Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice.

We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 μM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf, Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo

HAZARD Challenge: Embodied Decision Making in Dynamically Changing Environments

Recent advances in high-fidelity virtual environments serve as one of the major driving forces for building intelligent embodied agents to perceive, reason and interact with the physical world. Typically, these environments remain unchanged unless agents interact with them. However, in real-world scenarios, agents might also face dynamically changing environments characterized by unexpected events and need to rapidly take action accordingly. To remedy this gap, we propose a new simulated embodied benchmark, called HAZARD, specifically designed to assess the decision-making abilities of embodied agents in dynamic situations. HAZARD consists of three unexpected disaster scenarios, including fire, flood, and wind, and specifically supports the utilization of large language models (LLMs) to assist common sense reasoning and decision-making. This benchmark enables us to evaluate autonomous agents' decision-making capabilities across various pipelines, including reinforcement learning (RL), rule-based, and search-based methods in dynamically changing environments. As a first step toward addressing this challenge using large language models, we further develop an LLM-based agent and perform an in-depth analysis of its promise and challenge of solving these challenging tasks. HAZARD is available at https://vis-www.cs.umass.edu/hazard/.Comment: ICLR 2024. The first two authors contributed equally to this wor

Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy

Colorectal cancer is the third most commonly diagnosed cancer worldwide. Although surgery remains the best treatment for this disease, adjuvant chemotherapy and radiotherapy are also very important in clinical practice. However, the notorious refractory lack of responses to radiochemotherapy greatly limits the application of radiochemotherapy in the context of colorectal cancer. There is a growing interest in the role that Aurora B may play in colorectal cancer cell survival as well as other cancer subtypes. In the current study, we sought to ascertain whether blocking of Aurora B signaling machinery by a small molecule inhibitor, CCT137690, could synergize radiation-induced colorectal cancer cell death. Results showed that CCT137690 increases the sensitivity of SW620 cells to radiation. Mechanistic studies revealed that Aurora B-Survivin pathway may be involved in this synergistic effect. Taken together, our results for the first time show that Aurora B inhibition and radiation exert a synergistic effect, resulting in enhanced colorectal cancer cell death. This synergistic effect is clinically relevant as lower doses of radiation could be used for cancer treatment, and could provide significant clinical benefits in terms of colorectal cancer management, while reducing unwanted side-effects

High-Efficiency Irrigation: Local Water Users’ Responses to the Modernization of Village Irrigation Technology and Government Control in China

In this paper, we investigate China’s vigorously promoted high-efficiency irrigation policies for farmland water conservation, deploying a governmentality framework. The paper explains how the modernist irrigation policies follow global discourses but seek to imbue these with new ambition and the meaning of ecological civilization. At the same time, the government aims to mold water users’ subjectivity in accordance with its development strategies. Following a local village case study, the paper further elucidates how, amidst the decline of commons’ local governance and water user responses, the state’s high-efficiency irrigation water governmentality project is adapted and negotiated. Local government bureaucracy actors and ordinary villagers challenge irrigation policies through local noncongruent institutions. Thereby, villagers’ pragmatic, non-aligned irrigation technologies and actions contradict state-assumed collective collaboration and government-aligned smooth operation

Rural drinking water governance politics in China : Governmentality schemes and negotiations from below

This paper examines the politics of rural water governance in China through a governmentality lens and village water intervention case. The China Rural Drinking Water Safety Project (RDWSP) was an attempt to control water, while also serving as a tool of power to impel the rural population towards national development goals. The authors analyzed official documents and conducted interviews in a village in Shandong Province to investigate the RDWSP's rationale and practices, as well as how water access and management were negotiated by rural water users. The paper argues that (1) confronted with a decline in local governance capacity and in an effort to rectify the mistakes of the supply-driven, technocratic paradigm, the RDWSP attempted to integrate social, environmental and economic concerns but did not achieve that goal; (2) the decline in local governance capacity and people's pragmatic everyday strategies contributed to an individualized approach to solving water problems, reflected in people's disengagement from the government project and local participation, an effect that may sustain people's marginalization and exclusion from good-quality water access and management. Using the Chinese water project as an example, the paper contributes to the debate on state-induced water control versus civil society “counter-conduct” formed by daily interactions. Furthermore, it enriches the study of politics in general by presenting the state as a site of contested institutionalization and ongoing negotiations, confronted by everyday narratives and encounters with marginalized citizens that go far beyond and are far more complex than overt resistance or covert weapons of the weak

