YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway

SEMv2: Table Separation Line Detection Based on Instance Segmentation

Table structure recognition is an indispensable element for enabling machines to comprehend tables. Its primary purpose is to identify the internal structure of a table. Nevertheless, due to the complexity and diversity of their structure and style, it is highly challenging to parse the tabular data into a structured format that machines can comprehend. In this work, we adhere to the principle of the split-and-merge based methods and propose an accurate table structure recognizer, termed SEMv2 (SEM: Split, Embed and Merge). Unlike the previous works in the ``split'' stage, we aim to address the table separation line instance-level discrimination problem and introduce a table separation line detection strategy based on conditional convolution. Specifically, we design the ``split'' in a top-down manner that detects the table separation line instance first and then dynamically predicts the table separation line mask for each instance. The final table separation line shape can be accurately obtained by processing the table separation line mask in a row-wise/column-wise manner. To comprehensively evaluate the SEMv2, we also present a more challenging dataset for table structure recognition, dubbed iFLYTAB, which encompasses multiple style tables in various scenarios such as photos, scanned documents, etc. Extensive experiments on publicly available datasets (e.g. SciTSR, PubTabNet and iFLYTAB) demonstrate the efficacy of our proposed approach. The code and iFLYTAB dataset are available at https://github.com/ZZR8066/SEMv2

Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy

Background: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. Methods: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. Results: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. Conclusions: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors

Structure and function of trimeric intracellular cation channels (TRIC) and ryanodine receptors (RyR)

Controlled Ca2+-release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling (EC-coupling) is essential for cardiac and skeletal muscle contraction. Ca2+ is released through ryanodine receptors (RyR) in the SR membrane but there are other, different types of ion channels in the SR with unclear physiological roles, and some of these channels have not been identified. In this thesis, I have investigated the structural and biophysical properties of certain ion channels found in the SR, including SR K+ channels, trimeric intracellular cation channels (TRIC-A and B) and RyR. The gating and single-channel conductance of SR ion channels was examined after incorporation of vesicles of SR into planar phospholipid bilayers under voltage-clamp conditions. In the search for a ligand that binds to the SR K+ channel, I found that ebselen irreversibly inhibited the channel and that dithiothreitol could partly reverse this effect suggesting the ebselen modified cysteine residues on the channel. It is suggested that TRIC-A or TRIC-B could be the SR K+ channel and so I investigated this by characterising the biophysical properties of the ion channels observed after incorporating membrane vesicles obtained from HEK293 cells co-expressing RyR2 plus TRIC-A or RyR2 plus TRIC-B into bilayers. My results indicated that TRIC-A and TRIC-B are non-selective ion channels, permeable to both Cl- and K+, and therefore are unlikely to be SR K+ channels which are highly selective for monovalent cations. I also found that co-expression of TRIC-A or TRIC-B with RyR2 altered the response of RyR2 to cytosolic Ca2+ suggesting that both TRIC-A and TRIC-B interact with RyR2 to regulate RyR2 gating. I established a cardiac-specific Tric-a knockout (Tric-a-cKO) mouse colony as a platform to explore the physiological roles of TRIC channels in the heart. The colony was validated by mRNA and protein levels of other ion channels present in mice hearts. Using homology modelling, I also studied the putative structural changes to RyR2 caused by the mutations V2475F and R2474S that are associated with the lethal arrhythmic disease, catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1). The predicted models suggested that there are significant conformation changes to the RyR2 helical domain1, thus providing new information regarding the relationship between structural and function in CPVT1

On the design of a novel JPEG quantization table for improved feature detection performance

Keypoint or interest point detection is the first step in many com-puter vision algorithms. The detection performance of the state-of-the-art detectors is, however, strongly influenced by compression ar-tifacts, especially at low bit rates. In this paper, we design a novel quantization table for the widely-used JPEG compression standard which leads to improved feature detection performance. After an-alyzing several popular scale-space based detectors, we propose a novel quantization table which is based on the observed impact of scale-space processing on the DCT basis functions. Experimental results show that the novel quantization table outperforms the JPEG default quantization table in terms of feature repeatability, number of correspondences, matching score, and number of correct matches

