Abstract
PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour ...distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.
In this paper, a control algorithm based on Advantage Actor-Critic for the classical inverted pendulum system has been proposed. To enrich the observed states which are used to control, a CNN ...feature-based state is proposed. The direct control and the indirect control algorithms are introduced to address different control situations, such as the situation which only physical states like angle, velocity, etc. provided or the situation which only the indirect states provided like images, etc. A comparison experiment between the direct control and the indirect control algorithms based on the Advantage Actor-Critic has been evaluated. Besides, the comparison experiment with the Deep Q-Network algorithm has been performed. The experiment results show that the proposed method achieves comparable performance with the PID control algorithm and better than the Deep Q-Network based algorithm.
Background. Ischemic stroke is a severe acute cerebrovascular disease which can be improved with neuroprotective therapies at an early stage. However, due to the lack of effective neuroprotective ...drugs, most stroke patients have varying degrees of long-term disability. In the present study, we investigated the role of exosomes derived from CXCR4-overexpressing BMSCs in restoring vascular function and neural repair after ischemic cerebral infarction. Methods. BMSCs were transfected with lentivirus encoded by CXCR4 (BMSCCXCR4). Exosomes derived from BMSCCXCR4 (ExoCXCR4) were isolated and characterized by transmission electron microscopy and dynamic light scattering. Western blot and qPCR were used to analyze the expression of CXCR4 in BMSCs and exosomes. The acute middle cerebral artery occlusion (MCAO) model was prepared, ExoCXCR4 were injected into the rats, and behavioral changes were analyzed. The role of ExoCXCR4 in promoting the proliferation and tube formation for angiogenesis and protecting brain endothelial cells was determined in vitro. Results. Compared with the control groups, the ExoCXCR4 group showed a significantly lower mNSS score at 7 d, 14 d, and 21 d after ischemia/reperfusion (P<0.05). The bEnd.3 cells in the ExoCXCR4 group have stronger proliferation ability than other groups (P<0.05), while the CXCR4 inhibitor can reduce this effect. Exosomes control (ExoCon) can significantly promote the migration of bEnd.3 cells (P<0.05), while there was no significant difference between the ExoCXCR4 and ExoCon groups (P>0.05). ExoCXCR4 can further promote the proliferation and tube formation for the angiogenesis of the endothelium compared with ExoCon group (P<0.05). In addition, cobalt chloride (COCl2) can increase the expression of β-catenin and Wnt-3, while ExoCon can reduce the expression of these proteins (P<0.05). ExoCXCR4 can further attenuate the activation of Wnt-3a/β-catenin pathway (P<0.05). Conclusions. In ischemia/reperfusion injury, ExoCXCR4 promoted the proliferation and tube formation of microvascular endothelial cells and play an antiapoptotic role via the Wnt-3a/β-catenin pathway.
Drought is a frequent global phenomenon. Solar-induced chlorophyll fluorescence (SIF), an electromagnetic signal, has been proven to be an efficient tool for monitoring and assessing gross primary ...productivity (GPP) and drought. To address the issue of the sparse resolution of satellite-based SIF, researchers have developed different downscaling algorithms. Recently, the most frequently used SIF products had a spatial resolution of 0.05 degrees. However, these spatial resolution SIF data are not conducive to regional agricultural drought monitoring. In this study, we utilized the global ‘OCO-2’ solar-induced fluorescence (GOSIF) products along with normalized difference vegetation index (NDVI) and land surface temperature (LST) products. With the powerful advantages offered by Google Earth Engine (GEE), we could conveniently acquire the necessary data. Additionally, employing the random forest (RF) method, we successfully acquired downscaled SIF data at an enhanced spatial resolution of 1 km. Using those downscaled SIF results with 1 km resolution, an SIF anomaly index was established and calculated to monitor drought. Results showed that the RF-based downscaled SIF result followed the same trend as the GOSIF value. Subsequently, correlation coefficients between SIF and GPP were calculated. The downscaled SIF demonstrated a higher correlation with GPP from MODIS compared to 0.05-degree GOSIF, with coefficients of 0.74 and 0.68 in May 2018, respectively. Moreover, the SIF anomaly index showed positive correlations with crop yield; the correlation coefficients were 0.93 for wheat and 0.89 for maize. The drought index had a negative correlation with areas affected by drought, with a correlation coefficient of −0.58. Finally, the SIF anomaly index was used to monitor drought from 2001 to 2020 in Henan Province. The 1 km SIF results obtained through the RF-based downscaled method were deemed reliable, thereby establishing the suitability of the SIF anomaly index for drought monitoring at a regional scale.
