured in vitro. Phenotypes and functions of T cells were characterized upon drug restimulation using flow cytometry or ELISA. Emodin-pulsed antigen-presenting cells (APCs) or glutaraldehyde-fixed APCs were co-cultured with splenocytes from emodin-treated transgenic mice to detect their effect on T-cell activation. RESULTS: Emodin, the main component of PM, could non-covalently bind to the HLA-B*35:01-peptide complexes. TG mice were more sensitive to emodin-induced immune hepatic injury, as manifested by elevated aminotransferase levels, infiltration of inflammatory cells, increased percentage of CD8+T cells and release of effector molecules in the liver. However, these effects were not observed in wild-type mice. An increase in percentage of T cells and the levels of interferon-γ, granzyme B, and perforin was detected in emodin-restimulated splenocytes from TG mice. Anti-HLA-I antibodies inhibited the secretion of these effector molecules induced by emodin. Mechanistically, emodin-pulsed APCs failed to stimulate T cells, while fixed APCs in the presence of emodin could elicit the secretion of T cell effector molecules. CONCLUSION: The HLA-B*35:01-mediated CD8+ T cell reaction to emodin through the P-I mechanism may contribute to P. multiflorum-induced liver injury.

Continuous chiral separation process for high-speed countercurrent chromatography established and scaled up: A case of Voriconazole enantioseparation.

An efficient method for the continuous separation of Voriconazole enantiomers was developed using sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) as a chiral selector in high-speed countercurrent chromatography (HSCCC) with different types. The separation was performed using a two-phase solvent system consisting of n-hexane/ethyl acetate/100 mmol/L phosphate buffer solution (pH = 3.0, containing 50 mmol/L SBE-ß-CD) (1.5:0.5:2, v/v/v). A fast and predictable scale-up process was achieved using an analytical DE HSCCC instrument. The optimized parameters were subsequently applied to a preparative Tauto HSCCC instrument, resulting in consistent separation time and enantiomeric purity, with throughput boosted by a remarkable 11-fold. Preparative HSCCC successfully separated 506 mg of the racemate, delivering enantiomers exceeding 99% purity as confirmed by high-performance liquid chromatography analysis. This investigation presents an effective methodology for forecasting the HSCCC scale-up process and attaining continuous separation of chiral drugs.

Cuproptosis in cancers: Function and implications from bench to bedside.

Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.

Inhalation of ferrate-disinfected Escherichia coli caused lung injury via endotoxin-induced oxidative stress and inflammation response.

Ferrate (Fe(VI)) is an environmentally friendly disinfectant that is widely used to eradicate microbes in reclaimed water. However, the potential health risks associated with inhalation of Fe(VI)-treated bacteria-laden reclaimed water remains uncertain. We aimed to explore the inhalation hazards and potential mechanisms of K2FeO4-treated Escherichia coli (E. coli, ATCC 25922). Our findings indicated that Fe(VI) disinfection induced a dose- and time-dependent E. coli inactivation, accompanied by a rapid release of the bacterial endotoxin, lipopolysaccharide (LPS). Scanning electron microscopy (SEM) observations indicate that Fe(VI)-induced endotoxin production consists of at least two stages: initial binding of endotoxin to bacteria and subsequent dissociation to release free endotoxin. Furthermore, Fe(VI) disinfection was not able to effectively eliminate pure or E. coli-derived endotoxins. The E. coli strain used in this study lacks lung infection capability, thus the inhalation of bacteria alone failed to induce severe lung injury. However, mice inhaled exposure to Fe(VI)-treated E. coli showed severe impairment of lung structure and function. Moreover, we observed an accumulation of neutrophil/macrophage recruitment, cell apoptosis, and ROS generation in the lung tissue of mice subjected to Fe(VI)-treated E. coli. RNA sequencing (RNA-seq) and PCR results revealed that genes involved with endotoxin stimuli, cell apoptosis, antioxidant defence, inflammation response, chemokines and their receptors were upregulated in response to Fe(VI)-treated E. coli. In conclusion, Fe(VI) is ineffective in eliminating endotoxins and can trigger secondary hazards owing to endotoxin release from inactivated bacteria. Aerosol exposure to Fe(VI)-treated E. coli causes considerable damage to lung tissue by inducing oxidative stress and inflammatory responses.

The Role of Traditional Chinese Medicines in the Treatment of Osteoporosis.

