Identification of genomic alteration and prognosis using pathomics-based artificial intelligence in oral leukoplakia and head and neck squamous cell carcinoma: A multicenter experimental study.

BACKGROUND: Loss of chromosome 9p is an important biomarker in the malignant transformation of oral leukoplakia (OLK) to head and neck squamous cell carcinoma (HNSCC), and is associated with the prognosis of HNSCC patients. However, various challenges have prevented 9p loss from being assessed in clinical practice. The objective of this study was to develop a pathomics-based artificial intelligence (AI) model for the rapid and cost-effective prediction of 9p loss (9PLP). MATERIALS AND METHODS: 333 OLK cases were retrospectively collected with hematoxylin and eosin (H&E)-stained whole slide images and genomic alteration data from multicenter cohorts to develop the genomic alteration prediction AI model. They were divided into a training dataset (n=217), a validation dataset (n=93), and an external testing dataset (n=23). The latest Transformer method and XGBoost algorithm were combined to develop the 9PLP model. The AI model was further applied and validated in two multicenter HNSCC datasets (n=42, n=365, respectively). Moreover, the combination of 9PLP with clinicopathological parameters was used to develop a nomogram model for assessing HNSCC patient prognosis. RESULTS: 9PLP could predict chromosome 9p loss rapidly and effectively using both OLK and HNSCC images, with the area under the curve achieving 0.890 and 0.825, respectively. Furthermore, the predictive model showed high accuracy in HNSCC patient prognosis assessment (the area under the curve was 0.739 for 1-year prediction, 0.705 for 3-year prediction, and 0.691 for 5-year prediction). CONCLUSION: To the best of our knowledge, this study developed the first genomic alteration prediction deep learning model in OLK and HNSCC. This novel AI model could predict 9p loss and assess patient prognosis by identifying pathomics features in H&E-stained images with good performance. In the future, the 9PLP model may potentially contribute to better clinical management of OLK and HNSCC.

CD24-Targeted NIR-II Fluorescence Imaging Enables Early Detection of Colorectal Neoplasia.

Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting specific molecular characteristics of lesions. CD24 is upregulated during the adenoma-to-CRC transition, providing a potential target for FMI. Here, we developed a second near-infrared window (NIR-II) fluorescent probe with a high affinity for CD24 and evaluated its efficacy and targeting ability in cellular models, murine models, and clinical samples of CRC. CD24 expression was elevated in 76% of adenomas and 80% of CRCs. In a colitis-associated cancer mouse model, NIR-II imaging with the CD24-targeted probe achieved a significantly higher tumor-to-background ratio compared to conventional NIR-I imaging. The probe demonstrated exceptional sensitivity (92%) and specificity (92%) for detecting CRC, including small lesions less than 1 mm in size. This led to the identification of precancerous lesions missed by white-light detection and lesions missed by NIR-I imaging. Moreover, ex vivo human tissue incubation with the probe supported the potential for intraprocedural lesion identification via topical probe application during colonoscopy. In conclusion, this study successfully demonstrates the potential of CD24-targeted NIR-II imaging for identifying colorectal neoplasia, highlighting its significance for early CRC detection in the gastrointestinal tract.

GGC repeat expansions in NOTCH2NLC cause uN2CpolyG cerebral amyloid angiopathy.

The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. H&E staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.

Restriction Spectrum Imaging and Diffusion Kurtosis Imaging for Assessing Proliferation Status in Rectal Carcinoma.

