Preexisting discontinuities, such as joints and beddings, are widely distributed in unconventional reservoirs. During fluid injection, hydraulic fractures strongly interact with preexisting ...discontinuities, leading to great uncertainty in prediction of fracture geometry. To investigate how preexisting discontinuities affect fracture complexity, numerical simulations are carried out using the distinct element method. A discrete fracture network (DFN) model for a shale reservoir in the southeastern Ordos basin, China is built. Four cubic models, including the (1) rock matrix model, (2) bedding model, (3) joint model and (4) bedding and joint model, are extracted from the DFN model and then are used for numerical simulations. The results indicate that preexisting discontinuities strongly influence fracture complexity: they impose a barrier for fracture growth in most cases, and thus result in a smaller fracture area and a higher fluid pressure for fracture extension. However, the roles that joints and beddings play in fracture complexity differ. Compared with the bedding model, the joint model causes a less complex fracture geometry under the same injection condition, suggesting that the joints play a more significant role in reducing fracture complexity.
•A 3D DFN model coupling different kinds of preexisting discontinuities is built.•Interaction between hydraulic fractures and preexisting discontinuities is modeled.•Influence of preexisting discontinuities on fracturing complexity is discussed.•Results show that joints play a significant role in reducing fracture complexity.
With the rise of high-end technologies such as artificial intelligence and big data, many new consumption patterns are constantly emerging, from offline retail to online e-commerce and then to a New ...Retail mode combining online e-commerce, offline and logistics. The New Retail mode not only brings a strong impact to the traditional retail industry, but also provides many enterprises with new operation and marketing ideas. The research object selected by the author is Luckin coffee, a representative enterprise of the New Retail mode, by analyzing the operation mode of “online APP+ offline store + logistics” used by Luckin coffee and the marketing method implemented under this mode, the innovation of Luckin coffee’s marketing method is concluded, including Viral social fission marketing, Innovation of service process, Big data differentiated marketing, Novel scene positioning, Omni-channel retail, which can provide some ideas such as Social fission, Big data prediction, differentiated marketing, Fully integrated channels and so on for other traditional retail enterprises to reform and new Retail enterprises to formulate marketing strategies.
Purpose
Existing studies have shown that all kinds of audit risks greatly affect audit pricing for accounting firms. However, it is still unclear whether environmental risks caused by environmental ...violations lead to a high audit fee. This study aims to investigate whether accounting firms raise audit fees after client firms have violated environmental regulations or have been punished for such violations.
Design/methodology/approach
This study selects listed firms with environmental violations between 1994 and 2018 as the treatment sample and match the treatment group with a control group of firms from the same industry, of similar asset size and with no environmental violations for the same time period. Then, this study constructs a difference-in-difference (DID) model to explore the impact of firm environmental violations (or punishment for environmental violations) on the audit pricing.
Findings
This study finds that accounting firms tend to raise audit fees after client firms have violated environmental regulations or have been punished for such violations, and this increasing effect is different due to environmental regulation intensity, regional span and internal control defects. Further evidences show that environmental violations influence audit fees through financial restatement, whereas environmental punishments impact audit fees through earnings management and risk-taking.
Originality/value
This study enriches the literature on determining factors of audit fees and economic consequences of environmental violations and provides empirical supports to understand the pricing behavior of accounting firms.
Underground excavation often encountered rock masses embedded with pre-existing fractures. Conventional excavation analysis was generally based on a continuum description. In this study, to ...investigate the influence of randomly distributed discrete fractures on underground excavation, a finite element modeling approach based on a three-dimensional (3D) discrete fracture network (DFN) was utilized. The influence of fracture parameters including fracture intensity, dip angle and strike on the surrounding rock stability was considered in the simulation. The results suggested that fractures caused complexity in terms of the deformation behavior of rock masses around the underground cavern, facilitated the instability of surrounding rock. The intensity, dip angle and strike of fractures had different effects on the stress, displacement and failure modes of the jointed rock masses. The fracture intensity mainly affected the magnitudes of the induced stress and displacement of surrounding rock masses: a larger stress concentration and heterogeneous distribution were more likely to occur in rock masses with lower fracture intensity. While the dip angle and strike of fractures showed more impact on the distribution of displacement and failure modes of surrounding rock masses, especially for those on the roof and sidewall.
