Early identification of stroke through deep learning with multi-modal human speech and movement data.

JOURNAL/nrgr/04.03/01300535-202501000-00031/figure1/v/2024-05-14T021156Z/r/image-tiff Early identification and treatment of stroke can greatly improve patient outcomes and quality of life. Although clinical tests such as the Cincinnati Pre-hospital Stroke Scale (CPSS) and the Face Arm Speech Test (FAST) are commonly used for stroke screening, accurate administration is dependent on specialized training. In this study, we proposed a novel multimodal deep learning approach, based on the FAST, for assessing suspected stroke patients exhibiting symptoms such as limb weakness, facial paresis, and speech disorders in acute settings. We collected a dataset comprising videos and audio recordings of emergency room patients performing designated limb movements, facial expressions, and speech tests based on the FAST. We compared the constructed deep learning model, which was designed to process multi-modal datasets, with six prior models that achieved good action classification performance, including the I3D, SlowFast, X3D, TPN, TimeSformer, and MViT. We found that the findings of our deep learning model had a higher clinical value compared with the other approaches. Moreover, the multi-modal model outperformed its single-module variants, highlighting the benefit of utilizing multiple types of patient data, such as action videos and speech audio. These results indicate that a multi-modal deep learning model combined with the FAST could greatly improve the accuracy and sensitivity of early stroke identification of stroke, thus providing a practical and powerful tool for assessing stroke patients in an emergency clinical setting.

OpenDock: A pytorch-based open-source framework for protein-ligand docking and modelling.

MOTIVATION: Molecular docking is an invaluable computational tool with broad applications in computer-aided drug design and enzyme engineering. However, current molecular docking tools are typically implemented in languages such as C ++ for calculation speed, which lack flexibility and user-friendliness for further development. Moreover, validating the effectiveness of external scoring functions for molecular docking and screening within these frameworks is challenging, and implementing more efficient sampling strategies is not straightforward. RESULTS: To address these limitations, we have developed an open-source molecular docking framework, OpenDock, based on Python and PyTorch. This framework supports the integration of multiple scoring functions; some can be utilized during molecular docking and pose optimization, while others can be employed for post-processing scoring. In terms of sampling, the current version of this framework supports simulated annealing and Monte Carlo optimization. Additionally, it can be extended to include methods such as genetic algorithms and particle swarm optimization for sampling docking poses and protein side chain orientations. Distance constraints are also implemented to enable covalent docking, restricted docking or distance map constraints guided pose sampling. Overall, this framework serves as a valuable tool in drug design and enzyme engineering, offering significant flexibility for most protein-ligand modelling tasks. AVAILABILITY AND IMPLEMENTATION: OpenDock is publicly available at: Https://github.com/guyuehuo/opendock.

Non-invasive positive pressure ventilation can reduce perioperative mortality in acute aortic dissection patients with hypoxemia.

Background: Hypoxemia is a common critical respiratory complication in patients with acute aortic dissection (AAD) before operation and results in adverse outcomes. This study aimed to identify the optimal oxygenation treatment for AAD patients with hypoxemia in the emergency department (ED). Methods: This was a retrospective, observational, cohort study. We retrospectively collected data from 187 adult patients with AAD and hypoxemia who had been admitted to our ED. All patients were divided into nasal cannula group (n=91), Venturi mask group (n=60), and non-invasive positive pressure ventilation (NIPPV) group (n=36). The primary outcome was overall mortality in ED; the secondary outcomes were preoperative intubation rate and postoperative mortality, length of intensive care unit (ICU) stay, length of hospital stay, and length of intubation. Results: Among all patients, those who received NIPPV treatment showed the lowest ED intubation rate (2.78%, P=0.004), shortest postoperative length of ICU stay (median 2.31, P<0.001), postoperative length of intubation (median 25.10, P<0.001), and post-operative length of hospital stay (median 21.00, P<0.001). Kaplan-Meier analysis showed the highest 3-day survival (log-rank 7.387, P=0.03) and 5-day survival (log-rank 14.710, P=0.001) in the NIPPV group. After adjustment, NIPPV therapy was independently associated with the reduced 3-day [adjusted hazard ratio (HR) 0.102, 95% confidence interval (CI): 0.013-0.791, P=0.03] and 5-day (adjusted HR 0.057, 95% CI: 0.008-0.427, P=0.005) mortality in ED. Conclusions: Early utilization of NIPPV in AAD patients with hypoxemia in the ED can effectively decrease pre-operative intubation rate and perioperative mortality, and improve postoperative outcomes.

