Nearest Neighbor Machine Translation is Meta-Optimizer on Output Projection Layer

Nearest Neighbor Machine Translation ($k$NN-MT) has achieved great success in domain adaptation tasks by integrating pre-trained Neural Machine Translation (NMT) models with domain-specific token-level retrieval. However, the reasons underlying its success have not been thoroughly investigated. In this paper, we comprehensively analyze $k$NN-MT through theoretical and empirical studies. Initially, we provide new insights into the working mechanism of $k$NN-MT as an efficient technique to implicitly execute gradient descent on the output projection layer of NMT, indicating that it is a specific case of model fine-tuning. Subsequently, we conduct multi-domain experiments and word-level analysis to examine the differences in performance between $k$NN-MT and entire-model fine-tuning. Our findings suggest that: (1) Incorporating $k$NN-MT with adapters yields comparable translation performance to fine-tuning on in-domain test sets, while achieving better performance on out-of-domain test sets; (2) Fine-tuning significantly outperforms $k$NN-MT on the recall of in-domain low-frequency words, but this gap could be bridged by optimizing the context representations with additional adapter layers.Comment: Accepted by EMNLP202

OmniDrones: An Efficient and Flexible Platform for Reinforcement Learning in Drone Control

In this work, we introduce OmniDrones, an efficient and flexible platform tailored for reinforcement learning in drone control, built on Nvidia's Omniverse Isaac Sim. It employs a bottom-up design approach that allows users to easily design and experiment with various application scenarios on top of GPU-parallelized simulations. It also offers a range of benchmark tasks, presenting challenges ranging from single-drone hovering to over-actuated system tracking. In summary, we propose an open-sourced drone simulation platform, equipped with an extensive suite of tools for drone learning. It includes 4 drone models, 5 sensor modalities, 4 control modes, over 10 benchmark tasks, and a selection of widely used RL baselines. To showcase the capabilities of OmniDrones and to support future research, we also provide preliminary results on these benchmark tasks. We hope this platform will encourage further studies on applying RL to practical drone systems.Comment: Submitted to IEEE RA-

Gains and losses from collusion: an empirical study on market behaviors of China’s power enterprises

Purpose: Collusion is a common behavior of oligarch enterprises aiming to get an advantage in market competition. The purpose of the research is to explore positive or negative effects from the electricity generation manufacturers’ collusion through statistical analysis approach. To be exact, these effects are discovered both in market economy at a macro-economic level and in enterprise behaviors at a micro-economic level. Design/methodology/approach: This research designs a model as an extension of Porter’s model (Green & Porter, 1984). In this model FIML is applied. Taking price bidding project launched in China’s power industry as an example, this paper conducts an empirical research on its relevant price data collected from subordinate power plants of China’s five power generation groups in the pilots. Findings: It is found in this paper that power generation enterprises are facing collusion issues in the market. To be exact, it is such a situation in which non-cooperative competition and collusion alternate. Under the competition, market is relatively steady, thus forming a lower network price. It is helpful to the development of the whole industry. However, once Cartel is formed, the price will rise and clash with power enterprises and transmission-distribution companies concerning the interests conflicts. At the same time, a higher power price will form in the market, making consumers suffer losses. All of these are bad for industry development. Not only the collusion of power enterprises affects power price but also the market power that caused by long-time Cartel will reduce the market entrant in electricity generation. Market resources are centralized in the hands of Cartel, causing a low effective competition in the market, which has passive effects on users. Implications: The empirical research also indicates that collusion undoubtedly benefits the power enterprises that involved. As a cooperation pattern, collusion can lead to the synergy between relevant companies. However, collusion harms the benefits of other market entities. During the process of enterprises creating common interests cooperatively, collusion may bring harm to the outside industry. Originality/value: Using empirical research method, the paper takes China’s power industry as an example to show the gains and losses of collusion from two aspects, namely market economy and strategic management.Peer Reviewe

Assessing the Inbound Tourism Efficiency of European Countries in China: 2006-2019

Assessing inbound tourism efficiency helps to understand the potential levels and constraints of inbound tourism flows. In this study, 35 European countries and China were selected as samples and influencing factors oftourism efficiency were constructed within the gravity model (GM) and stochastic frontier analysis (SFA). Taking into account individual heterogeneity, a true fixed-effects stochastic frontier gravity model (TFE-SFA-GM) was developed and empirically analysed using data from 2006 to 2019. The results show that (1) the inbound tourism efficiency of European countries in China is jointly affected by many core factors, such as economic scale, geographic distance, and population size on both sides; (2) the inefficiency factors that affect the inbound tourism efficiency of European countries in China are diversified;(3) the inbound tourism efficiency of European countries in China generally shows an upward trend during the sample period, but there are significant differences in the gap between the frontier level of inbound tourism flow in China and the actual inbound tourism flow. These findings imply that to better attract European tourists, China must continue to maintain and strengthen economic and trade relations with European countries, create a favourable security environment for tourism, highlight the integration of international tourism resources with Chinese culture, and continue to promote them in Europ

USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients

LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy

Molecular mechanisms of therapy resistance in HCC: USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis and YAP/TAZ and ATF4 collaboratively drive resistance to Sorafenib therapy in hepatocellular carcinoma by preventing ferroptosis

Primary liver cancer is the 6th most common cancer and 4th leading cause of cancer-related death with over 780,000 new cases annually worldwide. Hepatocellular carcinoma (HCC) represents the most common type of primary malignant liver tumor and accounts for 90% of all liver cancers. But only 30% of all HCC patients are diagnosed at the early stage, most of the HCC patients are diagnosed at very advanced stage, when surgical resection, liver transplantation and percutaneous tumor ablation are not applicable. In 2007, Sorafenib was approved by the FDA as the first-line systemic treatment for advanced HCC patients, however, the prolonged median overall survival is only around 3 months, and resistance to Sorafenib often develops very fast in HCC patients. Therefore, the delineation of the detailed mechanisms of how HCC cells respond to Sorafenib will not only help us to improve the efficacy of Sorafenib therapy in HCC patients, but will also be critical to overcome the development of therapy resistance. To uncover the molecular mechanisms driving the response and resistance to Sorafenib in HCC cells, we first established Sorafenib-resistant HCC cell lines with treatment of either increasing concentration or constant high concentration of Sorafenib on two Sorafenib-susceptible HCC cell lines Huh7 and Hep3B in vitro. Transcriptomic analysis of the established Sorafenib-resistant cells in comparison with their Sorafenib-responsive counterparts were conducted to identify the genes and pathways underlying the development of Sorafenib-resistance in HCC cells. In a first project, I employed pathway analysis of established Sorafenib-resistant cells and found that HIF1 signaling was upregulated in Sorafenib-resistant HCC cells. As a well-known oncogene, HIF1 has been proved to upregulate drug resistance in many types of cancers, including Sorafenib resistance in HCC. But how HIF1 is regulated and activated in Sorafenib-resistant HCC remains unclear. To uncover the regulation of HIF1 in Sorafenib-resistant HCC, I performed a small-scale siRNA screen targeting different deubiquitylating enzymes (DUBs) in an intrinsic Sorafenib-resistant HCC cell line HLE which identified the DUB USP29 as the potential upstream regulator of HIF1 protein stability in therapy-resistant HCC. Further studies validated that the regulation of HIF1 by USP29 was through deubiquitylation of HIF1. As a consequence, USP29-stabilized HIF1 promoted high glycolysis levels in Sorafenib-resistant HCC cells. Together, the results indicate that USP29 could be a potential biomarker for the prediction of therapy response in HCC patients and highlight the USP29-HIF1-glycolysis regulatory network as an emerging therapeutic target to overcome therapy resistance in HCC patients. In a second project, I set out to identify potential novel therapeutic targets in HCC to overcome Sorafenib resistance. To achieve this, I performed a shRNA-based genome-wide synthetic lethality screen on Sorafenib-resistant HCC cells. Among several genes, this screen identified the Hippo signaling transcription factor WWTR1, also known as TAZ, as critical in providing Sorafenib-resistant HCC cells with the ability to overcome this therapy. As a functional homologue of TAZ, YAP was also considered as a synthetic lethal gene. Transcriptomic analysis of YAP/TAZ-deficient HCC cells revealed SLC7A11, the gene encoding a cystine importer required for glutathione synthesis, as a potential downstream target of YAP/TAZ transcriptional activity. Gene set enrichment analysis (GSEA) of the expression of YAP/TAZ-deficient cells and the synthetic lethal screening hits indicated that the YAP/TAZ-SLC7A11 axis was activated in Sorafenib-resistant HCC cells to overcome cell death by ferroptosis. Further studies revealed that the regulation of SLC7A11 expression by YAP/TAZ was further regulated by ATF4-dependent and independent mechanisms. Further experimental evidence indicated that a combination treatment of glutathione synthesis inhibitors and Sorafenib was able to re-install ferroptosis in Sorafenib-resistant HCC cells, thus offering a promising new therapeutic approach to overcome Sorafenib resistance in HCC. In summary, my PhD work generated novel insights into the molecular mechanisms underlying Sorafenib resistance in HCC. 1. As a positive regulator of HIF1, USP29 promotes its stability and transcriptional activation in HCC, thus conferring high glycolysis levels and resistance to Sorafenib in HCC. 2. YAP/TAZ and ATF4 exert critical roles in the regulation of ferroptosis in Sorafenib-resistant HCC by upregulating SLC7A11 expression which re-installs Sorafenib-induced ferroptosis of HCC cells. The findings thus have direct implications on potential therapeutic approaches of how to overcome the development of resistance to Sorafenib, one of the main therapies of advanced HCC in patients