Osteoporosis (OP) represents a substantial public health issue and is associated with increasing rates of morbidity and mortality. It is characterized by reduced bone mineral density, deterioration of bone tissue quality, disruption of the microarchitecture of bones, and compromised bone strength. These changes may be attributed to the following factors: intercellular communication between osteoblasts and osteoclasts; imbalanced bone remodeling; imbalances between osteogenesis and adipogenesis; imbalances in hormonal regulation; angiogenesis; chronic inflammation; oxidative stress; and intestinal microbiota imbalances. Treating a single aspect of the disease is insufficient to address its multifaceted nature. In recent decades, traditional Chinese medicine (TCM) has shown great potential in the treatment of OP, and the therapeutic effects of Chinese patent drugs and Chinese medicinal herbs have been scientifically proven. TCMs, which contain multiple components, can target the diverse pathogeneses of OP through a multitargeted approach. Herbs such as XLGB, JTG, GSB, Yinyanghuo, Gusuibu, Buguzhi, and Nvzhenzi are among the TCMs that can be used to treat OP and have demonstrated promising effects in this context. They exert their therapeutic effects by targeting various pathways involved in bone metabolism. These TCMs balance the activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells), and they exhibit anti-inflammatory, immunomodulatory, anti-oxidative, and estrogen-like functions. These multifaceted mechanisms underlie the efficacy of these herbs in the management and treatment of OP. Herein, we examine the efficacy of various Chinese herbs and Chinese patent drugs in treating OP by reviewing previous clinical trials and basic experiments, and we examine the potential mechanism of these therapies to provide evidence regarding the use of TCM for treating OP.

Causal inference and mechanism for unraveling the removal of four pesticides from lettuce (Lactuca sativa L.) via ultrasonic processing and various immersion solutions.

This study explores the reduction of carbamates (CAs) and pyrethroids (PYs) - commonly used pesticides - in lettuce using various immersion solutions and ultrasonic processing. It also examines the role of machine learning and molecular docking in understanding the mechanisms of pesticide reduction. The results revealed that the highest reduction of both CAs and PYs exceeded 80 % on lettuce leaves. In most samples, the reduction increased with the power of ultrasonic processing and processing time. The results of machine learning models (XGBoost and SHAP) showed that during the immersion cleaning of CAs and PYs, as well as during both immersion cleaning and ultrasonic processing of CAs + PYs, the reduction was most influenced by the initial pesticide levels and immersion time. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of lettuce's wax layer identified 24 compounds, including fatty alcohols, fatty acids, fatty acid esters, and triterpenoids. Despite the absence of active sites, the lipophilic nature of long-chain aliphatic compounds aids in pesticide binding, while triterpenoids form strong hydrogen bonds with pesticides, indicating a robust adsorption on the lettuce surface. This study aims to offer insights into the efficient removal of chemical pesticide residues from fruits and vegetables, addressing critical concerns for food safety and human health.

Imaging the dynamics of messenger RNA with a bright and stable green fluorescent RNA.

Fluorescent RNAs (FRs) provide an attractive approach to visualizing RNAs in live cells. Although the color palette of FRs has been greatly expanded recently, a green FR with high cellular brightness and photostability is still highly desired. Here we develop a fluorogenic RNA aptamer, termed Okra, that can bind and activate the fluorophore ligand ACE to emit bright green fluorescence. Okra has an order of magnitude enhanced cellular brightness than currently available green FRs, allowing the robust imaging of messenger RNA in both live bacterial and mammalian cells. We further demonstrate the usefulness of Okra for time-resolved measurements of ACTB mRNA trafficking to stress granules, as well as live-cell dual-color superresolution imaging of RNA in combination with Pepper620, revealing nonuniform and distinct distributions of different RNAs throughout the granules. The favorable properties of Okra make it a versatile tool for the study of RNA dynamics and subcellular localization.

Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis.

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 µM and 6.51 µM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.

Comparative effectiveness and safety of six antibiotics in treating MRSA infections: A network meta-analysis.