Pentachlorophenol impairs the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Due to past massive usage and persistent nature, pentachlorophenol (PCP) residues are prevalent in environments, posing a potential threat to various organisms such as sessile filter-feeding bivalves. Although humoral immunity and its crosstalk with cellular one are crucial for the maintaining of robust antimicrobic capability, little is known about the impacts of PCP on these critical processes in bivalve mollusks. In this study, pathogenic bacterial challenge and plasma antimicrobic capability assays were carried out to assess the toxic effects of PCP on the immunity of a common bivalve species, blood clam (Tegillarca granosa). Moreover, the impacts of PCP-exposure on the capabilities of pathogen recognition, hemocyte recruitment, and pathogen degradation were analyzed as well. Furthermore, the activation status of downstream immune-related signalling pathways upon PCP exposure was also assessed. Data obtained illustrated that 28-day treatment with environmentally realistic levels of PCP resulted in evident declines in the survival rates of blood clam upon Vibrio challenge along with markedly weakened plasma antimicrobic capability. Additionally, the levels of lectin and peptidoglycan-recognition proteins (PGRPs) in plasma as well as the expression of pattern recognition receptors (PRRs) in hemocytes were found to be significantly inhibited by PCP-exposure. Moreover, along with the downregulation of immune-related signalling pathway, markedly fewer chemokines (interleukin 8 (IL-8), IL-17, and tumor necrosis factor α (TNF-α)) in plasma and significantly suppressed chemotactic activity of hemocytes were also observed in PCP-exposed blood clams. Furthermore, compared to that of the control, blood clams treated with PCP had markedly lower levels of antimicrobic active substances, lysozyme (LZM) and antimicrobial peptides (AMP), in their plasma. In general, the results of this study suggest that PCP exposure could significantly impair the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Current Advances of CO Sensing Based on Low Dimensional Materials.

Carbon monoxide (CO) is a harmful gas with significant impacts on human health and the environment. Its timely detection, especially in the event of thermal runaway in automotive lithium batteries, is crucial to prevent casualties. This paper reviews the progress in the development of efficient, sensitive, and reliable CO sensors, focusing on electrochemical, optical, and resistive sensing materials. Low-dimensional materials have a large specific surface area, providing an abundant number of active sites, which has drawn extensive attention from researchers. According to the different sensor signals, we categorized these sensors into electrical and optical signal sensors. We hope that by systematically introducing the sensing mechanism and sensing performance of these two kinds of sensors, appropriate CO sensors can be developed in different application scenarios so as to realize early warning and monitoring to the maximum extent, reduce industrial losses, and ensure the life and health of personnel.

ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.

Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated ß-galactosidase (SA-ß-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.

Olfactory toxicity of tetrabromobisphenol A to the goldfish Carassius auratus.

Tetrabromobisphenol A (TBBPA) is one of the most extensively used brominated flame retardants and its increasing use in consumer products has raised concerns about its ecotoxicity. Given the ubiquity of TBBPA in aquatic environments, it is inevitable that these chemicals will enter the olfactory chambers of fish via water currents. Nevertheless, the olfactory toxicity of TBBPA to aquatic organisms and the underlying toxic mechanisms have yet to be elucidated. Therefore, we investigated the olfactory toxicity of TBBPA in the goldfish Carassius auratus, a model organism widely used in sensory biology. Results showed that exposure to TBBPA resulted in abnormal olfactory-mediated behaviors and diminished electro-olfactogram (EOG) responses, indicating reduced olfactory acuity. To uncover the underlying mechanisms of action, we examined the structural integrity of the olfactory epithelium (OE), expression levels of olfactory G protein-coupled receptors (GPCRs), enzymatic activities of ion transporters, and fluctuations in neurotransmitters. Additionally, comparative transcriptomic analysis was employed to investigate the molecular mechanisms further. Our study demonstrates for the first time that TBBPA at environmentally relevant levels can adversely affect the olfactory sensitivity of aquatic organisms by interfering with the transmission of aqueous stimuli to olfactory receptors, impeding the binding of odorants to their receptors, disrupting the olfactory signal transduction pathway, and ultimately affecting the generation of action potentials.