OBJECTIVES: To investigate the application of the three-compartment restriction spectrum imaging (RSI) model, diffusion kurtosis imaging (DKI), and diffusion-weighted imaging (DWI) in predicting Ki-67 status in rectal carcinoma. METHODS: A total of 80 rectal carcinoma patients, including 47 high-proliferation (Ki-67 > 50%) cases and 33 low-proliferation (Ki-67 ≤ 50%) cases, underwent pelvic MRI were enrolled. Parameters derived from RSI (f1, f2, and f3), DKI (MD and MK), and DWI (ADC) were calculated and compared between the two groups. Logistic regression (LR) analysis was conducted to identify independent predictors and assess combined diagnosis. Area under the receiver operating characteristic curve (AUC), DeLong analysis, and calibration curve analyses were performed to evaluate diagnostic performance. RESULTS: The patients with high-proliferation rectal carcinoma exhibited significantly higher f1 and MK values and significantly lower ADC, MD, f2, and f3 values than those with low-proliferation rectal carcinoma (P < 0.05). LR analysis showed that MD, MK, and f2 were independent predictors for Ki-67 status in rectal carcinoma. Moreover, the combination of these three parameters achieved an optimal diagnostic efficacy (AUC = 0.877, sensitivity = 80.85%, specificity = 84.85%) that was significantly better than that obtained using ADC (AUC = 0.783, Z = 2.347, P = 0.019), f2 (AUC = 0.732, Z = 2.762, P = 0.006), and f3 (AUC = 0.700, Z = 3.071, P = 0.002). The combined diagnosis also showed good performance (AUC = 0.859) in the internal validation analysis based on 1000 bootstrap samples, while the calibration curve demonstrated that the combined diagnosis provided good stability. CONCLUSION: RSI, DKI, and DWI can effectively differentiate between patients with high- and low-proliferation rectal carcinoma. Furthermore, the MD, MK, and f2 imaging parameters may be a novel and promising combination biomarker for examining Ki-67 status in rectal carcinoma.

Tandem mass tag-based quantitative proteomic analysis of metformin's inhibitory effects on ovarian cancer cells.

PURPOSE: Metformin (MET), a type 2 diabetes treatment, has attracted increased attention for its potential antitumor properties; however, the precise mechanism underlying this activity remains unclear. Our previous in vivo and in vitro studies revealed MET's inhibitory effect on ovarian cancer, with the synergistic effects of MET and the MDM2 inhibitor RG7388 contributing to ovarian cancer treatment. This study further explores the mechanism underlying MET's inhibition of ovarian cancer. MATERIALS AND METHODS: Following MET treatment, we analyzed the differentially expressed proteins in ovarian cancer cells using a tandem mass tag (TMT)-based proteomic approach coupled with bioinformatics. RESULTS: Using A2780 and SKOV3 ovarian cancer cells, we identified six upregulated and two downregulated proteins after MET treatment. Bioinformatics analysis revealed that these proteins predominately affect ovarian cancer cells by regulating iron ion transport, iron ion homeostasis, and mitochondrial and ribosomal functions. Validation via western blot confirmed MET-induced elevation of hydroxybutyrate dehydrogenase type 2 (BDH2) protein expression levels in A2780 and SKOV3 cells. CONCLUSIONS: Overall, our findings suggest that combining MET with other metabolic drugs, such as iron-chelating agents and mitochondrial inhibitors, may result in synergistic antitumor effects, thereby offering novel avenues for ovarian cancer treatment development.

Serine protease Rv2569c facilitates transmission of Mycobacterium tuberculosis via disrupting the epithelial barrier by cleaving E-cadherin.

Epithelial cells function as the primary line of defense against invading pathogens. However, bacterial pathogens possess the ability to compromise this barrier and facilitate the transmigration of bacteria. Nonetheless, the specific molecular mechanism employed by Mycobacterium tuberculosis (M.tb) in this process is not fully understood. Here, we investigated the role of Rv2569c in M.tb translocation by assessing its ability to cleave E-cadherin, a crucial component of cell-cell adhesion junctions that are disrupted during bacterial invasion. By utilizing recombinant Rv2569c expressed in Escherichia coli and subsequently purified through affinity chromatography, we demonstrated that Rv2569c exhibited cell wall-associated serine protease activity. Furthermore, Rv2569c was capable of degrading a range of protein substrates, including casein, fibrinogen, fibronectin, and E-cadherin. We also determined that the optimal conditions for the protease activity of Rv2569c occurred at a temperature of 37°C and a pH of 9.0, in the presence of MgCl2. To investigate the function of Rv2569c in M.tb, a deletion mutant of Rv2569c and its complemented strains were generated and used to infect A549 cells and mice. The results of the A549-cell infection experiments revealed that Rv2569c had the ability to cleave E-cadherin and facilitate the transmigration of M.tb through polarized A549 epithelial cell layers. Furthermore, in vivo infection assays demonstrated that Rv2569c could disrupt E-cadherin, enhance the colonization of M.tb, and induce pathological damage in the lungs of C57BL/6 mice. Collectively, these results strongly suggest that M.tb employs the serine protease Rv2569c to disrupt epithelial defenses and facilitate its systemic dissemination by crossing the epithelial barrier.

