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Experts have ranked Taiwan as the number one country regarding the exposure to disinformation. This assessment is not surprising as many exposed disinformation cases can be linked to Chinese state-aligned actors but also domestic political actors. Academic researchers, journalists, and the civic tech community have played an essential role in the fight against disinformation in Taiwan and the emergence of misinformation studies as a new research field. While disinformation in Taiwan is a major recurring issue, the "Western" debate within academia and journalism has taken a critical turn regarding the assumed effects of disinformation. Our study focuses on this potential disconnect between the international and the Taiwanese debate about disinformation. With automatic and manual content analysis, we evaluate what role academics and journalism play in the public discourse and what part of this debate reaches the largest audience. We show how Taiwan's public misinformation discourse has evolved vis-a-vis the international discourse, what role misinformation studies play in this discourse, what part of the discourse reaches the widest audience, and what parts of the discourse could be problematic. [ABSTRACT FROM AUTHOR]

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment. We identified a novel MAP4K4 inhibitor using a structure-based virtual screening strategy. Kinase profiling showed high selectivity towards MAP4K4. The identified inhibitor suppressed pancreatic cancer cell growth and viability in vitro. The inhibitor downregulated the MKK4-JNK signalling pathway. The inhibitor suppressed tumour growth in vivo. [ABSTRACT FROM AUTHOR]

In a Bayesian reliability analysis of a system with dependent components, an aggregate analysis (i.e. system-level analysis) or a simplified disaggregate analysis with independence assumptions may be preferable if the estimations obtained from employing these two approaches do not deviate substantially from those derived through a disaggregate analysis, which is generally considered the most accurate method. This study was conducted to identify the key factors and their range of values that lead to estimation errors of great magnitude. In particular, a copula-based Bayesian reliability model was developed to formulate the dependence structure for a products of probabilities model of a simple parallel system. Monte Carlo simulation, regionalised sensitivity analysis and classification tree learning were employed to investigate the key factors. The resulting classification tree achieved favourable predictive accuracy. Several decision rules suggesting the optimal approach under different combinations of conditions were also extracted. This study has made a methodological contribution in laying the groundwork for investigating systems with dependent components using copula-based Bayesian reliability models. With regard to practical implications, this study also derived useful guidelines for selecting the most appropriate analysis approach under different scenarios with different magnitude of dependence. [ABSTRACT FROM AUTHOR]

Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower KD's and more predicted residue interactions. Moreover, TP6 displayed the greatest growth inhibiting effect in the Panc1 pancreatic cancer cell line with an IC50 of 0.393 µM. This represents more than a 2-fold improvement over NSAH, making TP6 the most potent compound against pancreatic cancer emerging from the hydrazone inhibitors. NSAH was optimised by the addition of cyclic and polar groups replacing the naphthyl moiety, which occupies the phosphate-binding pocket in the C-site, establishing a new direction in inhibitor design. [ABSTRACT FROM AUTHOR]

The single-machine total weighted tardiness (SMTWT) problem is a typical discrete combinatorial optimization problem in the scheduling literature. This problem has been proved to be NP hard and thus provides a challenging area for metaheuristics, especially the variable neighbourhood search algorithm. In this article, a multiple variable neighbourhood search (m-VNS) algorithm with multiple neighbourhood structures is proposed to solve the problem. Special mechanisms named matching and strengthening operations are employed in the algorithm, which has an auto-revising local search procedure to explore the solution space beyond local optimality. Two aspects, searching direction and searching depth, are considered, and neighbourhood structures are systematically exchanged. Experimental results show that the proposed m-VNS algorithm outperforms all the compared algorithms in solving the SMTWT problem. [ABSTRACT FROM AUTHOR]