This study tests the hypothesis that middle school and high school students can improve their stroke knowledge using Stroke 1-2-0, a stroke educational tool, and pass this knowledge on to their ...family members.
A total of 625 students and 198 parents/grandparents participated in learning about stroke using Stroke 1-2-0. After a group training session for the students by a neurologist at school, the students took educational material to home and educated their parents/grandparents. A questionnaire was given to students, parents/grandparents before, immediately after, and 1 year after the educational event.
All participants agreed that Stroke 1-2-0 was a much easier tool to remember than FAST. Almost all the students (96.4%) remembered the meaning of Stroke 1-2-0 as compared to 7.3% from the base line (p < 0.001). The rate of complete Stroke 1-2-0 mastery from 96.3% fell to 84.4% at 3 months and 63.8% at 1 year after training (p < 0.001). Following education from children, the proportion of parents/grandparents who mastered Stroke 1-2-0 was significantly higher than baseline (79.9 vs. 24.8%).
Middle school and high school students can effectively use Stroke 1-2-0 to improve their stroke knowledge and pass this knowledge to their family members. Sustained educational efforts and repeated educational events are needed though.
Abstract Artificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations like lack of ...well-defined targets. While chemical-induced transcriptional profiles offer a comprehensive view of drug mechanisms, inherent noise often obscures the true signal, hindering their potential for meaningful insights. Here, we highlight the development of TranSiGen, a deep generative model employing self-supervised representation learning. TranSiGen analyzes basal cell gene expression and molecular structures to reconstruct chemical-induced transcriptional profiles with high accuracy. By capturing both cellular and compound information, TranSiGen-derived representations demonstrate efficacy in diverse downstream tasks like ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. Notably, in vitro validation of TranSiGen’s application in pancreatic cancer drug discovery highlights its potential for identifying effective compounds. We envisage that integrating TranSiGen into the drug discovery and mechanism research holds significant promise for advancing biomedicine.
Background
Colorectal cancer (CRC) is the second most common cause of cancer‐related death worldwide. Long noncoding RNA (lncRNA) is involved in many malignant tumors. This study aimed to clarify the ...role of the lncRNA plasmacytoma variant translocation 1 (PVT1) in CRC growth and metastasis.
Methods
Differentially expressed lncRNAs in CRC were analyzed using the Cancer Genome Atlas. Gene expression profiling interactive analysis and a comprehensive resource for lncRNAs from cancer arrays databases were used to analyze lncRNA PVT1 expression and CRC prognosis, respectively. Cell counting kit‐8, wound healing, colony formation, Transwell, and immunofluorescence assays were used to evaluate CRC cell proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT), respectively. Tumor growth and metastasis models were used to explore the PVT1 effect on the growth and metastasis of CRC in vivo.
Results
PVT1 was highly expressed in CRC, associated with a poor prognosis of CRC, and showed good diagnostic value. Transfection of sh‐PVT1 or pcDNA3.1‐PVT1 reduced or increased the proliferation, wound healing rate, colony formation, invasion, and EMT of CRC cells. PVT1 and miR‐3619‐5p were co‐expressed in CRC cytoplasm, and PVT1 acted as a competitive endogenous RNA (ceRNA) by sponging miR‐3619‐5p to up‐regulate tripartite motif containing 29 (TRIM29) expression. MiR‐3619‐5p overexpression and TRIM29 knockdown reduced proliferation, wound healing rate, invasion, and EMT of CRC cells. However, simultaneous PVT1 and miR‐3619‐5p overexpression or knockdown of miR‐3619‐5p and TRIM29 knockdown rescued the malignant phenotype of CRC cells.
Conclusions
We first clarified the ceRNA mechanism of PVT1 in CRC, which induced growth and metastasis by sponging with miR‐3619‐5p to regulate TRIM29.