Assessment of Lung Nodule Detection and Lung CT Screening Reporting and Data System Classification Using Zero Echo Time Pulmonary MRI.

BACKGROUND: The detection rate of lung nodules has increased considerably with CT as the primary method of examination, and the repeated CT examinations at 3 months, 6 months or annually, based on nodule characteristics, have increased the radiation exposure of patients. So, it is urgent to explore a radiation-free MRI examination method that can effectively address the challenges posed by low proton density and magnetic field inhomogeneities. PURPOSE: To evaluate the potential of zero echo time (ZTE) MRI in lung nodule detection and lung CT screening reporting and data system (lung-RADS) classification, and to explore the value of ZTE-MRI in the assessment of lung nodules. STUDY TYPE: Prospective. POPULATION: 54 patients, including 21 men and 33 women. FIELD STRENGTH/SEQUENCE: Chest CT using a 16-slice scanner and ZTE-MRI at 3.0T based on fast gradient echo. ASSESSMENT: Nodule type (ground-glass nodules, part-solid nodules, and solid nodules), lung-RADS classification, and nodule diameter (manual measurement) on CT and ZTE-MRI images were recorded. STATISTICAL TESTS: The percent of concordant cases, Kappa value, intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, Spearman's correlation, and Bland-Altman. The p-value <0.05 is considered significant. RESULTS: A total of 54 patients (age, 54.8 ± 11.9 years; 21 men) with 63 nodules were enrolled. Compared with CT, the total nodule detection rate of ZTE-MRI was 85.7%. The intermodality agreement of ZTE-MRI and CT lung nodules type evaluation was substantial (Kappa = 0.761), and the intermodality agreement of ZTE-MRI and CT lung-RADS classification was moderate (Kappa = 0.592). The diameter measurements between ZTE-MRI and CT showed no significant difference and demonstrated a high degree of interobserver (ICC = 0.997-0.999) and intermodality (ICC = 0.956-0.985) agreements. DATA CONCLUSION: The measurement of nodule diameter by pulmonary ZTE-MRI is similar to that by CT, but the ability of lung-RADS to classify nodes from MRI images still requires further research. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

A winged relative of ice-crawlers in amber bridges the cryptic extant Xenonomia and a rich fossil record.

Until the advent of phylogenomics, the atypical morphology of extant representatives of the insect orders Grylloblattodea (ice-crawlers) and Mantophasmatodea (gladiators) had confounding effects on efforts to resolve their placement within Polyneoptera. This recent research has unequivocally shown that these species-poor groups are closely related and form the clade Xenonomia. Nonetheless, divergence dates of these groups remain poorly constrained, and their evolutionary history debated, as the few well-identified fossils, characterized by a suite of morphological features similar to that of extant forms, are comparatively young. Notably, the extant forms of both groups are wingless, whereas most of the pre-Cretaceous insect fossil record is composed of winged insects, which represents a major shortcoming of the taxonomy. Here, we present new specimens embedded in mid-Cretaceous amber from Myanmar and belonging to the recently described species Aristovia daniili. The abundant material and pristine preservation allowed a detailed documentation of the morphology of the species, including critical head features. Combined with a morphological data set encompassing all Polyneoptera, these new data unequivocally demonstrate that A. daniili is a winged stem Grylloblattodea. This discovery demonstrates that winglessness was acquired independently in Grylloblattodea and Mantophasmatodea. Concurrently, wing apomorphic traits shared by the new fossil and earlier fossils demonstrate that a large subset of the former "Protorthoptera" assemblage, representing a third of all known insect species in some Permian localities, are genuine representatives of Xenonomia. Data from the fossil record depict a distinctive evolutionary trajectory, with the group being both highly diverse and abundant during the Permian but experiencing a severe decline from the Triassic onwards.