OBJECTIVES: This study conducted a network meta-analysis comparing linezolid, teicoplanin, daptomycin, tigecycline, and ceftaroline fosamil with vancomycin for treating MRSA-related diseases, addressing the lack of comprehensive evaluations in existing research on antibiotic therapy for MRSA infections. METHODS: We systematically searched databases including PubMed, Embase, Web of Science, the Cochrane Librar up to August 22, 2023. All eligible randomized controlled trials of the six antibiotics were included in the NMA, and their effectiveness and safety were compared across various MRSA-related diseases. Categorical data were used for the odds ratio (OR), and continuous data were used for mean difference (SMD). The surface under the cumulative ranking (SUCRA) was employed to evaluate the incidence rate. RESULTS: According to SUCRA results, daptomycin was the most effective treatment (73.0%) in bloodstream infections. In pulmonary infections and skin and soft tissue infections, linezolid out-performed other antibiotics in effectiveness rate (90.6% and 86.3%), microbial killing rate (93.3% and 93.1%). Vancomycin showed lower adverse reactions than teicoplanin, with less hepatotoxicity compared to linezolid and tigecycline. Linezolid had higher thrombocytopenia risk but lower nephrotoxicity risk than others. Vancomycin was less effective in microbial killing rates than linezolid across various infections. CONCLUSION: The present research suggests that in pulmonary infections and skin and soft tissue infections, linezolid may be a better option for treating MRSA-related diseases. However, caution is warranted due to the association of linezolid with thrombocytopenia. TRIAL REGISTRATION: Our study protocol was registered with the International Prospective Register of SystematicReviews (PROSPERO); Registration number: CRD42024535142.

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification.

BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.

Research on the impact mechanism of changes in the production of medical solid waste in China before and after COVID-19.

The changes of medical solid waste (MSW) output in recent years have had a significant impact on the spread of the virus. There is a high-risk transmission of MSW in various stages such as storage, transportation, and treatment during the COVID-19. To cope with the risks brought by the epidemic, normalized prevention consumes a large amount of protective clothing, medical masks, goggles, packaging bags, and other related medical supplies. There is a significant uncertainty in the amount of MSW output that poses a risk of COVID-19 infection in the event of an emergency, which increases the difficulty of collecting and handling epidemic prevention MSW. The analysis of MSW data from 2000 to 2022 found a stable growth trend before 2019. However, the MSW data was a sudden increase trend from 2020 to 2022, and the COVID-19 in China was characterized by an initial stage, an outbreak stage, and a stable growth stage. The range of MSW output during the epidemic was (1.19-1.75) × 106 t a-1. The amount of MSW was approximately 1.19 × 106 t a-1 during the normalized epidemic period, and its treatment cost was as high as 3.57 × 109 yuan (RMB)·a-1. The distribution of MSW output was uneven due to factors such as climate conditions, population data, and local economy. This study has important reference value for epidemic medical material reserves and MSW treatment.

High expression of SRSF1 facilitates osteosarcoma progression and unveils its potential mechanisms.

BACKGROUND: SRSF1, a member of Serine/Arginine-Rich Splicing Factors (SRSFs), has been observed to significantly influence cancer progression. However, the precise role of SRSF1 in osteosarcoma (OS) remains unclear. This study aims to investigate the functions of SRSF1 and its underlying mechanism in OS. METHODS: SRSF1 expression level in OS was evaluated on the TCGA dataset, TAGET-OS database. qRT-PCR and Western blotting were employed to assess SRSF1 expression in human OS cell lines as well as the interfered ectopic expression states. The effect of SRSF1 on cell migration, invasion, proliferation, and apoptosis of OS cells were measured by transwell assay and flow cytometry. RNA sequence and bioinformatic analyses were conducted to elucidate the targeted genes, relevant biological pathways, and alternative splicing (AS) events regulated by SRSF1. RESULTS: SRSF1 expression was consistently upregulated in both OS samples and OS cell lines. Diminishing SRSF1 resulted in reduced proliferation, migration, and invasion and increased apoptosis in OS cells while overexpressing SRSF1 led to enhanced growth, migration, invasion, and decreased apoptosis. Mechanistically, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA) revealed that the biological functions of SRSF1 were closely associated with the dysregulation of the protein targeting processes, location of the cytosolic ribosome, extracellular matrix (ECM), and proteinaceous extracellular matrix, along with the PI3K-AKT pathway, Wnt pathway, and HIPPO pathway. Transcriptome analysis identified AS events modulated by SRSF1, especially (Skipped Exon) SE events and (Mutually exclusive Exons) MXE events, revealing potential roles of targeted molecules in mRNA surveillance, RNA degradation, and RNA transport during OS development. qRT-PCR confirmed that SRSF1 knockdown resulted in the occurrence of alternative splicing of SRRM2, DMKN, and SCAT1 in OS. CONCLUSIONS: Our results highlight the oncogenic role of high SRSF1 expression in promoting OS progression, and further explore the potential mechanisms of action. The significant involvement of SRSF1 in OS development suggests its potential utility as a therapeutic target in OS.

