Digoxin and ouabain increase the synthesis of cholesterol in human liver cells

Digoxin and ouabain are steroid drugs that inhibit the Na⁺/K⁺-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells. Received 10 January 2009; received after revision 11 February 2009; accepted 6 March 2009     

Red blood cells carry out T cell growth and survival bioactivities that are sensitive to cyclosporine A

Red blood cells (RBC) have emerged as a novel regulatory cell type endowed with bioactivities toward activated human T cells. Herein we show that the RBC bioactivities act on intracellular pathways initiated by T cell receptor (TCR)-dependent and -independent stimuli, including IL-2, IL-15, and the mixture of phorbol dibutyrate and ionomycin. The RBC bioactivities preserve the antioxidant status and are capable of rescuing activated T cells from cell death induced by serum deprivation. They are not mediated by glycosylphosphatidylinositol-linked receptors or sialic acids, and kinetic studies revealed that they hasten the entrance into the cell cycle. By using cyclosporine A (CsA) and rapamycin (Rapa) we show that the RBC bioactivities are calcineurin-dependent. Thus, treatment of T cells with CsA, but not Rapa, impaired RBC bioactivities, and preincubation of RBC with CsA completely abolished their bioactivities. We have demonstrated that RBC carry out bioactivities that are sensitive to CsA.     

The response of human skeletal muscle tissue to hypoxia

Hypoxia refers to environmental or clinical settings that potentially threaten tissue oxygen homeostasis. One unique aspect of skeletal muscle is that, in addition to hypoxia, oxygen balance in this tissue may be further compromised when exercise is superimposed on hypoxia. This review focuses on the cellular and molecular responses of human skeletal muscle to acute and chronic hypoxia, with emphasis on physical exercise and training. Based on published work, it is suggested that hypoxia does not appear to promote angiogenesis or to greatly alter oxidative enzymes in skeletal muscle at rest. Although the HIF-1 pathway in skeletal muscle is still poorly documented, emerging evidence suggests that muscle HIF-1 signaling is only activated to a minor degree by hypoxia. On the other hand, combining hypoxia with exercise appears to improve some aspects of muscle O₂ transport and/or metabolism.     

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability. Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008     

Direct inhibition of phospholipid scrambling activity in erythrocytes by potassium ions

The exposure of phosphatidylserine (PS) at the cell surface plays a critical role in blood coagulation and serves as a macrophage recognition moiety for the engulfment of apoptotic cells. Previous observations have shown that a high extracellular [K⁺] and selective K⁺ channel blockers inhibit PS exposure in platelets and erythrocytes. Here we show that the rate of PS exposure in erythrocytes decreases by ~50% when the intracellular [K⁺] increases from 0 to physiological concentrations. Using resealed erythrocyte membranes, we further show that lipid scrambling is inducible by raising the intracellular [Ca²⁺] and that K⁺ ions have a direct inhibitory effect on this process. Lipid scrambling in resealed ghosts occurs in the absence of cell shrinkage and microvesicle formation, processes that are generally attributed to Ca²⁺-induced lipid scrambling in intact erythrocytes. Thus, opening of Ca²⁺-sensitive K⁺ channels causes loss of intracellular K⁺ that results in reduced intrinsic inhibitory effect of these ions on scramblase activity. Received 11 September 2008; received after revision 17 October 2008; accepted 27 October 2008     

Dual hesitant fuzzy information aggregation with Einstein t-conorm and t-norm

Dual hesitant fuzzy set (DHFS) is a new generalization of fuzzy set (FS) consisting of two parts (i.e., the membership hesitancy function and the non-membership hesitancy function), which confronts several different possible values indicating the epistemic degrees whether certainty or uncertainty. It encompasses fuzzy set (FS), intuitionistic fuzzy set (IFS), and hesitant fuzzy set (HFS) so that it can handle uncertain information more flexibly in the process of decision making. In this paper, we propose some new operations on dual hesitant fuzzy sets based on Einstein t-conorm and t-norm, study their properties and relationships and then give some dual hesitant fuzzy aggregation operators, which can be considered as the generalizations of some existing ones under fuzzy, intuitionistic fuzzy and hesitant fuzzy environments. Finally, a decision making algorithm under dual hesitant fuzzy environment is given based on the proposed aggregation operators and a numerical example is used to demonstrate the effectiveness of the method.     