Effect of different interventions on the treatment of high-risk human papillomavirus infection: a systematic review and network meta-analysis.

Background: Persistent infection with high-risk human papillomavirus (HR-HPV) can lead to cervical intraepithelial neoplasia and cancer. At present, there is no medication that specifically targets HR-HPV infection. Objective: This study aimed to evaluate the effectiveness of different interventions in promoting HR-HPV regression using a MeSH meta-analysis method. Methods: A search for randomized controlled trials (RCTs) reporting different interventions for the treatment of HR-HPV infection included PubMed, Web of Science, Embase and Cochrane Library from the inception of the databases to March 8, 2023. Two researchers independently screened the articles, extracted data, and evaluated the quality. The literature that met the inclusion criteria was selected, the quality and risk of bias of the included studies were assessed according to the Cochrane 5.1 manual, and NMA was performed using Stata 16.0. The area under the cumulative ranking probability graph (SUCRA) represented the probability that each treatment would be the best intervention. Results: Nine studies involving 961 patients and 7 treatment options were included in the analysis. The results of the network meta-analysis indicated the following rank order in terms of promoting HR-HPV conversion: Anti-HPV biological dressing > vaginal gel > imiquimod > REBACIN® > interferon > probiotics > observation/placebo > Polyphenon E. Conclusion: Anti-HPV biological dressing treatment was found to be significantly effective in promoting HR-HPV conversion. However, further validation of the findings is necessary due to the limited number and quality of studies included in the analysis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023413917.

A lone spike in blood glucose can enhance the thrombo-inflammatory response in cortical venules.

How transient hyperglycemia contributes to cerebro-vascular disease has been a challenge to study under controlled physiological conditions. We use amplified, ultrashort laser-pulses to physically disrupt brain-venule endothelium at targeted locations. This vessel disruption is performed in conjunction with transient hyperglycemia from a single injection of metabolically active D-glucose into healthy mice. The observed real-time responses to laser-induced disruption include rapid serum extravasation, platelet aggregation, and neutrophil recruitment. Thrombo-inflammation is pharmacologically ameliorated by a platelet inhibitor, by a scavenger of reactive oxygen species, and by a nitric oxide donor. As a control, vessel thrombo-inflammation is significantly reduced in mice injected with metabolically inert L-glucose. Venules in mice with diabetes show a similar response to laser-induced disruption and damage is reduced by restoration of normo-glycemia. Our approach provides a controlled method to probe synergies between transient metabolic and physical vascular perturbations and can reveal new aspects of brain pathophysiology.

Covalent drugs based on small molecules and peptides for disease theranostics.

Biomacromolecules, such as proteins, nucleic acids and polysaccharides, are widely distributed in the human body, and some of them have been recognized as the targets of drugs for disease theranostics. Drugs typically act on targets in two ways: non-covalent bond and covalent bond. Non-covalent bond-based drugs have some disadvantages, such as structural instability and environmental sensitivity. Covalent interactions between drugs and targets have a longer action time, higher affinity and controllability than non-covalent interactions of conventional drugs. With the development of artificial intelligence, covalent drugs have received more attention and have been developed rapidly in pharmaceutical research in recent years. From the perspective of covalent drugs, this review summarizes the design methods and the effects of covalent drugs. Finally, we discuss the application of covalent peptide drugs and expect to provide a new reference for cancer treatment.

DosR's multifaceted role on Mycobacterium bovis BCG revealed through multi-omics.