A simple model to predict early recurrence of hepatocellular carcinoma after liver resection.

PURPOSE: Multiple studies have reported models for predicting early recurrence of hepatocellular carcinoma (HCC) after liver resection (LR). However, these models are too complex to use in daily practice. We aimed to develop a simple model. METHOD: We enrolled 1133 patients with newly diagnosed HCC undergoing LR. The Kaplan - Meier method and log-rank test were used for survival analysis and Cox proportional hazards analysis to identify prognostic factors associated with early recurrence (i.e., recurrence within two years after LR). RESULTS: Early recurrence was identified in 403 (35.1%) patients. In multivariate analysis, alpha-fetoprotein (AFP) 20-399 vs. < 20 ng/ml (HR = 1.282 [95% confidence interval = 1.002-1.639]; p = 0.048); AFP ≥ 400 vs. < 20 ng/ml (HR = 1.755 [1.382-2.229]; p < 0.001); 7th edition American Joint Committee on Cancer (AJCC) stage 2 vs. 1 (HR = 1.958 [1.505-2.547]; p < 0.001); AJCC stage 3 vs. 1 (HR = 4.099 [3.043-5.520]; p < 0.001); and pathology-defined cirrhosis (HR = 1.46 [1.200-1.775]; p < 0.001) were associated with early recurrence. We constructed a predictive model with these variables, which provided three risk strata for recurrence-free survival (RFS): low risk, intermediate risk, and high risk, with two-year RFS of 79%, 57%, and 35%, respectively (p < 0.001). CONCLUSION: We developed a simple model to predict early recurrence risk for patients undergoing LR for HCC.

Structure-dependent destructive adsorption of organophosphate flame retardants on lipid membranes.

The widespread use of organophosphate flame retardants (OPFRs), a serious type of pervasive environmental contaminants, has led to a global concern regarding their diverse toxicities to living beings. Using a combination of experimental and theoretical approaches, we systematically studied the adsorption, accumulation, and influence of a series of OPFRs on the lipid membranes of bacteria and cells. Our results revealed that OPFRs can aggregate in lipid membranes, leading to the destruction of membrane integrity. During this process, the molecular structure of the OPFRs is a dominant factor that significantly influences the strength of their interaction with the lipid membrane, resulting in varying degrees of biotoxicity. Triphenyl phosphate (TPHP), owing to its large molecular size and strong hydrophobicity, causes severe membrane disruption through the formation of nanoclusters. The corresponding severe toxicity originates from the phase transitions of the lipid membranes. In contrast, smaller OPFRs such as triethyl phosphate (TEP) and tris(2-chloroethyl) phosphate (TCEP) have weaker hydrophobicity and induce minimal membrane disturbance and ineffective damage. In vivo, gavage of TPHP induced more severe barrier damage and inflammatory infiltration in mice than TEP or TCEP, confirming the higher toxicity of TPHP. Overall, our study elucidates the structure-dependent adsorption of OPFRs onto lipid membranes, highlighting their destructive interactions with membranes as the origin of OPFR toxicity.

Ciprofloxacin Accelerates Angiotensin-II-Induced Vascular Smooth Muscle Cells Senescence Through Modulating AMPK/ROS pathway in Aortic Aneurysm and Dissection.

Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-ß-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-ß-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-ß-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.

Exploring the correlation between paediatric narcolepsy and serum neurofilament light chain levels: An exploratory study.

BACKGROUND: The study seeks to assess serum neurofilament light chain (NfL) levels in paediatric narcolepsy-diagnosed patients. Moreover, it aims to explore the correlation between NfL levels and the severity of narcolepsy symptoms, sleep quality, and manifestations of anxiety and depression. METHODS: This retrospective analysis included 98 paediatric narcolepsy cases and 100 controls matched for age and gender. The study focused on comparing serum NfL levels across these groups. Severity of EDS in patients was measured with the Epworth Sleepiness Scale (ESS). Moreover, the Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Rating Scale-24 (HAMD-24), and Hamilton Anxiety Scale-14 (HAMA-14) were used to assess narcolepsy symptoms, sleep quality, and psychological conditions. RESULTS: Patients with paediatric narcolepsy had significantly higher serum NfL levels than controls (P < 0.05). Additionally, a positive correlation was found between serum NfL levels and ESS scores (P < 0.001). An independent link between serum NfL and paediatric narcolepsy was established via multiple logistic regression (OR = 0.943, 95 % CI = 0.921-0.993, P = 0.004). Moreover, serum NfL's diagnostic precision for paediatric narcolepsy was evident from the ROC curve area of 0.938 (95 % CI: 0.86-0.99, P < 0.001). CONCLUSION: The study implies a positive correlation between increased serum NfL levels and the severity of paediatric narcolepsy. Nevertheless, the causative link between serum NfL levels and paediatric narcolepsy remains uncertain, highlighting the need for larger sample sizes and well-structured cohort studies to offer more definitive.