Aflatoxin B1 induces ROS-dependent mitophagy by modulating the PINK1/Parkin pathway in HepG2 cells.

Aflatoxin B1 (AFB1) is extremely harmful to both humans and animals. Mitophagy is a selective process of self-elimination and has an important role in controlling mitochondrial quality. The present study aimed to investigate the effect of reactive oxygen species (ROS) accumulation on AFB1-induced mitophagy in HepG2 cells to provide a new perspective from which to design novel therapeutic strategies to treat AFB1 poisoning. ROS release was induced in HepG2 cells with AFB1 (10 µmol/L). Cell autophagy activity, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels, Parkin translocation and both the transcription and expression of mitophagy-related proteins were measured when N-acetyl-L-cysteine (NAC) partially decreased the ROS level, while the knockdown of nuclear factor erythroid 2-related factor 2 (Nrf2) resulted in a large accumulation of ROS. The results reveal that NAC pretreatment ameliorated the decline in both the MMP and the ATP levels while also activating phosphoglycerate mutase 5 (PGAM5)-PTEN-induced kinase 1 (PINK1)/Parkin, while the Nrf2 knockdown group exhibited the opposite trend. These results suggest that AFB1-induced mitophagy in HepG2 cells depends on ROS, and proper ROS activates mitophagy to play a protective role.

Dual-comb spectroscopy of ammonia formation in non-thermal plasmas.

Plasma-activated chemical transformations promise the efficient synthesis of salient chemical products. However, the reaction pathways that lead to desirable products are often unknown, and key quantum-state-resolved information regarding the involved molecular species is lacking. Here we use quantum cascade laser dual-comb spectroscopy (QCL-DCS) to probe plasma-activated NH3 generation with rotational and vibrational state resolution, quantifying state-specific number densities via broadband spectral analysis. The measurements reveal unique translational, rotational and vibrational temperatures for NH3 products, indicative of a highly reactive, non-thermal environment. Ultimately, we postulate on the energy transfer mechanisms that explain trends in temperatures and number densities observed for NH3 generated in low-pressure nitrogen-hydrogen (N2-H2) plasmas.

A Luciferase Immunosorbent Assay Based on Attachment Glycoprotein for the Rapid and Easy Detection of Nipah Virus IgG Antibodies.

Nipah virus (NiV) is a virulent zoonotic disease whose natural host is the fruit bat (Pteropus medius), which can coexist with and transmit the virus. Due to its high pathogenicity, wide host range, and pandemic potential, establishing a sensitive, specific, and rapid diagnostic method for NiV is key to preventing and controlling its spread and any outbreaks. Here, we established a luciferase immunosorbent assay (LISA) based on the NiV attachment glycoprotein (G) to detect NiV-specific immunoglobulin G by expressing a fusion protein of nanoluciferase (NanoLuc) and the target antigen. Sensitivity analysis was performed and compared to an indirect enzyme-linked immunosorbent assay (ELISA), and specificity and cross-reactivity assessments were performed using NiV-positive horse serum and Ebola virus-, Crimean-Congo hemorrhagic fever virus-, and West Nile virus-positive horse sera. The optimal structural domain for NiV detection was located within amino acids 176-602 of the NiV G protein head domain. Moreover, the LISA showed at least fourfold more sensitivity than the indirect ELISA, and the cross-reactivity results suggested that the LISA had good specificity and was capable of detecting NiV-specific immunoglobulin G in both mouse and horse serum. In conclusion, the establishment of a rapid, simple NiV LISA using the G protein head domain provides a resource for NiV monitoring.

Casein-quaternary chitosan complexes induced the soft assembly of egg white peptide and curcumin for ulcerative colitis alleviation.