Mycobacterium tuberculosis (Mtb) is an intracellular bacterium that causes a highly contagious and potentially lethal tuberculosis (TB) in humans. It can maintain a dormant TB infection within the host. DosR (dormancy survival regulator) (Rv3133c) has been recognized as one of the key transcriptional proteins regulating bacterial dormancy and participating in various metabolic processes. In this study, we extensively investigate the still not well-comprehended role and mechanism of DosR in Mycobacterium bovis (M. bovis) Bacillus Calmette-Guérin (BCG) through a combined omics analysis. Our study finds that deleting DosR significantly affects the transcriptional levels of 104 genes and 179 proteins. Targeted metabolomics data for amino acids indicate that DosR knockout significantly upregulates L-Aspartic acid and serine synthesis, while downregulating seven other amino acids, including L-histidine and lysine. This suggests that DosR regulates amino acid synthesis and metabolism. Taken together, these findings provide molecular and metabolic bases for DosR effects, suggesting that DosR may be a novel regulatory target.

5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression.

DNA methylation at the fifth position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification for regulating gene expression, but little is known about how it regulates gene expression in insects. Here, we pursue the detailed molecular mechanism by which DNMT1-mediated 5mC maintenance regulates female reproduction in the German cockroach, Blattella germanica. Our results show that Dnmt1 knockdown decreases the level of 5mC in the ovary, upregulating numerous genes during choriogenesis, especially the transcription factor ftz-f1. The hypomethylation at the ftz-f1 promoter region increases and prolongs ftz-f1 expression in ovarian follicle cells during choriogenesis, which consequently causes aberrantly high levels of 20-hydroxyecdysone and excessively upregulates the extracellular matrix remodeling gene Mmp1. These changes further impair choriogenesis and disrupt fertilization by causing anoikis of the follicle cells, a shortage of chorion proteins, and malformation of the sponge-like bodies. This study significantly advances our understanding of how DNA 5mC modification regulates female reproduction in insects.

A new method for examining the co-occurrence network of fossil assemblages.

Currently, studies of ancient faunal community networks have been based mostly on uniformitarian and functional morphological evidence. As an important source of data, taphonomic evidence offers the opportunity to provide a broader scope for understanding palaeoecology. However, palaeoecological research methods based on taphonomic evidence are relatively rare, especially for body fossils in lacustrine sediments. Such fossil communities are not only affected by complex transportation and selective destruction in the sedimentation process, they also are strongly affected by time averaging. Historically, it has been believed that it is difficult to study lacustrine entombed fauna by a small-scale quadrat survey. Herein, we developed a software, the TaphonomeAnalyst, to study the associational network of lacustrine entombed fauna, or taphocoenosis. TaphonomeAnalyst allows researchers to easily perform exploratory analyses on common abundance profiles from taphocoenosis data. The dataset for these investigations resulted from fieldwork of the latest Middle Jurassic Jiulongshan Formation near Daohugou Village, in Ningcheng County of Inner Mongolia, China, spotlighting the core assemblage of the Yanliao Fauna. Our data included 27,000 fossil specimens of animals from this deposit, the Yanliao Fauna, whose analyses reveal sedimentary environments, taphonomic conditions, and co-occurrence networks of this highly studied assemblage, providing empirically robust and statistically significant evidence for multiple Yanliao habitats.

Linkages of soil CO2 emission with plant functional traits in young subtropical plantations.

Soil respiration is a key process in forest biogeochemical cycling. Exploring the relationship between plant functional traits and soil respiration can help understand the effects of tree species conversion on soil carbon cycling. In this study, we selected 15 common subtropical tree species planted in the logging site of second-generation Chinese fir forest to measure soil CO2 emission fluxes, soil physicochemical properties, leaf and root functional traits of each species, and explored the effects of plant functional traits on soil respiration. The results showed that the annual flux of soil CO2 emissions varied from 7.93 to 22.52 Mg CO2·hm-2, with the highest value under Castanopsis carlesii (22.52 Mg CO2·hm-2) and the lowest value under Taxus wallichiana (7.93 Mg CO2·hm-2). Results of stepwise regression analysis showed that the annual flux of soil CO2 emission decreased with the increases of leaf nitrogen content and fine root diameter, and increased with increasing leaf non-structural carbohydrate. In the structural equation model, leaf non-structural carbohydrate had a direct and significant positive effect on soil CO2 emission fluxes, while leaf nitrogen content and fine root diameter had a direct negative effect by decreasing soil pH and soluble organic nitrogen content. Plantations of different tree species would affect soil CO2 emission directly by changing functional traits related to water and nutrient acquisition or indirectly through soil properties. When creating plantations, we should select tree species based on the relationship between plant functional traits and ecosystem functions, with a view to improving forest productivity and soil carbon sequestration potential.

