Counterfactual Monotonic Knowledge Tracing for Assessing Students' Dynamic Mastery of Knowledge Concepts

As the core of the Knowledge Tracking (KT) task, assessing students' dynamic mastery of knowledge concepts is crucial for both offline teaching and online educational applications. Since students' mastery of knowledge concepts is often unlabeled, existing KT methods rely on the implicit paradigm of historical practice to mastery of knowledge concepts to students' responses to practices to address the challenge of unlabeled concept mastery. However, purely predicting student responses without imposing specific constraints on hidden concept mastery values does not guarantee the accuracy of these intermediate values as concept mastery values. To address this issue, we propose a principled approach called Counterfactual Monotonic Knowledge Tracing (CMKT), which builds on the implicit paradigm described above by using a counterfactual assumption to constrain the evolution of students' mastery of knowledge concepts.Comment: Accepted by CIKM 2023, 10 pages, 5 figures, 4 table

No Length Left Behind: Enhancing Knowledge Tracing for Modeling Sequences of Excessive or Insufficient Lengths

Knowledge tracing (KT) aims to predict students' responses to practices based on their historical question-answering behaviors. However, most current KT methods focus on improving overall AUC, leaving ample room for optimization in modeling sequences of excessive or insufficient lengths. As sequences get longer, computational costs will increase exponentially. Therefore, KT methods usually truncate sequences to an acceptable length, which makes it difficult for models on online service systems to capture complete historical practice behaviors of students with too long sequences. Conversely, modeling students with short practice sequences using most KT methods may result in overfitting due to limited observation samples. To address the above limitations, we propose a model called Sequence-Flexible Knowledge Tracing (SFKT).Comment: Accepted by CIKM 2023, 10 pages, 8 figures, 5 table

Cognition-Mode Aware Variational Representation Learning Framework for Knowledge Tracing

The Knowledge Tracing (KT) task plays a crucial role in personalized learning, and its purpose is to predict student responses based on their historical practice behavior sequence. However, the KT task suffers from data sparsity, which makes it challenging to learn robust representations for students with few practice records and increases the risk of model overfitting. Therefore, in this paper, we propose a Cognition-Mode Aware Variational Representation Learning Framework (CMVF) that can be directly applied to existing KT methods. Our framework uses a probabilistic model to generate a distribution for each student, accounting for uncertainty in those with limited practice records, and estimate the student's distribution via variational inference (VI). In addition, we also introduce a cognition-mode aware multinomial distribution as prior knowledge that constrains the posterior student distributions learning, so as to ensure that students with similar cognition modes have similar distributions, avoiding overwhelming personalization for students with few practice records. At last, extensive experimental results confirm that CMVF can effectively aid existing KT methods in learning more robust student representations. Our code is available at https://github.com/zmy-9/CMVF.Comment: Accepted by ICDM 2023, 10 pages, 5 figures, 4 table

An Improved D-α-Tocopherol-Based Nanocarrier for Targeted Delivery of Doxorubicin with Reversal of Multidrug Resistance