ThermoLink: Bridging disulfide bonds and enzyme thermostability through database construction and machine learning prediction.

Disulfide bonds, covalently formed by sulfur atoms in cysteine residues, play a crucial role in protein folding and structure stability. Considering their significance, artificial disulfide bonds are often introduced to enhance protein thermostability. Although an increasing number of tools can assist with this task, significant amounts of time and resources are often wasted owing to inadequate consideration. To enhance the accuracy and efficiency of designing disulfide bonds for protein thermostability improvement, we initially collected disulfide bond and protein thermostability data from extensive literature sources. Thereafter, we extracted various sequence- and structure-based features and constructed machine-learning models to predict whether disulfide bonds can improve protein thermostability. Among all models, the neighborhood context model based on the Adaboost-DT algorithm performed the best, yielding "area under the receiver operating characteristic curve" and accuracy scores of 0.773 and 0.714, respectively. Furthermore, we also found AlphaFold2 to exhibit high superiority in predicting disulfide bonds, and to some extent, the coevolutionary relationship between residue pairs potentially guided artificial disulfide bond design. Moreover, several mutants of imine reductase 89 (IR89) with artificially designed thermostable disulfide bonds were experimentally proven to be considerably efficient for substrate catalysis. The SS-bond data have been integrated into an online server, namely, ThermoLink, available at guolab.mpu.edu.mo/thermoLink.

Schisandrin inhibits VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway.

Abnormal proliferation, migration, and foam cell formation of Vascular smooth muscle cells (VSMCs) each play a role in the development of atherosclerosis (AS). Schisandrin (Sch) is the active lignan ingredient with broad-spectrum pharmacological effects. However, the role of Sch in the AS process is not clear. Therefore, this study was proposed to explore the therapeutic effect and potential mechanism of Sch on VSMCs. Ox-LDL was selected to create an atherosclerosis injury environment for VSMCs and macrophages. The MTT assay, Oil red O staining, wound healing, transwell experiments and ELISA were used to investigate the phenotype effects of Sch. Network pharmacology, molecular docking, flow cytometry, and western blot were used to investigate the underlying mechanisms of Sch on AS progression. Our findings implied that Sch treatment inhibited the proliferation and migration of VSMCs, and suppressed the ROS production and inflammatory cytokines up-regulation of VSMCs and macrophages. Moreover, Sch reduced lipid uptake and foam cell formation through downregulating LOX-1. Mechanistically, we found that Sch can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2, and arrest cell cycle in GO/G1 phase. In summary, Sch can inhibit VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway. Sch may serve as a potential drug for patients with AS.

Computed tomography (CT) quantitative assessment of single lobe emphysema correlates with chronic obstructive pulmonary disease (COPD) severity: a cross-sectional study with retrospective data collection.