PE12 interaction with TLR4 promotes intracellular survival of Mycobacterium tuberculosis by suppressing inflammatory response.

Macrophages serve as the primary immune cells responsible for the innate immune defense against Mycobacterium tuberculosis (MTB) infection within the host. Specifically, NLRP3, a member of the NLRs family, plays a significant role in conferring resistance against MTB infection. Conversely, MTB evades innate immune killing by impeding the activation of the NLRP3 inflammasome, although the precise mechanism remains uncertain. In this study, we have identified PE12 (Rv1172c), a member of the PE/PPE family proteins, as an extracellular protein of MTB. PE12 interacts with Toll like receptor 4 (TLR4) in macrophages, forming the PE12-TLR4 complex which subsequently inhibits the transcription and expression of NLRP3. As a result, the transcription and secretion of IL-1ß are reduced through the PE12-TLR4-NLRP3-IL-1ß immune pathway. In vitro and in vivo experiments using a PE12-deficient strain (H37RvΔPE12) demonstrate a weakening of the suppression of the inflammatory response to MTB infection. Our findings highlight the role of the PE12 protein in not only inhibiting the transcription and release of inflammatory cytokines but also mediating the killing of MTB escape macrophages through TLR4 and inducing lung injury in MTB-infected mice. These results provide evidence that PE12 plays a significant role in the inhibition of the host immune response by MTB.

Optimizing decision trees for English Teaching Quality Evaluation (ETQE) using Artificial Bee Colony (ABC) optimization.

Changes in educational systems and English teaching strategies have increased the need for automatic methods for English Teaching Quality Evaluation (ETQE). A practical model for ETQE applies in different fields, determines the most relevant factors in teaching quality (TQ), and has optimal performance in different conditions. This paper presents a new method based on Artificial Intelligence (AI) and meta-heuristic algorithms to solve the ETQE problem. The proposed method performs the prediction process in two phases: "determination of related indicators" and "quality prediction". During the first phase, after introducing a set of 24 candidate indicators, an optimal subset of them having maximum correlation with ETQE and minimum redundancy are selected using Artificial Bee Colony (ABC) algorithm. In the second phase of the proposed method, a Classification and Regression Tree (CART) model optimized by ABC are applied to predict ETQ based on the indicators determined in the first phase. In this learning model, split points of decision nodes are determined by ABC in a way that the prediction accuracy would be maximized. The performance of the proposed method has been evaluated in two different teaching environments. The performance of the proposed method has been evaluated in two different teaching environments. The studied teaching environments are face-to-face (FF) and online classes that were held for middle school and university students, respectively. Based on the obtained results, the proposed method can predict the ETQ with an accuracy of more than 98.99% in both tested scenarios, which results in an increase of at least 1.11% compared to the previous methods. The efficiency of the proposed model in both studied scenarios prove the generality of this method to be used in real-world applications.

Exploring the therapeutic potential of a nano micelle containing a carbon monoxide-releasing molecule for metabolic-associated fatty liver disease by modulating hypoxia-inducible factor-1α.