HRDoc: Dataset and Baseline Method toward Hierarchical Reconstruction of Document Structures

The problem of document structure reconstruction refers to converting digital or scanned documents into corresponding semantic structures. Most existing works mainly focus on splitting the boundary of each element in a single document page, neglecting the reconstruction of semantic structure in multi-page documents. This paper introduces hierarchical reconstruction of document structures as a novel task suitable for NLP and CV fields. To better evaluate the system performance on the new task, we built a large-scale dataset named HRDoc, which consists of 2,500 multi-page documents with nearly 2 million semantic units. Every document in HRDoc has line-level annotations including categories and relations obtained from rule-based extractors and human annotators. Moreover, we proposed an encoder-decoder-based hierarchical document structure parsing system (DSPS) to tackle this problem. By adopting a multi-modal bidirectional encoder and a structure-aware GRU decoder with soft-mask operation, the DSPS model surpass the baseline method by a large margin. All scripts and datasets will be made publicly available at https://github.com/jfma-USTC/HRDoc

Evaluation of urban flooding and potential exposure risk in central and southern Liaoning urban agglomeration, China

Urban flooding is an important natural hazard that affects urban security in the context of global climate change and urbanization. The simulation of stormwater inundation and risk assessment in urban environments is critical for the sustainable development of urban agglomerations. However, few studies have focused on rainstorm flooding at the urban agglomeration scale. In this study, the Central and Southern Liaoning Urban Agglomeration (CSLN) was selected a case study. A method was proposed to assess the urban flooding and potential exposure risk. The urban flooding of CSLN was characterized by the average flooding depth (AFD) of each sub-catchment, and exposure risk was indicated by potential regional and population exposure risk. The results illustrate that the AFD increased with an increase in the rainfall return period, especially in the urban core. The AFD of each city in the CSLN ranged from 10 to 80 mm, and there were strong differences among cities. The spatial distribution of urban flooding in the nine cities presented aggregation characteristics, and hotspots were mainly concentrated in the old urban districts. The potential regional exposure risk tended to increase as the rainfall return period increased from 10 to 100 years; however, there were significant differences among cities. Among them, the area of potential regional exposure risk in Shenyang was the largest, increasing from 365 km2 under a 10-year rainfall return period to 463 km2 under a 100-year rainfall return period. The largest proportion of potential regional exposure risk was in Anshan, which increased from 3% under 10-year to 13.8% under 100-year rainfall return periods. Most cities had some potential population exposure risk. More residents in populous cities, such as Shenyang and Dalian, were subject to higher exposure risks. However, Benxi, Anshan, and Tieling had a high proportion of severely affected areas, although the size of their cities is much smaller than that of Shenyang and Dalian. Urban flooding and potential exposure risk were apparently higher in the business and government zones than in the industrial and greenspace zones. These methods and results may provide references for rainstorm flooding mitigation through urban planning in urban agglomeration areas

Discovery of 4,5-Dihydro-1H-thieno[2′,3′:2,3]thiepino [4,5-c]pyrazole-3-carboxamide Derivatives as the Potential Epidermal Growth Factor Receptors for Tyrosine Kinase Inhibitors

The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1H-thieno [2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A Docking simulation was performed to fit compound 6g and gifitinib into the EGFR to determine the probable binding models, and the binding sites and modes conformation of 6g and gifitinib were exactly similar, the two compounds were stabilized by hydrogen bond interactions with MET769. Combining with the biological activity evaluation, compound 6g demonstrated the most potent inhibitory activity (IC50 = 9.68 ± 1.95 μmol·L–1 for A549). Conclusively, 4,5-dihydro-1H-thieno[2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the EGFR tyrosine kinase inhibitors were discovered, and could be used as potential lead compounds against cancer cells