Feature network-driven quadrant mapping for summarizing customer reviews

With the rapid growth of e-commerce, customers increasingly write online reviews of the product they purchase. These customer reviews are one of the most valuable sources of information affecting selection of products or services. Summarizing these customer reviews is becoming an interesting area of research, inspiring researchers to develop a more condensed, concise summarization for users. However, most of the current efforts at summarization are based on general product features without feature’s relationship. As a result, these summaries either ignore feedback from customers or do a poor job of reflecting the opinions expressed in customer reviews. To remedy this summarization shortcoming, we propose a feature network-driven quadrant mapping that captures and incorporates opinions from customer reviews. Our focus is on construction of a feature network, which is based on co-occurrence and sematic similarities, and a quadrant display showing the opinions polarity of feature groups. Moreover, the proposed approach involves clustering similar product features, and thus, it is different from standard text summarization based on abstraction and extraction. The summarized results can help customers better understand the overall opinions about a product.     

A partial robust optimization approach to inventory management for the offline-to-online problem under different selling prices

This study examines an optimal inventory strategy when a retailer markets a product at different selling prices through a dual-channel supply chain, comprising an online channel and an offline channel. Using the operating pattern of the offline-to-online (O2O) business model, we develop a partial robust optimization (PRO) model. Then, we provide a closed-form solution when only the mean and standard deviation of the online channel demand distribution is known and the offline channel demand follows a uniform distribution (partial robust). Specifically, owing to the good structural properties of the solution, we obtain a heuristic ordering formula for the general distribution case (i.e., the offline channel demand follows a general distribution). In addition, a series of numerical experiments prove the rationality of our conjecture. Moreover, after comparing our solution with other possible policies, we conclude that the PRO approach improves the performance of incorporating the internet into an existing supply chain and, thus, is able to adjust the level of conservativeness of the solution. Finally, in a degenerated situation, we compare our PRO approach with a combination of information approach. The results show that the PRO approach has more “robust” performance. As a result, a reasonable trade-off between robustness and performance is achieved.     

Supply chain performance for deteriorating items with cooperative advertising

To study the effect of cooperative advertising on the supply chain of deteriorating items, this paper establishes a Stackelberg game model for a two-echelon deteriorating items supply chain composed of one manufacturer and one retailer under a given support program with an exogenous participation rate. The manufacturer as the leader determines the wholesale price and production rate, and the retailer as the follower determines the retail price and advertising strategies. The strategies of the players under the decentralized scenario and the centralized scenario are respectively characterized. Numerical simulations and sensitivity analysis are conducted to gain some managerial insights. It is shown that the pricing, advertising and production strategies are negatively correlated to deteriorating coefficient, and both the profit and the channel efficiency decrease with deteriorating coefficient; The interaction between price, advertising investment and production rate results in a higher retail price of the centralized channel compared to that of the decentralized channel; Implementing the cooperative advertising program does improve the performance of the supply chain in some cases and the participation rate roughly at 0.5 is most preferable, but it is also possible to distort incentive and damage the channel performance when the participation rate reaches a relatively high level.     

Bell state preparation based on switching between quantum system models

For the preparation of any target Bell state under continuous quantum measurement, this paper proposes a method which achieves the control objective by switching between two different models or by switching between two control channels under one model. Proper control Hamiltonians are selected for the two system models, a switching strategy between the two models is designed, and the stability of the whole switching system is proved in theory. For a given target Bell state, the effectiveness of the proposed switching control strategy between different models is illustrated through simulation experiments.