Metabolic-associated fatty liver disease (MAFLD) encompasses a spectrum of chronic liver diseases, including steatohepatitis, cirrhosis, and liver cancer. Despite the increasing prevalence and severity of MAFLD, no approved pharmacological interventions are currently available. Hypoxia-inducible factor-1α (HIF-1α) has emerged as a crucial early mediator in the pathogenesis of MAFLD. Previously, we demonstrated the potent anti-inflammatory properties of the nano-designed carbon monoxide (CO) donor, styrene maleic acid copolymer (SMA) encapsulating CO-releasing molecule (SMA/CORM2), which effectively suppressed HIF-1α in various inflammatory disorders. Here, we investigated the therapeutic potential of SMA/CORM2 in a mouse model of MAFLD induced by a high-fat methionine- and choline-deficient (HF-MCD) diet. Following 4 weeks of HF-MCD diet consumption, we observed pronounced hepatic lipid accumulation accompanied by disrupted lipid metabolism, polarization of macrophages towards the pro-inflammatory M1 phenotype, activation of the NLRP3 inflammasome, and upregulation of the TGF-ß fibrosis signaling pathway. Notably, the early and upstream event driving these pathological changes was the upregulation of HIF-1α. Treatment with SMA/CORM2 (10 mg/kg, three times per week) led to a significant increase in CO levels in both the circulation and liver, resulting in remarkable suppression of HIF-1α expression even before the onset of apparent pathological changes induced by the HF-MCD diet. Consequently, SMA/CORM2 administration exerted a significantly protective and therapeutic effect on MAFLD. In vitro studies using hepatocytes treated with high concentrations of fatty acids further supported these findings, as knockdown of HIF-1α using short hairpin RNA (shRNA) elicited similar effects to SMA/CORM2 treatment. Collectively, our results highlight the therapeutic potential of SMA/CORM2 in the management of MAFLD through suppression of HIF-1α. We anticipate that SMA/CORM2, with its ability to modulate HIF-1α expression, may hold promise for future applications in the treatment of MAFLD. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) is a crucial gaseous signaling molecule that plays a vital role in maintaining homeostasis and is a potential target for treating many inflammatory diseases. Developing drug delivery systems that can deliver CO stably and target specific tissues is of great interest. Our team previously developed a nano micellar CO donor, SMA/CORM2, which exhibits superior bioavailability to native CORM2 and shows therapeutic potential in many inflammatory disease models. In this study, we showed that SMA/CORM2, through controlled CO release, significantly ameliorated steatohepatitis and liver fibrosis induced by an HF-MCD diet by suppressing an HIF-1α mediated inflammatory cascade. These findings provide new insight into the anti-inflammatory function of CO and a promising approach for controlling metabolic-associated fatty liver disease.

Glutathione-sensitive mesoporous nanoparticles loaded with cinnamaldehyde for chemodynamic and immunological therapy of cancer.

Chemodynamic therapy as a novel type of chemotherapy can damage the DNA structures and induce cell apoptosis and immunogenic cell death (ICD) through generating reactive oxygen species (ROS) to aggravate oxidative stress. Nonetheless, as an intrinsic antioxidative response of tumor cells, the expression of glutathione (GSH) can be upregulated to maintain the cellular redox balance and protect the tumor cells from ROS-mediated damage. In this context, it is feasible to simultaneously boost ROS generation and GSH depletion in tumor cells; however, the precise delivery and release of GSH scavengers at specific subcellular sites is of great importance. Herein, we propose a GSH-responsive mesoporous organosilica nanoparticle (MON)-based nanomedicine MON-CA-TPP@HA through sequentially covalently attaching triphenylphosphine (TPP) and electrostatically coating hyaluronic acid (HA) onto the surface of cinnamaldehyde (CA)-loaded MONs, known as MON-CA-TPP@HA, which has been demonstrated to be an extremely effective therapeutic strategy for cancer treatment through inducing ICD and apoptosis of breast cancer cells. Systematic in vitro experimental results clearly revealed that the nanomedicine can actively target the tumor cells with the help of HA, subsequently enter the tumor cells, and precisely bind with the mitochondria through TPP residues. Upon cleavaging the disulfide bond in the MONs triggered by over-expressed GSH within tumors, the CA molecules can be released inducing the excessive ROS in situ surrounding the mitochondria to activate oxidative stress to induce apoptosis and ICD of breast cancer cells. The results of the in vivo experiments confirm that the MON-CA-TPP@HA nanomedicine can effectively promote dendritic cell (DC) maturation and CD 8+ T cell activation and regulate the ratio of M1/M2 macrophages, which improve tumor immunosuppressive microenvironment. It is thus believed that the current nanomedicine has paved a new way for future cancer therapy.