Background-Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results-Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased Ϸ4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3Ј-nitrotyrosine or 4-hydroxynonenal expression (PϽ0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (PϽ0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions-Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF. (Circulation. 2010;121:1474-1483.)Key Words: heart failure Ⅲ oxidative stress Ⅲ cyclic nucleotide phosphodiesterases, type 5 C ongestive heart failure (CHF) is the leading cause of mortality in developed countries and continues to increase in prevalence. Phosphodiesterase type 5 (PDE5) selectively hydrolyzes cyclic 3Ј,5Ј-guanosine monophosphate (cGMP), and selective inhibition of PDE5 can increase cGMP bioavailability. It is generally believed that PDE5 is not present in normal cardiac myocytes, so that selective PDE5 inhibition has no direct inotropic effect in normal hearts. 1 However, recent work by Kass et al demonstrated that selective inhibition of PDE5 with sildenafil markedly attenuated the left ventricular (LV) hypertrophy and dysfunction produced by chronic pressure overload secondary to transverse aortic constriction (TAC) in mice. 2 Thus PDE5 inhibition has also been reported to attenuate myocardial infarctinduced LV remodeling 3 and LV hypertrophy produc...

Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor g coactivator 1a (PGC-1a) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1a can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1a deficiency (PGC-1a -=-) on oxidative stress and expression of a group of mitochondrial antioxidants in normal hearts and in hearts exposed to chronic systolic pressure overload produced by transverse aortic constriction (TAC). We found that PGC-1a -=-caused moderate but significant decreases of myocardial mitochondrial antioxidant enzymes such as SOD2, and thioredoxin (Trx2), but had no effect on expression of myocardial oxidative stress markers and left ventricular (LV) function under basal conditions. However, in response to TAC for 6 weeks, PGC-1a -=-mice showed greater increases of myocardial oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal, more severe LV hypertrophy and dilatation, pulmonary congestion, and a greater reduction of LV fractional shortening and dP=dt max than did wild-type hearts. SOD mimetic MnTMPyP treatment (6 mg=kg=day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1a -=-mice. These data indicate that PGC-1a plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction. Antioxid.

ᅟThere are many existing methodologies on measuring health equity, while seldom has method aiming at health resource allocation. We collected 6 method of measuring equity in health resource allocation. This paper presents key contents of methods on measuring horizontal equity in health service allocation, yet each method has its advantages and disadvantages as well as range of application, which may help researchers or government to make wise decision when choosing appropriate method for measuring equity. Through comparative analysis, we concluded that socioeconomic factors were considered in concentration index; although the Lorenz curve and Gini-coefficient are widely used, which exist uncertainty and incompleteness; overall inequality can be decomposed by Theil index, which is of significance for the planning of urban and rural areas; preferences on a certain class can be set artificially by Atkinson index; it is easy for Chi-square to analyze aided with statistical software; specific regional differences can be calculated by index of dissimilarity.Classification codesI1Electronic supplementary materialThe online version of this article (doi:10.1186/s13561-014-0010-x) contains supplementary material, which is available to authorized users.

The ability to sieve ions through nanopores with high throughput has significant importance in seawater desalination and other separation applications. In this study, a plasma etching process has been demonstrated to be an efficient way to produce high-density nanopores on graphene membranes with tunable size in the sub-nanometer range. Besides the pore size, the nanopore density is also controllable through adjusting the exposure time of the sample to argon or oxygen plasma. The plasma-treated graphene membranes can selectively transport protons, Na and Cl ions. Density function theory calculations uncover that the sp and vacancy-type defects construct different energy barriers for different ions, which allow the defected graphene membrane to selectively transport ions. Our study indicates that oxygen plasma etching can be used as a very convenient and efficient method for fabricating a monolayer filtration graphene membrane with tunable sub-nanometer pores.

Activation of AMP-activated protein kinase (AMPK) α2 protects the heart against pressure overload-induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardio-protection acts independently of an AMPKα2-dependent pathway. Because the role of AMPKα1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPKα1 and AMPKα2 genes on the response to transverse aortic constriction (TAC)-induced left ventricular (LV) hypertrophy and dysfunction in mice. AMPKα2 gene knockout (KO) significantly exacerbated the degree of TAC-induced LV hypertrophy and dysfunction, whereas AMPKα1 gene KO had no effect on the degree of TAC-induced LV hypertrophy and dysfunction. Administration of metformin to both wild type (WT) and AMPKa2 KO mice attenuated the degree of TAC-induced LV remodeling, as evidenced by reduced LV and lung weights, a more favorable body weight to tibia length ratio, preserved LV ejection fraction, and lower levels of p-mTORser2481 and p-p70S6KThr389. These data support the notion that activation of AMPKα1 plays a negligible role in protecting the heart against the adverse effects of chronic pressure overload, and that metformin protects against adverse remodeling through a pathway that appears independent of AMPKα2.

Silver nanowires have been widely adopted as nanofillers in composite materials used for various applications. Electrical and thermal properties of these composites are critical for proper device operation, and highly depend on transport through the nanowires and their contacts, yet studies on silver nanowires have been limited to one or two samples and no solid data have been reported for individual contacts. Through systematic measurements of silver nanowires of different sizes, we show that the Lorenz number increases with decreasing wire diameter and has a higher value at wire contacts. Examination of the corresponding electrical and thermal conductivities indicates that these changes are due to contributions of phonons that become more important as a result of elastic stiffening. The derived contact thermal conductance per unit area between silver nanowires is ∼10 times that between carbon nanotubes. This helps to explain the more significant thermal conductivity enhancement of silver nanowires-based composites.

The discovery of a record high figure of merit (ZT) of ≈2.6 associated with bulk SnSe has stimulated considerable enthusiasm in searching for 2D systems with similar high ZT. However, previously reported 2D thermoelectric (TE) materials generally possess very low ZT due to the high lattice thermal conductivity (κ L ) and/or small power factor (PF). Herein, a very high ZT (≈2.08) value associated with atomically thin 2D KAgSe nanosheet is reported, which also exhibits an unprecedented low intrinsic κ L (≈0.03 Wm −1 K −1 at 700 K for trilayer) and fairly large PF. The low κ L mainly stems from the high lattice anharmonicity induced by both the "interfacial shear slip" vibrations and the asymmetric "AgSe pair" vibrations from distorted AgSe 4 tetrahedrons. Meanwhile, the complete band-extrema alignment and coexistence of heavy and light bands result in an optimal Seebeck coefficient and electrical conductivity, thereby a large PF. This work suggests not only an alternative way to acquiring high lattice anharmonicity but also a highly competitive 2D TE candidate for wide applications.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.202001200.devices, recently much attention has been devoted to the development of 2D highefficiency TE materials with controllable thickness. [5][6][7] In general, the TE efficiency is characterized by the dimensionless figure of merit ZT = S 2 σT/(κ L + κ e ), where S, σ, T, κ L , and κ e are Seebeck coefficient, electrical conductivity, absolute temperature, lattice thermal conductivity and electronic thermal conductivity, respectively. Apparently, the high TE efficiency can be achieved by increasing the power factor (PF = S 2 σ) together with suppressing the sum of thermal conductivity (κ L + κ e ).Currently, the TE efficiency can be improved by two approaches: i) Tuning effective mass to improve the electronic transport and ii) increasing phonon scattering to suppress the lattice thermal transport. [8][9][10][11] For a given carrier concentration, a large carrier effective mass (m*) contributes to a large S, and the m* is proportional to the band effective mass (m b *) according to m* = N V 2/3 m b *, where N V refers to the band degeneracy. [10,12] A large m b *, however, will reduce the carrier mobility μ since m b 1/ * 2 µ ∝ (2D systems). [13][14][15][16] Hence, to optimize S 2 σ, it is important to attain high N V and moderate m b * simultaneously. A high N V can be achieved either by mixing two types of low-symmetric compounds into a reconstructed highly symmetric structure or by alloying/doping to converge different bands in the Brillouin zone. [8,[17][18][19] For electronic bands at the band edge, a moderate m b * can be realized in principle through element doping or strain engineering. [20] However, in practice, many compounds have limited doping capability and are easily damaged by strain; and the crystal symmetry of the reconstructed structure is uncontrollable. Regarding increasing phonon scattering, intro...

The last two decades have seen tremendous progress in quantitative understanding of several major phonon scattering mechanisms (phonon-phonon, phonon-boundary, phonon-defects), as they are the determinant factors in lattice thermal transport, which is critical for the proper functioning of various electronic and energy conversion devices. However, the roles of another major scattering mechanism, electron-phonon (e-ph) interactions, remain elusive. This is largely due to the lack of solid experimental evidence for the effects of e-ph scattering in the lattice thermal conductivity for the material systems studied thus far. Here we show distinct signatures in the lattice thermal conductivity observed below the charge density wave transition temperatures in NbSe3 nanowires, which cannot be recaptured without considering e-ph scattering. Our findings can serve as the cornerstone for quantitative understanding of the e-ph scattering effects on lattice thermal transport in many technologically important materials.