Background: In the past, many researchers have studied the correlation between quantitative parameters of computed tomography (CT) and parameters of pulmonary function test (PFT) in patients with chronic obstructive pulmonary disease (COPD) with good results. Most of these studies have focused on the whole-lung level. In this study, we analyzed the biphasic CT lung volume parameters and the percentage of emphysema volume in different lobes of the lungs of patients with different grades of COPD and assessed their relationship with different lung function indices. Methods: We retrospectively collected patients who underwent PFTs at The First Affiliated Hospital of Guangzhou Medical University from 1 July 2019 to 27 January 2020, and underwent chest respiratory dual-phase CT scans within 1 week, including 112 non-COPD patients and 297 COPD patients. We quantified the biphasic CT lung volume parameters and the percentage of emphysema volume in different lobes using a pulmonary image analysis tool. One-way analysis of variance (ANOVA) and Kruskal-Wallis H method were used to compare the quantitative CT parameters of each lung lobe in different groups. The correlation between quantitative CT parameters of different lung lobes and lung function indices was assessed using multiple linear regression. Results: Among the 3 biphasic CT lung volume parameters, only volume change/inspiratory lung volume (∆LV/LVin) in the non-COPD control, mildly to moderately severe, and severe to extremely severe groups had statistical differences in each lobe level (all P<0.05). Correlation was significant between LVin and different lung function indices and between low attenuation areas percent below the threshold of -950 in the inspiratory phase [low attenuation area below -950 in the inspiratory phase (%LAA-950in)] and lung function indices in the left lower lobe (all P<0.05). There was statistically significant correlation between expiratory lung volume and ∆LV/LVin and lung function indices in the right lower lung (all P≤0.001). In the remaining lobes, LVin, expiratory lung volume, ∆LV/LVin, and %LAA-950in correlated with only some of the lung function indices. Conclusions: The percentage of emphysema volume did not differ between lobes in the non-COPD control and severe to extremely severe COPD populations. LVin and %LAA-950in in the left upper lobe, expiratory lung volume and ∆LV/LVin in the right lower lobe were more reflective of the changes in lung function indices of the patients, whereas the correlation of the 3 biphasic CT lung volume parameters and the percentage of emphysema volume in the upper lobes of both lungs and the right middle lung with lung function indices was unclear.

Risk Factors, Pathogens, and Outcomes of Ventilator-Associated Pneumonia in Non-Cardiac Surgical Patients: A Retrospective Analysis.

Ventilator-associated pneumonia (VAP) is a critical hospital-acquired infection following non-cardiac surgeries, leading to poor outcomes. This study identifies VAP risk factors in non-cardiac surgical patients and determines the causative pathogens. A retrospective analysis with 1:4 propensity-score matching was conducted on patients in a surgical intensive care unit (ICU) from 2010 to 2020 at a private tertiary medical center. Among 99 VAP patients, the mortality rate was 64.7%. VAP risk factors included prolonged mechanical ventilation (odds ratio [OR] 6.435; p < 0.001), repeat intubation (OR 6.438; p < 0.001), lower oxygenation levels upon ICU admission (OR 0.950; p < 0.001), and undergoing gastrointestinal surgery (OR 2.257; p = 0.021). The 30-day mortality risk factors in the VAP group were late-onset VAP (OR 3.450; p = 0.022), inappropriate antibiotic treatment (OR 4.083; p = 0.041), and undergoing gastrointestinal surgeries (OR 4.776; p = 0.019). Nearly half of the Gram-negative infections were resistant strains, and a third were polymicrobial infections. Non-cardiac surgical patients with VAP face adverse hospital outcomes. Identifying high-risk patients and understanding VAP's resistant and microbial nature are crucial for appropriate treatment and improved health outcomes.

Clusterin attenuates blood-brain barrier damage and cognitive impairment by inhibiting astrocyte aging in mice with sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, however, its exact mechanism remains unknown. This study aimed to evaluate whether clusterin is essential to the development of SAE during the aging process of astrocytes. In the study, septic mice were established with cecal ligation and puncture (CLP) and lipopolysaccharides were applied to astrocytes in vitro. Evan's blue dye was used in vivo to show blood-brain barrier (BBB) permeability. A morris water maze test was conducted to assess cognitive functions of the mice. Clusterin-knockout mice were used to examine the effect of clusterin on sepsis. The astrocytes were transfected with lentivirus expressing clusterin cDNA for clusterin overexpression or pYr-LV-clusterin small hairpin RNA for clusterin knockdown in vitro . The expression of clusterin, p-p53, p21, GDNF, and iNOS was detected. he CLP mice exhibited a higher clusterin expression in hippocampus tissue, aging astrocytes, lower GDNF expression and higher iNOS expression, accompanied with BBB damage and cognitive deficiency. Following clusterin knockout, this pathological process was further enhanced. In vitro , following lipopolysaccharides treatment, astrocytes exhibited increased clusterin, p-p53, p21, iNOS and decreased GDNF. Following clusterin knockdown, the cells exhibited a further increase in p-p53, p21, and iNOS and decrease in GDNF. Clusterin overexpression, however, helped inhibit astrocytes aging and neuroinflammation evidenced by decreased p-p53, p21, iNOS and increased GDNF. The present study has revealed that clusterin may exert its neuroprotective effect by preventing aging in astrocytes, suppressing the secretion of iNOS and promoting GNDF release.

