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abstract: 'We observe a spontaneous parity breaking bifurcation to a ferromagnetic state in a spatially-trapped exciton-polariton condensate. At a critical bifurcation density under nonresonant excitation, the whole condensate spontaneously magnetizes and randomly adopts one of two elliptically-polarized (up to 95% circularly-polarized) states with opposite handedness of polarization. The magnetized condensate remains stable for many seconds at , but at higher temperatures it can flip from one magnetic orientation to another. We optically address these states and demonstrate the inversion of the magnetic state by resonantly injecting 100-fold weaker pulses of opposite spin. Theoretically, these phenomena can be well described as spontaneous symmetry breaking of the spin degree of freedom induced by different loss rates of the linear polarizations.'
author:
- 'H. Ohadi'
- 'A. Dreismann'
- 'Y. G. Rubo'
- 'F. Pinsker'
- 'Y. del Valle-Inclan Redondo'
- 'S. I. Tsintzos'
- 'Z. Hatzopoulos'
- 'P. G. Savvidis'
- 'J. J. Baumberg'
bibliography:
- 'main.bib'
title: 'Spontaneous spin bifurcations and ferromagnetic phase transitions in a spinor exciton-polariton condensate'
---
Condensation of exciton-polaritons (polaritons) spontaneously breaks the global phase symmetry [@deng_condensation_2002; @kasprzak_bose-einstein_2006; @balili_bose-einstein_2007; @baumberg_spontaneous_2008; @ohadi_spontaneous_2012]. Owing to their easy optical interrogation, high-speed (ps) interactions, and macroscopic coherence (over hundreds of microns) [@nelsen_dissipationless_2013], polariton condensates are excellent candidates to probe and exploit for sensing [@sturm_all-optical_2014; @dreismann_coupled_2014], spinoptronics [@amo_exciton-polariton_2010; @ballarini_all-optical_2013; @cerna_ultrafast_2013], new optoelectronic devices [@nguyen_realization_2013; @bhattacharya_solid_2013; @schneider_electrically_2013], and quantum simulators [@buluta_quantum_2009]. The driven-dissipative multicomponent polariton system can undergo additional bifurcations and condense into states which are not eigenstates of the single-particle Hamiltonian, but many-body states with reduced symmetry [@aleiner_radiative_2012; @zhang_weak_2015]. Thus, we should expect that two-component exciton-polariton condensates can also show spontaneous symmetry breaking bifurcations in their polarization state. Spin studies of microcavity polaritons have been of great interest in recent years [@lagoudakis_stimulated_2002; @martin_polarization_2002; @kavokin_polarization_2003; @kavokin_quantum_2004; @renucci_microcavity_2005; @krizhanovskii_rotation_2006; @gippius_polarization_2007; @leyder_observation_2007; @paraiso_multistability_2010; @gao_polariton_2012; @kammann_nonlinear_2012; @takemura_polaritonic_2014]. However, spontaneous symmetry-breaking bifurcation of spin has not been observed before.
Here, we demonstrate spontaneous magnetization in an exciton-polariton condensate, as a direct result of bifurcations in the spin degree of freedom. Utilizing an optically trapped geometry, condensates spontaneously emerge in either of two discrete spin-polarized states that are stable for many seconds, $>10^{10}$ longer than their formation time. These states emit highly circularly-polarized coherent light (up to 95%) and have opposite circular polarizations. The condensate stochastically condenses in a left- or right-circularly polarized state, with an occurrence likelihood that can be controlled by the ellipticity of the nonresonant pump. The two spin-polarized states can be initialized and switched from one state to another with weak resonant optical pulses. Our system has potential applications in sensing, optical spin memories and spin switches, and it can be implemented for studying long-range spin interactions in polariton condensate lattices.
This article is structured as follows: in Section \[sec:intro\] we review trapped polariton condensates and the current understanding of polarization in untrapped polariton condensates. In Section \[sec:circbuildup\] we present the key theme of this work, which is the spontaneous buildup of stochastic circular polarization. In Section \[sec:theory\] we propose a theoretical framework for the phenomena discussed in this work. We show that stochastic circular polarization is a signature of spontaneous parity breaking. In Section \[sec:res\] we time-resolve the coherent driving of the spin, with resonant excitation. We furthermore investigate the stability of the spin-polarized states against thermal noise and conclude in Section \[sec:conc\].
Introduction\[sec:intro\]
=========================
Exciton-polaritons are spinor particles formed by the strong coupling of excitons in a semiconductor quantum well with photons in the microcavity in which they are embedded [@kavokin_microcavities_2007]. We create optically-trapped polariton condensates by nonresonant excitation of a semiconductor microcavity membrane \[see FIG. \[fig:1\](a) and Appendix \[app:expmethods\]\]. The excitation beam is shaped into a 4-spot pattern \[shown by dashed circles in FIG. \[fig:1\](b)\]. The short-wavelength continuous wave (CW) linearly-polarized pump injects an electron-hole plasma at each pump spot, which rapidly relaxes to form excitons, in the process losing all phase information. These reservoir excitons then scatter into polariton states via multiple phonon-polariton and stimulated polariton-polariton collisions [@savvidis_angle-resonant_2000], and they feed the zero-momentum ground state at the center of the trap. Because of their large effective mass, excitons typically diffuse only very small distances and stay within of the pump spots. Microcavity polaritons, however, are times lighter giving longer diffusion lengths. Driven by their repulsive excitonic interactions, polaritons can thus travel large distances away from the pump spots within their lifetime [@wertz_spontaneous_2010]. Once the density inside the trap exceeds the condensation threshold, a macroscopically coherent condensate is formed \[FIG. \[fig:1\](c)\]. Because the condensate overlaps only weakly with the pump spots, it shows a narrower linewidth and less decoherence than unconfined condensates [@askitopoulos_polariton_2013]. The optical trapping method used here is similar to optical lattices in cold atomic systems [@bloch_ultracold_2005], but with the major difference that the optical potential also provides gain [@wertz_spontaneous_2010; @wouters_excitations_2007; @tosi_sculpting_2012].
