PBK/TOPK INHIBITOR OTS964 RESISTANCE IS MEDIATED BY ABCG2- AND ABCB1-DEPENDENT TRANSPORT FUNCTION IN CANCER

Accumulating evidence has suggested that multi-drug resistance (MDR) in cancer cells is a phenotype whereby cancer cells have attenuated sensitivity to drugs. ATP-binding cassette super-family G member 2 (ABCG2/BCRP) and ATP-binding cassette sub-family B member 1 (ABCB1/P-gp) are members of the ATP-binding cassette (ABC) transporter family and involved in MDR. OTS964 is a potent inhibitor targeting to PDZ-binding kinase (PBK)/T-lymphokine-activated killer cell-originated protein kinase (TOPK). Herein, we aimed to explore the relationship between MDR-associated ABC transporters, including ABCG2 and ABCB1, and the regulation of OTS964 efficacy. PBK/TOPK inhibitor OTS964 resistance is mediated by ABCG2-dependent transport function in cancer: in vitro study The efficacy of OTS964 is limited in drug-selected and drug resistant gene-transfected cells, which overexpress ABCG2, compared to those of corresponding drug-sensitive cells. Also, a verified ABCG2 inhibitor Ko143 can re-sensitize the acquired resistance to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2. Furthermore, OTS964 stimulates ATPase activity of ABCG2 and upregulates ABCG2 expression, resulting in enhanced resistance to substrate-drugs transported by ABCG2. The in silico molecular docking analysis suggested that OTS964 interacts with drug-binding pocket of ABCG2. PBK/TOPK inhibitor OTS964 resistance is mediated by ABCB1-dependent transport function in cancer: in vitro and in vivo study The overexpression of ABCB1 significantly desensitizes both drug-selected and gene-transfected cell lines, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by a verified ABCB1 inhibitor verapamil. Also, a similar trend was observed in tumor-bearing mouse model. In mechanistic studies, OTS964 inhibits the efflux function mediated by ABCB1. Moreover, OTS964 stimulates ATPase activity and expression levels of ABCB1, leading to induced resistance to substrate-drugs transported by ABCB1. OTS964 receives a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein. Altogether, OTS964 is susceptible to ABCG2- and ABCB1-mediated drug resistance, and that this effect can be antagonized by known inhibitors. Our findings strongly support the importance of monitoring the level of ABCG2 and ABCB1 in cancer patients under OTS964 treatment. These findings may also serve as a valuable indication for follow-up clinical investigation on potential use of OTS964

PLoc: A New Evaluation Criterion Based on Physical Location for Autonomous Driving Datasets

Autonomous driving has garnered significant attention as a key research area within artificial intelligence. In the context of autonomous driving scenarios, the varying physical locations of objects correspond to different levels of danger. However, conventional evaluation criteria for automatic driving object detection often overlook the crucial aspect of an object's physical location, leading to evaluation results that may not accurately reflect the genuine threat posed by the object to the autonomous driving vehicle. To enhance the safety of autonomous driving, this paper introduces a novel evaluation criterion based on physical location information, termed PLoc. This criterion transcends the limitations of traditional criteria by acknowledging that the physical location of pedestrians in autonomous driving scenarios can provide valuable safety-related information. Furthermore, this paper presents a newly re-annotated dataset (ApolloScape-R) derived from ApolloScape. ApolloScape-R involves the relabeling of pedestrians based on the significance of their physical location. The dataset is utilized to assess the performance of various object detection models under the proposed PLoc criterion. Experimental results demonstrate that the average accuracy of all object detection models in identifying a person situated in the travel lane of an autonomous vehicle is lower than that for a person on a sidewalk. The dataset is publicly available at https://github.com/lnyrlyed/ApolloScape-R.gi

Segment Anything is A Good Pseudo-label Generator for Weakly Supervised Semantic Segmentation

Weakly supervised semantic segmentation with weak labels is a long-lived ill-posed problem. Mainstream methods mainly focus on improving the quality of pseudo labels. In this report, we attempt to explore the potential of 'prompt to masks' from the powerful class-agnostic large segmentation model, segment-anything. Specifically, different weak labels are used as prompts to the segment-anything model, generating precise class masks. The class masks are utilized to generate pseudo labels to train the segmentation networks. We have conducted extensive experiments on PASCAL VOC 2012 dataset. Experiments demonstrate that segment-anything can serve as a good pseudo-label generator. The code will be made publicly available.Comment: Technical repor

Multi-omics integration reveals molecular networks and regulators of psoriasis.

BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility

A mechanism for the latitudinal dependence of peak-spectrum sea surface height variability

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 119 (2014): 1431–1444, doi:10.1002/2013JC009642.Previous studies have shown that the power spectrum of satellite-observed sea surface height (SSH) variability peaks at a certain frequency (or a wave number) band at a given latitude. Lin et al. (2008) attributed this latitudinal dependence to the critical frequency of the first baroclinic mode Rossby waves in the tropical and subtropical oceans. Their study was based on the linear Rossby wave theory and focused on SSH variability in the tropical and subtropical oceans since the altimetry data do not adequately resolve lengths of baroclinic Rossby waves at and near the critical frequency in high latitudes. In this study, we expand their analysis to high-latitude oceanic basins and to include nonlinear eddy effects, by using a linear wave model and a high-resolution model output from the OGCM for the Earth Simulator (OFES). It is found that the linear wave mechanism by and large remains valid in the tropical and subtropical oceans. In higher latitudes as well as in some regions in the western tropical and subtropical oceans, other mechanisms, like nonlinear eddy, play more important role in determining the SSH variability.This work was supported by the China’s National Basic Research Priorities Programmer (2013CB956202), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA11010103), the Natural Science Foundation of China (41222037 and 41221063), the project of Global Change and Air-Sea interaction (GASI-03-01-01–02), the Ministry of Education’s 111 Project (B07036), the National Natural Science Foundation of Shandong (JQ201111), and the National Special Research Fund for Non-Profit Marine Sector (201205018). J. Y. is supported by US NSF (OCE 0927017 and OCE 1028739).2014-08-2

Exploring the Privacy Protection Capabilities of Chinese Large Language Models

Large language models (LLMs), renowned for their impressive capabilities in various tasks, have significantly advanced artificial intelligence. Yet, these advancements have raised growing concerns about privacy and security implications. To address these issues and explain the risks inherent in these models, we have devised a three-tiered progressive framework tailored for evaluating privacy in language systems. This framework consists of progressively complex and in-depth privacy test tasks at each tier. Our primary objective is to comprehensively evaluate the sensitivity of large language models to private information, examining how effectively they discern, manage, and safeguard sensitive data in diverse scenarios. This systematic evaluation helps us understand the degree to which these models comply with privacy protection guidelines and the effectiveness of their inherent safeguards against privacy breaches. Our observations indicate that existing Chinese large language models universally show privacy protection shortcomings. It seems that at the moment this widespread issue is unavoidable and may pose corresponding privacy risks in applications based on these models.Comment: 11 page