The effects in field manipulation experiments are strongly influenced by amplified interannual variation in ambient climate as the experimental duration increases. Soil respiration (SR), as an ...important part of the carbon cycle in terrestrial ecosystems, is sensitive to climate changes such as temperature and precipitation changes. A growing body of evidence has indicated that ambient climate affects the temperature sensitivity of SR, which benchmarks the strength of terrestrial soil carbon–climate feedbacks. However, whether SR sensitivity to precipitation changes is influenced by ambient climate is still not clear. In addition, the mechanism driving the above phenomenon is still poorly understood. Here, a long‐term field manipulation experiment with five precipitation treatments (−60%, −40%, +0%, +40%, and +60% of annual precipitation) was conducted in a marsh in the Yellow River Delta, China, which is sensitive to soil drying–wetting cycle caused by precipitation changes. Results showed that SR increased exponentially along the experimental precipitation gradient each year and the sensitivity of SR (standardized by per 100 mm change in precipitation under precipitation treatments) exhibited significant interannual variation from 2016 to 2021. In addition, temperature, net radiation, and ambient precipitation all exhibited dramatic interannual variability; however, only ambient precipitation had a significant negative correlation with SR sensitivity. Moreover, the sensitivity of SR was significantly positively related to the sensitivity of belowground biomass (BGB) across 6 years. Structural equation modeling and regression analysis also showed that precipitation treatments significantly affected SR and its autotrophic and heterotrophic components by altering BGB. Our study demonstrated that ambient precipitation determines the sensitivity of SR to precipitation treatments in marshes. The findings underscore the importance of ambient climate in regulating ecosystem responses in long‐term field manipulation experiments.
Ambient precipitation had a significant negative correlation with the sensitivity of SR to field precipitation treatments in marshes. Based on the increase in the interannual variability of ambient precipitation over the past 61 years (1961–2021), amplified interannual variation in ambient precipitation in the future may modulate the sensitivity of SR to climate changes. DPPT, decreased precipitation; IPPT, increased precipitation; PV, precipitation variability; SR, soil respiration.
Background and Purpose
Before advancing to clinical trials, new drugs are screened for their pro‐arrhythmic potential using a method that is overly conservative and provides limited mechanistic ...insight. The shortcomings of this approach can lead to the mis‐classification of beneficial drugs as pro‐arrhythmic.
Experimental Approach
An in silico–in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell‐derived cardiomyocyte (iPSC‐CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC‐CMs before and after treatment with a control solution or a low‐ (verapamil), intermediate‐ (cisapride or quinine) or high‐risk (quinidine) drug.
Key Results
Significant AP prolongation (a pro‐arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of IKr (a source of arrhythmias) by all strong IKr blockers, including cisapride, quinidine and quinine. The protocol also detected block of ICaL by verapamil and Ito by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified If block by quinine, which was confirmed with experiments using a HEK‐293 expression system and automated patch‐clamp.
Conclusion and Implications
We developed an in silico–in vitro pipeline that simultaneously identifies pro‐arrhythmia risk and mechanism of ion channel‐blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening.
This research presents a simulation of hydraulic fracturing process in a naturally fractured reservoir based on a discrete fracture network (DFN) model coupling different kinds of pre-existing ...discontinuities. Natural fractures and bedding planes obtained from outcrops and downhole camera in the Ordos Basin of China are used to build a three-dimensional DFN model. The propagation of hydraulic fractures in the layered and naturally-fractured reservoir, and the complex interactions between hydraulic fractures, natural fractures and bedding planes are simulated using the displacement discontinuity method. The results show that strong interactions between hydraulic fractures and pre-existing discontinuities occur during fluid injection, causing complex fracture geometry. When the injection rate is 0.01 m3/min, only one major hydraulic fracture is induced, and crack growth along bedding interface does not occur since the fluid pressure is not high enough. With increasing injection rate (0.1 m3/min and 1.0 m3/min), natural fracture and bedding planes are activated, inducing multiple major hydraulic fractures and reticulated fractures. For each injection scheme, fracture geometry in the horizontal and vertical directions becomes more complex with the injection of fracturing fluid. However, fracture complexity in the horizontal direction is smaller than that in the vertical direction when the injection rate varies from 0.01 m3/min to 1.0 m3/min. Besides, the results show that injection rate has a strong positive influence on the increment of fracture complexity.
•A DFN model coupling different kinds of geological discontinuities is built.•Simulation of hydraulic fracturing in a fractured reservoir is conducted using DDM.•Influence of natural fractures and bedding planes on hydraulic fracturing is studied.