Nanocarriers have recently emerged as an attractive platform for delivery of various types of therapeutics including anticancer agents. Previously, we developed an improved TPGS delivery system (PEG5K-VE2) which demonstrated improved colloidal stability and greater in vivo antitumor activity. Nevertheless, the application of this system is still limited by a relatively low drug loading capacity (DLC). In this study we report that incorporation of a fluorenylmethyloxycarbonyl (Fmoc) motif at the interfacial region of PEG5K-VE2 led to significant improvement of the system through the introduction of an additional mechanism of drug/carrier interaction. Doxorubicin (DOX) could be effectively loaded into PEG5K-Fmoc-VE2 micelles at a DLC of 39.9%, which compares favorably to most reported DOX nanoformulations. In addition, PEG5K-Fmoc-VE2/DOX mixed micelles showed more sustained release of DOX in comparison to the counterpart without Fmoc motif. MTT assay showed that PEG5K-Fmoc-VE2/DOX exerted significantly higher levels of cytotoxicity over DOX, Doxil as well as PEG5K-VE2/DOX in PC-3 and 4T1.2 cells. Cytotoxicity assay with NCI/ADR-RES, a drug resistant cell line, suggested that PEG5K-Fmoc-VE2 may have a potential to reverse the multidrug resistance, which was supported by its inhibition on P-gp ATPase. Pharmacokinetics (PK) and biodistribution studies showed an increased half-life in blood circulation and more effective tumor accumulation for DOX formulated in PEG5K-Fmoc-VE2 micelles. More importantly, DOX-loaded PEG5K-Fmoc-VE2 micelles showed an excellent safety profile with a MTD (~30 mg DOX/kg) that is about 3 times as much as that for free DOX. Finally, superior antitumor activity was demonstrated for PEG5K-Fmoc-VE2/DOX in both drug-sensitive (4T1.2 and PC-3) and drug-resistant (KB 8-5) tumor models compared to DOX, Doxil, and PEG5K-VE2/DOX

A PEG-Fmoc conjugate as a nanocarrier for paclitaxel

We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25–30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and 13C-NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study

Genome-wide analysis and identification of stress-responsive genes of the CCCH zinc finger family in Capsicum annuum L.

The CCCH zinc finger gene family encodes a class of proteins that can bind to both DNA and RNA, and an increasing number of studies have demonstrated that the CCCH gene family plays a key role in growth and development and responses to environmental stress. Here, we identified 57 CCCH genes in the pepper (Capsicum annuum L.) genome and explored the evolution and function of the CCCH gene family in C. annuum. Substantial variation was observed in the structure of these CCCH genes, and the number of exons ranged from one to fourteen. Analysis of gene duplication events revealed that segmental duplication was the main driver of gene expansion in the CCCH gene family in pepper. We found that the expression of CCCH genes was significantly up-regulated during the response to biotic and abiotic stress, especially cold and heat stress, indicating that CCCH genes play key roles in stress responses. Our results provide new information on CCCH genes in pepper and will aid future studies of the evolution, inheritance, and function of CCCH zinc finger genes in pepper

第774回 千葉医学会例会・第二内科例会 64.

The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 μM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRβ, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 μM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists

Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence

Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated β-galactosidase (SA-β-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP

AXL receptor tyrosine kinase regulates Apolipoprotein E expression

Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. One of the hallmarks of AD is the accumulation of amyloid plaques in the brain. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. The APOE gene is the most validated genetic risk factor for late onset AD, and has well-established associations with amyloid deposition and clearance from the brain. We and others have shown that lipidation of apoE can assist amyloid clearance, raising interest in augmenting apoE function as a proposed therapeutic strategy for AD. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. A subset of AXL receptor tyrosine kinase inhibitors, which we term AXL modulators were identified as positive hits. The objective of this thesis is to dissect the mechanism of action (MoA) by which AXL modulators upregulate apoE expression. We initially understood their dependency on AXL by treating AXL-/- CCF-STTG1 cells generated using CRISPR-Cas9 method with the lead compound. We then determined if Liver X Receptor (LXR) activity was required utilizing LXR knock-out (KO) mouse embryonic fibroblasts (MEF) cells. Immunoblotting analysis of AXL protein indicated the ability of AXL modulators to promote AXL receptor cleavage and stabilize the intracellular domain (ICD). To investigate the role of AXL-ICD in apoE homeostasis, various Axl variants, including WT AXL, kinase-dead AXL mutant, Axl-ICD, and AXL N-terminal fragment were stably reconstituted in AXL-/- CCF-STTG1 cells. ApoE baseline expression was significantly upregulated only upon reconstitution of ICD-containing AXL variants. In summary, AXL protein plays a significant role in apoE homeostasis through its intracellular domain.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat