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Objective Sick sinus syndrome (SSS) is associated with loss of HCN4 (hyperpolarization-activated cyclic nucleotide-gated potassium channel 4) function in the cardiac conduction system. The underlying mechanism for SSS remains elusive. This study is to investigate how mitochondrial oxidative stress induces HCN4 downregulation associated with in sick sinus syndrome. Methods and results Trx2lox/lox mice were crossed with α-myosin heavy chain (α-Mhc)-Cre and Hcn4-CreERT2 deleter mice to generate Trx2 deletion mice in the whole heart (Trx2cKO) and in the conduction system (Trx2ccsKO), respectively. Echocardiography was applied to measure hemodynamics and heart rhythm. Histological analyses, gene profiling and chromatin immunoprecipitation were performed to define the mechanism by which thioredoxin-2 (Trx2) regulates HCN4 expression and cardiac function. Trx2cKO mice displayed dilated cardiomyopathy, low heart rate, and atrial ventricular block (AVB) phenotypes. Immunofluorescence revealed that HCN4 expression was specifically reduced within the sinoatrial node in Trx2cKO mice. Interestingly, Trx2ccsKO mice displayed low heart rate and AVB without dilated cardiomyopathy. Both mRNA and protein levels of HCN4 were reduced in the sinoatrial node, suggesting transcriptional HCN4 regulation upon Trx2 deletion. ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion. Moreover, HDAC4 binding to the HCN4 enhancer was mediated by MEF2. Mitochondrial ROS were increased by Trx2 deletion and importantly, mitochondria-specific ROS scavenger MitoTEMPO suppressed HDAC4 elevation, HCN4 reduction, and sinus bradycardia in Trx2ccsKO mice. Conclusion In the conduction system, Trx2 is critical for maintaining HCN4-mediated normal heart rate. Loss of Trx2 reduces HCN4 expression via a mitochondrial ROS-HDAC4-MEF2C pathway and subsequently induces sick sinus syndrome in mice.

In this paper, by means of the weight coefficients, the transfer formula, Hermite-Hadamard’s inequality and the technique of real analysis, a more accurate multidimensional Hardy-Hilbert-type inequality with a best possible constant factor is given, which is an extension of some published results. Moreover, the equivalent forms and the operator expressions are considered. 2000 Mathematics Subject Classification: 26D15, 47A05, Keywords: Hardy-Hilbert’s inequality, Weight coefficient, Hermite-Hadamard’s inequality, Equivalent form, Operator

A new Hilbert-type integral inequality in the whole plane with the non-homogeneous kernel and parameters is given. The constant factor related to the hypergeometric function and the beta function is proved to be the best possible. As applications, equivalent forms, the reverses, some particular examples, two kinds of Hardy-type inequalities, and operator expressions are considered.

In this paper a multidimensional Hilbert-type integral inequality with the best possible constant factor associated to the gamma function is proved. An equivalent form and some reverses are obtained. We also consider the operator expressions and some particular results related to the non-homogeneous kernels and a homogeneous kernel of degree zero.

We provide a dynamic, game-theoretic model to examine a firm’s quality and pricing decisions for its new experience goods. Early consumers do not observe product quality prior to purchase but can learn it after purchase and share that product-quality information with later consumers—for example, through online reviews. Both the firm’s quality decision and its cost efficiency are the firm’s private information and not directly observed by the consumer. The early consumers can make a rational inference from the firm’s price about its cost and quality taking into account the firm’s profit incentive from the later informed consumers. We find that in equilibrium a more cost-efficient firm chooses higher quality than does an inefficient firm. One might intuit that a firm will offer higher quality if its high efficiency is known to consumers than if its efficiency is not known, because it will no longer need to convince consumers that it is not the inefficient firm. Our analysis shows that, surprisingly, the opposite may be true—when a firm’s high efficiency is publicly known, the firm may reduce its product quality rather than increase it. Furthermore, consumers’ knowledge about the firm’s cost efficiency can reduce the consumer surplus. We also show that an improvement in the average cost efficiency in the market can lower the consumer surplus. The online appendix is available at https://doi.org/10.1287/mnsc.2017.2930 . This paper was accepted by J. Miguel Villas-Boas, marketing.