Traditional time-series clustering methods usually perform poorly on high-dimensional data. However, image clustering using deep learning methods can complete image annotation and searches in large ...image databases well. Therefore, this study aimed to propose a deep clustering model named GW_DC to convert one-dimensional time-series into two-dimensional images and improve cluster performance for algorithm users. The proposed GW_DC consisted of three processing stages: the image conversion stage, image enhancement stage, and image clustering stage. In the image conversion stage, the time series were converted into four kinds of two-dimensional images by different algorithms, including grayscale images, recurrence plot images, Markov transition field images, and Gramian Angular Difference Field images; this last one was considered to be the best by comparison. In the image enhancement stage, the signal components of two-dimensional images were extracted and processed by wavelet transform to denoise and enhance texture features. Meanwhile, a deep clustering network, combining convolutional neural networks with K-Means, was designed for well-learning characteristics and clustering according to the aforementioned enhanced images. Finally, six UCR datasets were adopted to assess the performance of models. The results showed that the proposed GW_DC model provided better results.
Many epidemiologic studies have explored the association between dairy product consumption and the risk of non-Hodgkin lymphoma (NHL), but the results remain controversial. A literature search was ...performed in PubMed, Web of Science and Embase for relevant articles published up to October 2015. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. The dose-response relationship was assessed by restricted cubic spline. A total of 16 articles were eligible for this meta-analysis. The pooled RRs (95% CIs) of NHL for the highest vs. lowest category of the consumption of total dairy product, milk, butter, cheese, ice cream and yogurt were 1.20 (1.02, 1.42), 1.41 (1.08, 1.84), 1.31 (1.04, 1.65), 1.14 (0.96, 1.34), 1.57 (1.11, 2.20) and 0.78 (0.54, 1.12), respectively. In subgroup analyses, the positive association between total dairy product consumption and the risk of NHL was found among case-control studies (RR = 1.41, 95% CI: 1.17-1.70) but not among cohort studies (RR = 1.02, 95% CI: 0.88-1.17). The pooled RRs (95% CIs) of NHL were 1.21 (1.01, 1.46) for milk consumption in studies conducted in North America, and 1.24 (1.09, 1.40) for cheese consumption in studies that adopted validated food frequency questionnaires. In further analysis of NHL subtypes, we found statistically significant associations between the consumption of total dairy product (RR = 1.73, 95% CI: 1.22-2.45) and milk (RR = 1.49, 95% CI: 1.08-2.06) and the risk of diffuse large B-cell lymphoma. The dose-response analysis suggested that the risk of NHL increased by 5% (1.05 (1.00-1.10)) and 6% (1.06 (0.99-1.13)) for each 200 g/day increment of total dairy product and milk consumption, respectively. This meta-analysis suggested that dairy product consumption, but not yogurt, may increase the risk of NHL. More prospective cohort studies that investigate specific types of dairy product consumption are needed to confirm this conclusion.
Land-use and land-cover changes constitute pivotal components in global environmental change research. Through an examination of spatiotemporal variations in land cover, we can deepen our ...understanding of land-cover change dynamics, shape appropriate policy frameworks, and implement targeted environmental conservation strategies. The judicious management of land is a critical determinant in fostering the sustainable growth of urban economies and enhancing quality of life for residents. This study harnessed remote sensing data to analyze land-cover patterns in Tianjin over five distinct time points: 2000, 2005, 2010, 2015, and 2020. It focused on evaluating the evolving dynamics, transition velocities, and transformation processes across various land categories within the region. Utilizing dynamic analysis and a transition matrix, the study traced shifts among different land-use classes. The center-of-gravity migration model was employed to elucidate land-cover pattern evolution. This research also integrated pertinent land-cover statistics to offer a holistic perspective on Tianjin’s land-cover transformations. Employing the CA–Markov model, we projected the prospective spatial layout of land cover for the area. Our findings revealed the following. (1) From 2000 to 2020, Tianjin experienced a significant reduction in cropland, forest, grassland, and water areas, alongside a substantial increase in impervious. (2) The impervious surface’s center of gravity, initially in Beichen District, shifted 4.20 km northwestward at an average rate of 0.84 km per year. (3) Principal component analysis indicated that the growth in the output value of the secondary and forestry industries is a key driver in expanding Tianjin’s impervious-surface area. (4) Predictions for 2025 suggest an increase in Tianjin’s impervious-surface area to 4659.78 km2, with a concurrent reduction in cropland to 5656.18 km2. The insights gleaned from this study provide a solid theoretical foundation and empirical evidence, aiding in the formulation of informed land-use strategies, the preservation of urban land resources, and guiding principles for sustainable urban development.
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