Central nervous system disturbances by thiamethoxam in Japanese quail (Coturnix japonica): In vivo, ex vivo, and in silico study.

The neurotoxic effects of neonicotinoids (NEOs) have been widely reported in relation to the poisoning of wild birds, yet the underlying molecular mechanism has remained elusive. This study employed Japanese quails (Coturnix japonica) and primary quail embryonic neurons as in vivo and ex vivo models, respectively, to investigate the neurotoxic effects and mechanism of thiamethoxam (TMX), a representative neonicotinoid insecticide, at environmentally relevant concentrations. Following a 28-day exposure to TMX, metabolomic analysis of quail brain revealed TMX-induced changes in glutamatergic, GABA-ergic, and dopaminergic function. Subsequent ex vivo and in silico experimentation revealed that the activation of nicotinic acetylcholine receptors and calcium signaling, induced by clothianidin (CLO), the primary metabolite of TMX, served as upstream events for the alterations in neurotransmitter synthesis, metabolism, release, and uptake. Our findings propose that the disruption of the central nervous system, caused by environmentally significant concentrations of NEOs, may account for the avian poisoning events induced by NEOs.

Identification, molecular profiling and immune functions of cystatin M in silver pomfret (Pampus argenteus).

Cystatins play an important role in various physiological and pathological processes of organisms, including regulating protein metabolism, antigen processing, inflammatory response, nutritional disorders, and controlling enzyme activity. However, research on immunity functions of fish cystatin M is limited. In this study, Pampus argenteus cystatin M (Pacystatin M) was identified and analyzed. Its amino acid sequence was highly conserved in teleosts, and included the conserved cystatin cysteine protease inhibitor motifs. Pacystatin M was highly expressed in the gill, spleen, and intestine, whereas the expression levels of liver and kidney were lower. Furthermore, Nocardia seriolae infection up-regulated the expression of Pacystatin M in the kidney, spleen and liver, with particularly significant expression observed in the liver on day 15 post-infection. Functional analysis indicated that the recombinant Pacystatin M showed increasing inhibitory activity against papain within a certain concentration range, suggesting that the inhibition was likely competitive. Additionally, Pacystatin M demonstrated the ability to inhibit bacterial growth and high thermal stability. These results suggested that Pacystatin M might be involved in the immune response to microbial invasion and provided new reference addressing disease issues in the large-scale farming of silver pomfret.

Capturing RAS oligomerization on a membrane.

RAS GTPases associate with the biological membrane where they function as molecular switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize on membranes, and disrupting these assemblies represents an alternative therapeutic strategy. However, conflicting reports on RAS assemblies, ranging in size from dimers to nanoclusters, have brought to the fore key questions regarding the stoichiometry and parameters that influence oligomerization. Here, we probe three isoforms of RAS [Kirsten Rat Sarcoma viral oncogene (KRAS), Harvey Rat Sarcoma viral oncogene (HRAS), and Neuroblastoma oncogene (NRAS)] directly from membranes using mass spectrometry. We show that KRAS on membranes in the inactive state (GDP-bound) is monomeric but forms dimers in the active state (GTP-bound). We demonstrate that the small molecule BI2852 can induce dimerization of KRAS, whereas the binding of effector proteins disrupts dimerization. We also show that RAS dimerization is dependent on lipid composition and reveal that oligomerization of NRAS is regulated by palmitoylation. By monitoring the intrinsic GTPase activity of RAS, we capture the emergence of a dimer containing either mixed nucleotides or GDP on membranes. We find that the interaction of RAS with the catalytic domain of Son of Sevenless (SOScat) is influenced by membrane composition. We also capture the activation and monomer to dimer conversion of KRAS by SOScat. These results not only reveal the stoichiometry of RAS assemblies on membranes but also uncover the impact of critical factors on oligomerization, encompassing regulation by nucleotides, lipids, and palmitoylation.