Soil moisture remarkably influences soil organic carbon (SOC) decomposition and is one of the key variables in ecological models influencing changes in soil carbon (C) storage. However, the ...mechanisms determining the impact of soil moisture on SOC decomposition in coastal wetlands are poorly understood. We collected and incubated soil samples from a coastal wetland of the Yellow River Delta, China, to investigate the response of SOC decomposition (the sum of CO
2
–C and CH
4
–C) to soil moisture. Soil samples were incubated at 20%, 60%, 100%, 140% and 180% water holding capacity (WHC), respectively. Compared to drought condition (20% WHC), moist (60% and 100% WHC) and flooding (140% and 180% WHC) conditions were observed with significantly higher SOC decomposition, explained by increased soil microbial biomass and altered soil physical parameters (pH and electronic conductivity (EC)). Excluding the effect of drought, we found decreased SOC decomposition with increased microbial biomass in flooding conditions compared to moist conditions. Structural equation modeling analysis showed that SOC decomposition and soil C storage were associated with changes in soil environment and soil microbial biomass resulted from soil moisture variation. This study highlights the importance of soil moisture in soil carbon dynamics, which is enlightening for the evaluation of soil C cycling with a decline of soil moisture under a warmer climate in coastal wetlands.
The neonatal intestinal tract is immature and can be easily infected by pathogens causing inflammation. Maternal diet manipulation is a promising nutritional strategy to enhance the gut health of ...offspring. A fermented diet is a gut microbiota targeting diet containing live probiotics and their metabolites, which benefit the gut and overall health host. However, it remains unclear how a maternal fermented diet (MFD) affects neonatal intestinal inflammation. Here, in vivo and in vitro models together with multi-omics analysis were applied to investigate the impacts and the underlying mechanism through which an MFD prevents from gut inflammation in neonates. An MFD remarkably improved the performance of both sows and piglets and significantly altered the gut microbiome and milk metabolome of sows. In addition, the MFD significantly accelerated the maturation of the gut microbiota of neonates and increased the abundance of gut Lactobacillus and the microbial functions of amino acid-related enzymes and glucose metabolism on the weaning day. Notably, the MFD reduced susceptibility to colonic inflammation in offspring. The fecal microbiota of sows was then transplanted into mouse dams and it was found that the mouse dams and pups in the MFD group alleviated the LPS-induced decrease in gut Lactobacillus abundance and barrier injury. Milk L-glutamine (GLN) and gut Lactobacillus reuteri (LR) were found as two of the main MFD-induced sow effectors that contributed to the gut health of piglets. The properties of LR and GLN in modulating gut microbiota and alleviating colonic inflammation by inhibiting the phosphorylation of p38 and JNK activation of Caspase 3 were further verified. These findings provide the first data revealing that an MFD drives neonate gut microbiota development and ameliorates the colonic inflammation by regulating the gut microbiota. This fundamental evidence might provide references for modulating maternal nutrition to enhance early-life gut health and prevent gut inflammation.
Introduction
Hepatocellular carcinoma (HCC) prevalence is rising annually, but the existing treatment strategies are limited; therefore, it is crucial to explore new therapeutic approaches.
Methods
...Here, we investigate the potential anti-cancer mechanism of an herbal medicine called Tian Yang Wan (TYW) in the treatment of HCC. The relationship of CCDC43 with immunity and cell death was analyzed by bioinformatics. Confirming the tumor suppressor effect of TYW on HCC cells by proliferation, invasion, migration and apoptosis assays
Results
First, we analyzed by proteomics that CCDC43 expression was downregulated after TYW administration and promoted the hippo pathway. Then, a large sample's transcriptome study demonstrated that elevated CCDC43 expression was strongly correlated with clinical traits and a bad prognosis in HCC patients. Next, we observed through multiple advanced algorithms that CCDC43 is involved in a variety of oncology and immunology related pathways. Notably, we found higher tumor immune microenvironment with high CCDC43 expression. Furthermore, we demonstrated that CCDC43 is associated with immune checkpoints and found that it is a sensitive indicator of a large number of chemotherapeutic agents. Subsequently, we conducted experimental investigations to demonstrate the capacity of TYW to impede proliferation and migration, while inducing apoptosis in human HCC cell lines. Finally, we performed analysis of two cell death patterns which showed CCDC43 to be strongly correlated with multiple ferroptosis factors and cuproptosis factors.
Discusion
In conclusion, our study comprehensively examined the prognostic, immunological, and therapeutic implications of CCDC43 in HCC, thereby elucidating the therapeutic mechanism of action in TYW.
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