Measurement and Analysis of Dielectric Properties of Agricultural By-product Powders in Microwave Frequency Range

Dielectric properties play an important role in the microwave-assisted application of nonmagnetic agriculture-related media. In this paper, the practical requirements for the lack of quantitative data on the dielectric properties of agricultural media in microwave-assisted applications are obtained. The dielectric properties data of four kinds of agricultural by-products powder (Potato powder, Pseudo -ginseng Powder, Gastrodia elata powder, Dendrobium chrysotoxum Lindl powder) under microwave frequency were measured, and related factors were analyzed. The results show that the uncalibrated coaxial transmission reflection method can be used to measure and analyse the dielectric properties of high frequency bands of powder materials. Dielectric constant (ε ′) and Dielectric loss factor (ε '') of agricultural by-products at room temperature have a relationship between microwave frequency and moisture content. It is a dependent and the mathematical relation is satisfied. The influence of microwave frequency and moisture content on the dielectric properties is as follows: lows: ε′>ε′′>tanδ. Under the conditions of civil microwave frequency (2.45GHz) and moisture content (2% ~ 25%), the dielectric constant and the dielectric loss factor of different kinds of agricultural by-products powder are in the range of 3.5 ~ 9 and 0.1 ~ 3.2 respectively. The results provide data basis for microwave processing and quality monitoring of agricultural by-products powder. The technical method is suitable for the measurement and analysis of the dielectric properties of powder materials

A functional +61G/A polymorphism in epidermal growth factor is associated with glioma risk among Asians.

BACKGROUND: Epidermal growth factor (EGF), a potent mitogenic protein, plays an important role in the development of cancers, including glioma. Previous studies showed that the EGF +61G/A polymorphism (rs4444903) may lead to an alteration in EGF production and/or activity, which can result in individual susceptibility to glioma. However, published data regarding the association between the +61G/A polymorphism and glioma risk was contradictory. OBJECTIVE: The aim of this study was to perform a meta-analysis of eligible studies to derive precise estimation of the association of EGF +61G/A with glioma risk. METHODS: We performed a pooled analysis of seven published studies that included 1,613 glioma cases and 2,267 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. RESULTS: Overall, no significant associations between the EGF +61G/A polymorphism and glioma cancer risk were found for AA versus GG (OR=0.95, 95% CI=0.62-1.45), GA versus GG (OR=0.94, 95% CI=0.72-1.22), AA/GA versus GG (OR=0.93, 95% CI=0.70-1.23), and AA versus GA/GG (OR=1.04, 95% CI=0.77-1.39). However, in the stratified analysis by ethnicity, the EGF +61G/A polymorphism had a higher risk of glioma development among Asians, but a lower risk among Caucasians. CONCLUSIONS: Taken together, the results suggest that the EGF +61G/A polymorphism may contribute to the susceptibility of glioma in different ethnic groups

A One-Pot Hydrothermal Preparation of High Loading Ni/La₂O₃ Catalyst for Efficient Hydrogenation of Cinnamaldehyde

It is a challenging task for selective hydrogenation of cinnamaldehyde (CAL) to hydrocinnamaldehyde (HCAL) without additional by-product formation. In this work, a La2O3 supported high Ni content nanoparticle catalyst was prepared for CAL selective hydrogenation. Meanwhile, Co-La2O3 catalysts were used as a reference catalyst. XRD, TEM, STEM-HAADF, XPS, and H2-TPR measurements were used to investigate the physicochemical properties of Ni-La2O3 catalysts. The experimental results confirmed that the CAL conversion and HCAL selectivity were effectively promoted with the increase of Ni loading amounts. At a Ni/La molar ratio of four, a high HCAL selectivity of 87.4% was obtained at a CAL conversion of 88.1% under mild reaction conditions. The catalyst was recycled five times without activity loss. Combined with various characterizations, it could be inferred that the good hydrogen adsorption and dissociation capacity of Ni and the presence of a certain amount of oxygen vacancies on the La2O3 support have a positive effect on the improvement of HCAL selectivity. This work provided an effective path to design transition-metal-based supported oxide catalyst for the cinnamaldehyde hydrogenation to hydrocinnamaldehyde