Safety and efficacy of bilateral superselective adrenal arterial embolization for treatment of idiopathic hyperaldosteronism: a prospective single-center study.

OBJECTIVE: This study aimed to assess the efficacy and safety of bilateral superselective adrenal arterial embolization (SAAE) in patients with bilateral idiopathic hyperaldosteronism (IHA), a subtype of PA. METHODS: Ninety-eight patients with bilateral IHA underwent bilateral SAAE between August 2022 and August 2023. Sixty-eight patients were followed up for up to 12 months. The study outcomes were evaluated using the criteria provided by the Primary Aldosteronism Surgical Outcome (PASO) guidelines. RESULTS: The mean reductions in systolic and diastolic blood pressure were 27.4 ± 21.3 mmHg and 23.1 ± 17.4 mmHg, respectively (p < 0.001). The rates of clinical success and biochemical success after adrenal artery ablation were 63.2% (43/68) and 39.7% (27/68), respectively. Overall, there were significant reductions in daily defined doses (DDD), aldosterone/renin ratio (ARR), and plasma aldosterone levels (p < 0.001). Plasma renin levels increased by a mean value of 10.4 ± 39.0 pg/mL (p = 0.049), and potassium levels increased by 0.40 ± 0.63 mmol/L (p < 0.001). No significant adverse events were reported during SAAE or the follow-up period of up to one year. Additionally, no abnormalities were detected by adrenal 68Ga-Pentixafor PET/CT scans before or after SAAE. CONCLUSION: Bilateral SAAE appears to lead to sustained improvements in blood pressure and biochemical parameters in patients with bilateral PA, with minimal adverse effects. This suggests that bilateral SAAE could serve as an effective alternative approach for treating bilateral IHA, potentially curing this condition.

Efficient adsorption of cationic dyes by a novel honeycomb-like porous hydrogel with ultrahigh mechanical property.

The optimization of hydrogel structure is crucial for adsorption capacity, mechanical stability, and reusability. Herein, a chitosan and laponite-XLS co-doped poly(acrylic acid-co-acrylamide) hydrogel (CXAA) with honeycomb-like porous structures is synthesized by cooperative cross-linking of 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) and laponite-XLS in reticular frameworks of acrylic acid (AAc) and acrylamide (AM). The CXAA exhibits extraordinary mechanical performances including tough tensile strength (3.36 MPa) and elasticity (2756 %), which facilitates recycling in practical adsorption treatment and broadens potential applications. Since the regular porous structures can fully expose numerous adsorption sites and electronegative natures within polymer materials, CXAA displays efficient and selective adsorption properties for cationic dyes like methylene blue (MB) and malachite green (MG) from mixed pollutants and can reach record-high values (MB = 6886 mg g-1, MG = 11,381 mg g-1) compared with previously reported adsorbents. Therefore, CXAA exhibits promising potential for separating cationic and anionic dyes by their charge disparities. Mechanism studies show that the synergistic effects of HACC, laponite-XLS, and functional groups in monomers promote highly efficient adsorption. Besides, the adsorption capacity of CXAA remains stable even after undergoing five cycles of regeneration. The results confirm that CXAA is a promising adsorbent for effectively removing organic dyes in wastewater.

STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy.

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

KIS, a target of SOX4, regulates the ID1-mediated enhancement of ß-catenin to facilitate lung adenocarcinoma cell proliferation and metastasis.

PURPOSE: Kinase interacting with stathmin (KIS) is a serine/threonine kinase involved in RNA processing and protein phosphorylation. Increasing evidence has suggested its involvement in cancer progression. The aim of this study was to investigate the role of KIS in the development of lung adenocarcinoma (LUAD). Dual luciferase assay was used to explore the relationship between KIS and SOX4, and its effect on ID1/ß-catenin pathway. METHODS: Real-time qPCR and western blot were used to assess the levels of KIS and other factors. Cell proliferation, migration, and invasion were monitored, and xenograft animal model were established to investigate the biological functions of KIS in vitro and in vivo. RESULTS: In the present study, KIS was found to be highly expressed in LUAD tissues and cell lines. KIS accelerated the proliferative, migratory and invasive abilities of LUAD cells in vitro, and promoted the growth of LUAD in a mouse tumor xenograft model in vivo. Mechanistically, KIS activated the ß-catenin signaling pathway by modulating the inhibitor of DNA binding 1 (ID1) and was transcriptionally regulated by SOX4 in LUAD cells. CONCLUSION: KIS, a target of SOX4, regulates the ID1-mediated enhancement of ß-catenin to facilitate LUAD cell invasion and metastasis.

H-Net: Heterogeneous Neural Network for Multi-Classification of Neuropsychiatric Disorders.

Clinical studies have proved that both structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) are implicitly associated with neuropsychiatric disorders (NDs), and integrating multi-modal to the binary classification of NDs has been thoroughly explored. However, accurately classifying multiple classes of NDs remains a challenge due to the complexity of disease subclass. In our study, we develop a heterogeneous neural network (H-Net) that integrates sMRI and fMRI modes for classifying multi-class NDs. To account for the differences between the two modes, H-Net adopts a heterogeneous neural network strategy to extract information from each mode. Specifically, H-Net includes an multi-layer perceptron based (MLP-based) encoder, a graph attention network based (GAT-based) encoder, and a cross-modality transformer block. The MLP-based and GAT-based encoders extract semantic features from sMRI and features from fMRI, respectively, while the cross-modality transformer block models the attention of two types of features. In H-Net, the proposed MLP-mixer block and cross-modality alignment are powerful tools for improving the multi-classification performance of NDs. H-Net is validate on the public dataset (CNP), where H-Net achieves 90% classification accuracy in diagnosing multi-class NDs. Furthermore, we demonstrate the complementarity of the two MRI modalities in improving the identification of multi-class NDs. Both visual and statistical analyses show the differences between ND subclasses.

Functional responses of two species of predatory mites (Acari: Phytoseiidae) to eggs and first-instar nymphs of Bactericera Gobica Logniova (Homoptera: Psyllidae).

The goji berry psyllid, Bactericera gobica Logniova (Homoptera: Psyllidae), is one of the most important pests on goji berry plants (Lycium barbarum L.), whose fruits are widely used in traditional Chinese medicine and food. However, chemical control is still the predominant control strategy of this pest. Recently, two species of predatory mites, Neoseiulus setarius Ma, Meng & Fan and Neoseiulus barkeri Hughes were found to be associated with B. gobica in China. To assess their predation potential against B. gobica, the functional responses of these two phytoseiid species feeding on different densities (2, 4, 8, 12, 16, 24 and 32 individuals) of B. gobica eggs and 1st instar nymphs were compared at a temperature of 25ºC ± 1º C. Logistic regression analysis revealed that both predatory mite species exhibited type Holling-II functional responses on eggs and 1st instar nymphs of B. gobica, with the predation number increased for both predators as the density of prey increased. Overall, N. setarius consumed more prey compared to N. barkeri across all levels of prey densities. Meanwhile, the highest attack rate (α = 0.0283), the lowest handling time (Th = 1.1324 h prey- 1), and the highest estimated maximum predation rate (T/Th = 21.19 prey day- 1) were all observed for N. setarius fed with 1st instar nymphs of B. gobica. These findings suggest that it is worthy considering utilizing N. setarius and N. barkeri as candidate biocontrol agents of B. gobica, with N. setarius appearing to be a more effective predator than N. barkeri.

Effect of Yogurt Intake Frequency on Blood Pressure: A Cross-Sectional Study.

Yogurt consumption is a significant factor in reducing the risk of hypertension and preventing cardiovascular diseases. Although increasing evidence has emerged regarding the potential benefits of probiotics in hypertension, there is a lack of large, cross-sectional studies assessing the association between yogurt intake and blood pressure parameters. We aimed to evaluate the association between yogurt intake frequency and blood pressure. A cross-sectional study was designed using data from the National Health and Nutrition Examination Survey from 2003 to 2004 and 2005 to 2006. We included 3, 068 adults with blood pressure data and yogurt intake data. Multivariate regression analyses revealed significant inverse associations between yogurt and systolic blood pressure (P < 0.05), diastolic blood pressure (P < 0.05), and mean arterial pressure (P < 0.05) in nonhypertensive participants (n = 1 822) but not in hypertensive participants (n = 1 246). Furthermore, a high frequency of yogurt intake prevented hypertension; however, no additional antihypertensive effects were observed in patients already diagnosed with hypertension.

Rapid Sample Pretreatment Facilitating SERS Detection of Trace Weak Organic Acids/Bases in Complex Matrices.

Fast and efficient sample pretreatment is the prerequisite for realizing surface-enhanced Raman spectroscopy (SERS) detection of trace targets in complex matrices, which is still a big issue for the practical application of SERS. Recently, we have proposed a highly performed liquid-liquid extraction (LLE)-back extraction (BE) for weak acids/bases extraction in drinking water and beverage samples. However, the performance efficiency decreased drastically on facing matrices like food and biological blood. Based on the total interaction energies among target, interferent, and extractant molecules, solid-phase extraction (SPE) with a higher selectivity was introduced in advance of LLE-BE, which enabled the sensitive (µg L-1 level) and rapid (within 10 min) SERS detection of both koumine (a weak base) and celastrol (a weak acid) in different food and biological samples. Further, the high SERS sensitivity was determined unmanned by Vis-CAD (a machine learning algorithm), instead of the highly demanded expert recognition. The generality of SPE-LLE-BE for various weak acids/bases (2 < pKa < 12), accompanied by the high efficiency, easy operation, and low cost, offers SERS as a powerful on-site and efficient inspection tool in food safety and forensics.

A ubiquitous tire rubber additive induced serious eye injury in zebrafish (Danio rerio).

Previous studies have indicated that tire wear particles (TWPs) leachate exposure induced serious eye injury in fish through inhibiting the thyroid peroxidase (TPO) enzyme activity. However, the main TPO inhibitors in the leachate were still unknown. In this study, we identified 2-Mercaptobenzothiazole (MBT) as the potential TPO inhibitor in the TWPs leachate through references search, model prediction based on Danish QSAR and ToxCast database, molecular docking, and in vivo assay. We further explored the toxic mechanism of MBT under environmentally relevant concentrations. The decreased eye size of zebrafish larvae was mainly caused by the decreased lens diameter and cell density in the inner nuclear layer (INL) and outer nuclear layer (ONL) of the retina. Transcriptomics analysis demonstrated that the eye phototransduction function was significantly suppressed by inhibiting the photoreceptor cell proliferation process after MBT exposure. The altered opsin gene expression and decreased opsin protein levels were induced by weakening thyroid hormone signaling after MBT treatment. These results were comparable to those obtained from a known TPO inhibitor, methimazole. This study has identified MBT as the primary TPO inhibitor responsible for inducing eye impairment in zebrafish larvae exposed to TWPs leachate. It is crucial for reducing the toxicity of TWPs leachate in fish.

A multi-scale feature fusion neural network for multi-class disease classification on the maize leaf images.

Maize is a globally important cereal crop, however, maize leaf disease is one of the most common and devastating diseases that afflict it. Artificial intelligence methods face challenges in identifying and classifying maize leaf diseases due to variations in image quality, similarity among diseases, disease severity, limited dataset availability, and limited interpretability. To address these challenges, we propose a residual-based multi-scale network (MResNet) for classifying multi-type maize leaf diseases from maize images. MResNet consists of two residual subnets with different scales, enabling the model to detect diseases in maize leaf images at different scales. We further utilize a hybrid feature weight optimization method to optimize and fuse the feature mapping weights of two subnets. We validate MResNet on a maize leaf diseases dataset. MResNet achieves 97.45% accuracy. The performance of MResNet surpasses other state-of-the-art methods. Various experiments and two additional datasets confirm the generalization performance of our model. Furthermore, thermodynamic diagram analysis increases the interpretability of the model. This study provides technical support for the disease classification of agricultural plants.

Absorption, distribution, metabolism, and elimination of epoxiconazole enantiomers in lizards (Eremias argus).

Epoxiconazole (EPX) is a world widely used chiral triazole fungicide in the agriculture field. The excessive application of this triazole may cause damage to lizards. However, limited information is known about the toxicokinetics of EPX on lizards. Our study aimed to investigate the enantioselective absorption, distribution, metabolism, and elimination (ADME) of EPX in lizards following low and high dose exposure (10 and 100 mg kg-1 bodyweitht (bw)). The results demonstrated that (+)-EPX was easier absorbed than (-)-EPX in lizard plasma. Both (+)-EPX and (-)-EPX were detected in the liver, gonad, kidney, skin, brain, and intestine, with (+)-EPX preferentially distributed in these tissues. The elimination of (-)-EPX was faster than that of (+)-EPX in lizard liver and kidney in the high dose groups. Chiral conversion was found between EPX enantiomers in lizard skin. Simultaneously, five metabolites including M2, M4, M10, M18 and M19 were detected in lizard liver and kidney after EPX enantiomers exposure. The relative concentrations of M2, M4, and M10 were higher in the liver and kidney of (-)-EPX groups than those produced from (+)-EPX groups. The metabolic enzymes CYP3A4 and SULT1A1 primarily mediated enantioselective metabolism of EPX. The conclusions drawn from this study significantly enhance our understanding of the enantioselective behaviors of chiral triazole fungicides in reptiles, offering essential guidance for assessing the risks associated with different enantiomers of triazole fungicides.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

BACKGROUND: Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs. METHODS: haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model. RESULTS: The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors. CONCLUSION: haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

Baicalein exerts beneficial effects in lipopolysaccharide-induced pulmonary inflammation by modulating macrophage polarization and inhibiting pyroptosis.

The disruption of the immune system by viral attack is a major influencing factor in the lethality of COVID-19. Baicalein is one of the key effective compounds against COVID-19. The molecular mechanisms regarding the anti-inflammatory properties of Baicalein are still unclear. In this study, we established LPS-induced mice to elucidate the role of Baicalein in the treatment of acute lung injury (ALI) and its potential molecular mechanisms. In vivo experiments showed that Baicalein could significantly ameliorate LPS-induced acute lung injury and reduce proteinous edema in lung tissue. In addition, Baicalein inhibited M1 macrophage polarization, promote M2 macrophage polarization, and regulate inflammatory responses. Furthermore, Baicalein could inhibit the expression of protein molecules associated with pyroptosis and mitigate the lung tissue injury. In summary, we revealed the therapeutic effects of Baicalein in acute lung injury, providing the theoretical basis for its clinical application.

"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

Research Progress on Cognitive Frailty in Older Adults with Chronic Kidney Disease.

BACKGROUND: As the medical challenges posed by the ageing population become increasingly severe, the proportion of older people among patients with chronic kidney disease (CKD) is increasing every year. SUMMARY: The prevalence of frailty in patients with CKD is significantly higher than that in the general population, and older patients are also a high-risk group for frailty and cognitive impairment. Cognitive frailty, as an important subtype of frailty, is a syndrome characterised by cognitive dysfunction caused by physiological factors, excluding Alzheimer's disease and other types of dementia. It is characterised by the coexistence of physical frailty and cognitive impairment. Previous studies have mainly focused on cognitive impairment, and there is limited research on cognitive frailty, particularly in older patients with CKD. KEY MESSAGES: This article provides a comprehensive review of the concept, epidemiology, screening methods, prevention, and treatment measures and possible pathogenesis of cognitive frailty in patients with CKD.