Soft assembly of peptide and curcumin (Cur) molecules enables functional integration by finding dynamic equilibrium states through non-covalent interactions. Herein, we developed two soft assembly systems, curcumin-egg white peptides (Cur-EWP) aggregations (AGs) and Cur-EWP-casein-quaternary chitosan (Cur-EWP-CA-QC) nanoparticles (NPs) to comparatively investigate their therapeutic effects on ulcerative colitis in mice and elucidate their underlying mechanism. Results revealed that Cur-EWP AGs, despite gastrointestinal tract instability, exhibited a propensity for swift accumulation within the colorectal region, enriching mucus-associated and short-chain fatty acid (SCAF)-producing bacteria, restoring the intestinal barrier damage. Whereas, Cur-EWP-CA-QC NPs, benefiting from their remarkable stability and exceptional mucosal adsorption properties, not only enhanced permeability of Cur and EWP in the small intestine to activate the immune response and boost tight junction protein expression but also, in their unabsorbed state, regulated the intestinal flora, exerting potent anti-inflammatory activity. Soft assembly of peptides and hydrophobic nutraceuticals could synergize biological activities to modulate chronic diseases.

Oral Synergism of Egg-White-Derived Peptides (EWDP) and Curcumin for Colitis Mitigation via Polysaccharide/Cyclodextrin Metal-Organic Framework-Based Assemblies.

Recently, oral deliverable strategies of multiple nutraceuticals for ulcerative colitis (UC) mitigation have attracted increasing attention. This study aimed to fabricate facile oral assemblies loaded with egg-white-derived peptides (EWDP) and curcumin based on carboxymethyl chitosan (CMCS) and an γ-cyclodextrin metal-organic framework (MOF). Herein, outer CMCS could coassemble with EWDP (both nutraceuticals and building blocks) into cobweb-like fibrils to promote bridging with inner MOF via coordinative noncovalent interactions (hydrogen bonding, hydrophobic interaction, and electrostatic interaction). Compared with conventional γ-cyclodextrin/MOF-based composites, the above coassembly could also endow the biocompatible assemblies with superior nanoscale colloidal properties, processing applicability (curcumin storage stability, bioaccessibility, and aqueous solubility), and bioactivity. Moreover, the oral synergism of EWDP and curcumin (initially nonsynergistic) for UC mitigation was achieved by alleviating inflammatory damage and gut microbiota imbalance. Overall, the novel assemblies could be a promising amplifier and platform to facilitate oral formulations of various nutraceuticals for food processing and UC relief.

Fates and models for exposure pathways of pyrethroid pesticide residues: A review.

Pyrethroids (PYs) are widely applied pesticides whose residues pose potential health risks. This review describes current knowledge on PY chemical properties, usage patterns, environmental and food contamination, and human exposure models. It evaluates life cycle assessment (LCA), chemical alternatives assessment (CAA), and high-throughput screening (HTS) as tools for pesticide policy. Despite efforts to mitigate PY presence, their pervasive residues in the environment and food persist. And the highest concentrations ranged from 54,360 to 80,500 ng/L in water samples from agricultural fields. Food processing techniques variably reduce PY levels, yet no method guarantees complete elimination. This review provides insights into the fates and exposure pathways of PY residues in agriculture and food, and highlights the necessity for improved PY management and alternative practices to safeguard health and environment.

Structural basis for dimerization of a paramyxovirus polymerase complex.

The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L-P complex with the connector domain (CD') of a second L built, while reconstruction of the rest of the second L-P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique ß-strand latch. Furthermore, we report the structural basis of L-L dimerization, with CD' located at the putative template entry of the adjoining L. Disruption of the L-L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.

Linking Periodontitis with Inflammatory Bowel Disease through the Oral-Gut Axis: The Potential Role of Porphyromonas gingivalis.

Periodontitis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases that are characterized by abnormal host immune responses and microbiota dysbiosis. Emerging evidence implies potential associations between periodontitis and IBD. Porphyromonas gingivalis (P. gingivalis), a primary cause of periodontitis, is thought to play a role in the development of IBD through the oral-gut disease axis. However, the precise mechanisms of its involvement remain enigmatic. In this narrative review, we begin with a discussion of the bidirectional relationship between periodontitis and IBD and the involvement of P. gingivalis in each of the two diseases. Further, we summarize the possible routes by which P. gingivalis links periodontitis and IBD through the oral-gut axis, as well as the underlying mechanisms of its involvement in the pathogenesis of IBD. Collectively, P. gingivalis participates in the progression of IBD through gut dysbiosis, impairment of the intestinal barrier, release of inflammatory mediators, and disturbance of the immune response. The above findings may provide new insights for exploring novel biomarkers and potential therapeutic approaches for IBD.