In the process of continuous reform and development of education and teaching, some traditional teaching modes are gradually eliminated, whereas new teaching modes are gradually recognized by ...teachers and students. These modes are widely used in education and teaching due to their overwhelming characteristics. Among these emerging teaching modes, massive open online course (MOOC) is a relatively advanced teaching mode with a better application effect. Quickly and accurately detecting the cheating behavior of MOOC learners is of great significance for maintaining the development of the MOOC platform and English education counseling. This paper studies a deep-learning-based hybrid model for MOOC cheating detection. The model greatly improves the detection performance of a single model by integrating CNN, a bidirectional gated recurrent unit, and an attention mechanism. The proposed model selects the English learning behavior data of a MOOC platform to verify the performance of the algorithm. Simulation results show that the proposed scheme can greatly help MOOC-based English education tutoring.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive therapeutic target for human cancers and other human diseases. Herein, we report our discovery of potent small-molecule SHP2 ...degraders whose design is based upon the proteolysis-targeting chimera (PROTAC) concept. This work has led to the discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. SHP2-D26 achieves DC50 values of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that induced SHP2 degradation is a very effective approach to inhibit the function of SHP2. Further optimization of these SHP2 degraders may lead to the development of a new class of therapies for cancers and other human diseases.
A reaction-diffusion predator-prey model with the dormancy of predators is considered in this paper. We are concerned with the long-time behaviors of the solutions of this system. We divided our ...investigations into two cases: for the ODEs system, we study the existence and stability of the equilibrium solutions and derive precise conditions on system parameters so that the system can undergo Hopf bifurcations around the positive equilibrium solution. Moreover, the properties of Hopf bifurcation are studied in detail. For the reaction-diffusion system, we are able to derive conditions on the diffusion coefficients so that the spatially homogeneous Hopf bifurcating periodic solutions can undergo diffusion-triggered instability. To support our theoretical analysis, we also include several numerical results.
We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate ...cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.
Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, ...nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.
Image segmentation is the foundation of object-based image analysis, and many researchers have sought optimal segmentation results. The initial image oversegmentation and the optimal segmentation ...scale are two vital factors in high spatial resolution remote sensing image segmentation. With respect to these two issues, a novel image segmentation method combining superpixels with a minimum spanning tree is proposed in this paper. First, the image is oversegmented using a simple linear iterative clustering algorithm to obtain superpixels. Then, the superpixels are clustered by regionalization with a dynamically constrained agglomerative clustering and partitioning (REDCAP) algorithm using the initial number of segments, and the local variance (LV) and the rate of LV change (ROC-LV) indicator diagrams corresponding to the number of segments are obtained. The suitable number of image segments is determined according to the LV and ROC-LV indicator diagrams corresponding to the number of segments. Finally, the superpixels are reclustered using the REDCAP algorithm based on the suitable number of image segments to obtain the image segmentation result. Through two sets of experiments, the proposed method is compared with two other segmentation algorithms. The experimental results show that the proposed method outperforms the others and obtains good image segmentation results.
The study of the vibration phenomenon of pebbles under turbulence is still a gap despite recent technological advancements in measurement capabilities. In this study, the vibration process of a fully ...exposed, isolated smart pebble on a rough bed was measured using a miniature inertial accelerometer and combined with simultaneous local measurements of the near-bed velocities. The paper conducts a series of experimental studies with different flow conditions. The test data match well with the manually observed phenomena, indicating the authenticity of the sediment vibration data collected by the measurement system. The test results show that the pebble motion (before entrainment) subjected to turbulence is a nonlinear vibration process, and its vibration types include in-situ vibration and ex-situ strong vibration. The probability distribution for the amplitude of vibration acceleration is well parameterized by the normal distribution. The vibration intensity tends to increase before approaching the threshold, but it weakens when approaching the point. The sediment vibration frequency is within 20-25 Hz, similar to the flow pulsation frequency and belongs to low-frequency vibration. The data indicate that the near-bed flow velocity is most directly related to the particle vibration events.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The serotonin (5-HT) hypothesis of depression has played an important role in the history of psychiatry, yet it has also been criticized for the delayed onset and inadequate efficacy of selective ...serotonin reuptake inhibitors (SSRIs). With evolvement of neuroscience, the neuroplasticity hypothesis of major depressive disorder (MDD) has been proposed and may provide a better framework for clarification the pathogenesis of MDD and antidepressant efficacy. In this article, we first summarized the evidence challenging the monoamine hypothesis and proposed that the antidepressant efficacy of SSRIs is not derived from elevated monoamine (5-HT, noradrenaline (NE), or dopamine (DA)) concentration or monoamine neurotransmission. Second, we reviewed the role of stress in the pathogenesis of MDD and gave a brief introduction to the neuroplasticity hypothesis of MDD. Third, we explored the possible mechanisms underlying the antidepressant efficacy of typical antidepressants in the context of neuroplasticity theory. Fourth, we tried to provide an explanatory framework for the significant difference in onset of efficacy between typical antidepressants and ketamine. Finally, we provided a brief summarization about this review article and some perspectives for future studies.
Porcine epidemic diarrhea virus (PEDV) causes lethal diarrhea in suckling piglets, leading to severe economic losses worldwide. There is an urgent need to find new therapeutic methods to prevent and ...control PEDV. Not only is there a shortage of commercial anti-PEDV drugs, but available commercial vaccines fail to protect against highly virulent PEDV variants. We screened an FDA-approved library of 911 natural products and found that tomatidine, a steroidal alkaloid extracted from the skin and leaves of tomatoes, demonstrates significant inhibition of PEDV replication in Vero and IPEC-J2 cells in vitro. Molecular docking and molecular dynamics analysis predicted interactions between tomatidine and the active pocket of PEDV 3CL protease, which were confirmed by fluorescence spectroscopy and isothermal titration calorimetry (ITC). The inhibiting effect of tomatidine on 3CL protease was determined using cleavage visualization and FRET assay. Tomatidine-mediated blocking of 3CL protease activity in PEDV-infected cells was examined by western blot detection of the viral polyprotein in PEDV-infected cells. It indicates that tomatidine inhibits PEDV replication mainly by targeting 3CL protease. In addition, tomatidine also has antiviral activity against transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), encephalo myocarditis virus (EMCV) and seneca virus A (SVA) in vitro. These results may be helpful in developing a new prophylactic and therapeutic strategy against PEDV and other swine disease infections.
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