Fully Flexible Molecular Alignment Enables Accurate Ligand Structure Modeling.

Accurate protein-ligand binding poses are the prerequisites of structure-based binding affinity prediction and provide the structural basis for in-depth lead optimization in small molecule drug design. However, it is challenging to provide reasonable predictions of binding poses for different molecules due to the complexity and diversity of the chemical space of small molecules. Similarity-based molecular alignment techniques can effectively narrow the search range, as structurally similar molecules are likely to have similar binding modes, with higher similarity usually correlated to higher success rates. However, molecular similarity is not consistently high because molecules often require changes to achieve specific purposes, leading to reduced alignment precision. To address this issue, we propose a new alignment method─Z-align. This method uses topological structural information as a criterion for evaluating similarity, reducing the reliance on molecular fingerprint similarity. Our method has achieved success rates significantly higher than those of other methods at moderate levels of similarity. Additionally, our approach can comprehensively and flexibly optimize bond lengths and angles of molecules, maintaining a high accuracy even when dealing with larger molecules. Consequently, our proposed solution helps in achieving more accurate binding poses in protein-ligand docking problems, facilitating the development of small molecule drugs. Z-align is freely available as a web server at https://cloud.zelixir.com/zalign/home.

ß-Cyclodextrin and Hyaluronic Acid-Modified Targeted Nanodelivery System for Atherosclerosis Prevention.

Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.

Micro/nanoplastics impair the feeding of goldfish by disrupting the complicated peripheral and central regulation of appetite.

The ubiquitous presence of plastic particles in water bodies poses a potential threat to aquatic species. Although numerous adverse effects of microplastics (MPs) and nanoplastics (NPs) have been documented, their effects on fish feeding, one of the most important behaviors of animals, are far from being fully understood. In this study, the effects of MPs and NPs (at environmentally realistic levels) on fish food consumption and feeding behavior were assessed using goldfish (Carassius auratus) and polystyrene (PS) particles as representatives. In addition, to reveal the potential mechanisms, the effects of MPs and NPs on peripheral and central regulation of appetite were evaluated by examining appetite-regulation related intestinal, serous, and hypothalamic parameters. The results obtained indicated that the 28-day MP- and NP-exposure significantly impaired goldfish feeding by disrupting peripheral and central appetite regulation. Based on differences observed in their effects on the abovementioned behavioral, histological, and physiological parameters, MPs and NPs may interfere with appetite regulation in a size-dependent manner. Blocking the gastrointestinal tract and causing histopathological and functional damage to inner organs may be the main routes through which MPs and NPs disrupt appetite regulation. Our findings suggested that plastic particles exposure may have far-reaching effects on fish species through impaired feeding, which warrants further attention.

(-)-Epicatechin gallate prevented atherosclerosis by reducing abnormal proliferation of VSMCs and oxidative stress of AML 12 cells.

(-)-Epicatechin gallate (ECG) is beneficial to the treatment of cardiovascular diseases (CVDs), especially atherosclerosis (AS) through antioxidant stress, but there is a lack of detailed mechanism research. In this study, the therapeutic target of ECG was determined by crossing the drug target and disease target of CVDs and AS. The combination ability of ECG with important targets was verified by Discovery Studio software. The abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by Ang-II and the oxidative damage of AML 12 induced by H2O2 were established to verify the reliability of ECG intervention on the target protein. A total of 120 ECG targets for the treatment of CVDs-AS were predicted by network pharmacology. The results of molecular docking showed that ECG has strong binding force with VEGFA, MMP-9, CASP3 and MMP-2 domains. In vitro experiments confirmed that ECG significantly reduced the expression of VEGFA, MMP-9, CASP3 and MMP-2 in Ang-II-induced VSMCs, and also blocked the abnormal proliferation, oxidative stress and inflammatory reaction of VSMCs by inhibiting the phosphorylation of PI3K signaling pathway. At the same time, ECG also interfered with H2O2-induced oxidative damage of AML 12 cells, decreased the expression of ROS and MDA and cell foaming, and increased the activities of antioxidant enzymes such as SOD, thus playing a protective role.