Aim Promoter-targeted small activating RNAs (saRNAs) have been shown to be able to induce target gene expression, a mechanism known as RNA activation (RNAa). The present study tested whether saRNA can induce the overexpression of TRPV5 in human cells derived from the kidney and subsequently manipulate cell calcium uptake. Main methods Three saRNAs complementary to the TRPV5 promoter were synthesized and transfected into cells. TRPV5 expression at the RNA and protein levels was analyzed by quantitative real-time PCR and Western blotting respectively. For functional study, transcellular Ca2 + transportation was tested by fura-2 analysis. Dihydrotestosterone (DHT), a suppressor of cellular calcium transportation, was administered to challenge the activating effect of selected saRNA. Key findings One of these synthesized saRNAs, ds-2939, significantly induced the expression of TRPV5 at both mRNA and protein levels. Fura-2 analysis revealed that the intracellular Ca2 + concentration was elevated by ds-2939. DHT treatment reduced transmembrane Ca2 + transport, which was partially antagonized by ds-2939. Significance Our results suggest that a saRNA targeting TRPV5 promoter can be utilized to manipulate the transmembrane Ca2 + transport by upregulating the expression of TRPV5 and may serve as an alternative for the treatment of Ca2 + balance-related diseases.

In this paper, by the application of methods of weight functions and the use of analytic techniques, a multidimensional more accurate half-discrete Hilbert-type inequality with the kernel of the hyperbolic cotangent function is proved. We show that the constant factor related to the Riemann zeta function is the best possible. Equivalent forms as well as operator expressions are also investigated.

In this paper, by applying methods of weight functions and techniques of real analysis, a more accurate multidimensional half-discrete Hilbert's inequality with the best possible constant factor related to the Riemann zeta function is proved. Equivalent forms and some reverses are also obtained. Additionally, we consider the operator expressions with the norms and finally present a corollary related to the non-homogeneous kernel.

In this paper we provide an application of the Euler-Maclaurin summation formula with the Bernoulli function for the proof of a strengthened version of the half-discrete Hilbert inequality with the best constant factor in terms of the Euler-Mascheroni constant. Some equivalent numerical representations, operator representations, two kinds of reverses as well as an extension in terms of parameters and the Beta function are also studied.

This paper studies how salespeople affect the choices of which products consumers choose, and from that, how a firm should set optimal commissions as a function of the appeal, substitutability, and profit margins of different products. We also examine whether firms are better off promoting products through sales incentives or price discounts. To achieve these goals, we develop a salesforce-driven consumer choice model to study how performance-based commissions incentivize a salesperson’s service effort toward heterogeneous, substitutable products carried by a firm. The model treats the selling process as a joint decision by the salesperson and the consumer. It allows the salesperson’s efforts to vary across different transactions, depending on the unique preferences of each consumer, and incorporates the effects of commissions and other marketing mix elements on the selling outcome in a unified framework. We estimate the model using data from a car dealership. We find that the optimal commissions should be lower for popular items and for items that are closer substitutes with other products. We also find that for the car industry we study, the cost of selling more cars using sales incentives is cheaper than the cost of selling the same number of cars using price discounts.

In this work, by introducing some parameters and estimating the weight coefficient, a new inequality with a best constant factor is established, which is a relation between Hilbert’s inequality and a Hilbert-type inequality. As applications, the reverse form and some particular results are considered.

In this paper, the norm of an integral operator T : L r ( 0 , ∞ ) → L r ( 0 , ∞ ) ( r > 1 ) is obtained. As applications, a new bilinear integral operator inequality with the norm and the equivalent forms are given, and some new Hilbert's type inequalities with the best constant factors as the particular cases are established.

Using a fixed-point theorem in cone, existence criteria are proved for the periodic positive solutions of a delay differential equation with piecewise constant arguments. Several examples concerning biological models for the survival of red blood cells are given.

In this paper, by introducing three parameters A , B , and λ , and estimating the weight coefficient, we give a generalization of the extended Hardy–Hilbert's inequality with a best possible constant factor, involving the β function. We also consider its equivalent inequality and the associated double series form.

In this paper, the existence of positive, radially symmetric entire solutions for the equations @D^mu=f(|x|,u,|@?u|)(m=2,3,...) on R^2 is proved. Some properties of the solutions are obtained. The results of this paper are generalizations of these proved in [W. Water, Math. Z 67 (1957) 32-37; W. Water, Arch. Math 9 (1958) 308-312; W. Water, H. Rhee, Proc. Royal Soc. Edinburgh A 82 (1979) 189-192; T. Kusno, C.A. Swanson, Hiroshima Math. J. 17 (1989) 13-28].

Some inequalities involving π are proved. As an application, we give some strengthened Hilbert's inequalities.