Polaritons in quantum-well microcavities have two $J_z = \pm 1$ (spin-up or spin-down) projections of their total angular momentum along the growth axis of the structure, which correspond to right- and left-circularly polarized photons emitted by the cavity, respectively. When the excitation is linearly-polarized an equal population of spin-up and spin-down excitons forms in the reservoir. An initially spin-balanced reservoir, in the absence of pinning to any crystallographic axis, is expected to give a condensate with a stochastic linear polarization [@shelykh_polarization_2006]. In most experiments with polariton lasers the condensates have been found to be linearly polarized along one of the crystallographic axes [@deng_condensation_2002; @kasprzak_bose-einstein_2006]. Nevertheless, in some cases a circularly polarized polariton lasing has also been observed [@martin_polarization_2002; @shelykh_semiconductor_2004; @krizhanovskii_rotation_2006; @roumpos_signature_2009; @ohadi_spontaneous_2012]. Formation of a circularly polarized condensate is usually associated with the effects of TE-TM splitting, or bosonic amplification of the seed polarization of condensates. In all these cases, a circularly polarized condensate is observed when the symmetry between the spin-up and spin-down polaritons has been *explicitly* broken in some fashion, by either the pumping geometry (seeding with a circularly polarized pump) or by the imposed rotation of the Stokes parameters due to polarization splitting. As a result, the observed circular polarization was never stochastic (i.e. it is fixed each time the condensate is excited, but it is different on each realization).
Spontaneous buildup of circular polarization\[sec:circbuildup\]
===============================================================
Our experiments reveal a completely different behavior to the previous reports on the polarization of polariton condensates. We observe a strong degree of circular polarization $60\%<\vert s_z \vert<95\%$ \[FIG. \[fig:Random\](a)\] when the excitation is linearly polarized (to better than 1 in $10^{5}$), which is stable for many seconds \[FIG. \[fig:Random\](b)\]. The condensate stochastically adopts either of two opposite circular-polarization states in each realization of the experiment. We call these two states the spin-up ($s_\uparrow$) and spin-down ($s_\downarrow$) states. By mapping the polarization of the photoluminescence (PL) we measure the polarization vector $s_{x,y,z}=(I_{H,D,\circlearrowright}-I_{{V,A,\circlearrowleft}})/(I_{H,D,\circlearrowright}+I_{{V,A,\circlearrowleft}})$, where $I$ is the measured intensity for horizontal ($H$), vertical ($V$), diagonal ($D$), anti-diagonal ($A$), right-circular ($\circlearrowright$) and left-circular ($\circlearrowleft$) polarizations. We measure all components of the polarization vector (pseudospin) simultaneously and plot the mean of the spin-up and spin down states on the Poincaré sphere separately for 1000 realizations \[FIG. \[fig:Random\](c)\]. In each realization the wavefunction of the condensate spontaneously collapses into one of the two discrete spin-polarized states which have opposing circular and diagonal components, marked by blue and orange vectors in FIG. \[fig:Random\](c). The linear axis along which the pseudospin flips (marked here as diagonal) does not depend on the geometry of the trap, and it changes direction with the position of the condensate on the sample.
To demonstrate that the buildup of circular polarization is truly spontaneous, we illuminate the sample with a long-duration pulse of using an acousto-optic modulator (AOM). A condensate builds up and picks a random state (e.g. $s_{\downarrow}$) and stays in that particular state as long as the pump pulse lasts \[FIG. \[fig:pulsetrain\](a)\]. We then repeat the same measurement but this time we modulate the pump intensity so that a condensate is created and destroyed every . FIG. \[fig:pulsetrain\](b) shows how the condensate, although being stable for many seconds, picks a random polarization at every successive realization due to random initial conditions at the onset of condensation. In this case the parity symmetry is broken spontaneously. The buildup of circular polarization is independent of the precise position on the sample, of the sample orientation, of the pump spot orientation, and of the polariton detuning.
We can also *explicitly* break the symmetry in our experiments by changing the ellipticity of the pump laser and measure the contrast of the occurrence frequency of spin-up ($f_{\uparrow}$) to spin-down ($f_{\downarrow}$) condensate realizations, $\xi=(f_{\uparrow}-f_{\downarrow})/(f_{\uparrow}+f_{\downarrow})$. The probability of a realization resulting in state $f_{\uparrow\downarrow}$ is equal to $(1\pm\xi)/2$ respectively. FIG. \[fig:pulsetrain\](c) shows $\xi$ as a function of the pump circular polarization ($s_{z,\text{pump}}$) averaged over 1000 realizations for each point. As the ellipticity of the pump is increased from linear ($s_{z,\text{pump}}=0$) to right circular ($s_{z,\text{pump}}>0$) the probability of creating a condensate in the spin-up state increases; conversely, for the left-circularly polarized pump ($s_{z,\text{pump}}<0$), the probability of creating a spin-down condensate increases. With a linearly-polarized pump we have an equal probability of creating a spin-up or spin-down condensate. Although the pump laser is nonresonant with the final polariton states, the initially created carrier spin is not entirely randomized during their multiple carrier-carrier and exciton-phonon scatterings [@roumpos_signature_2009; @ohadi_spontaneous_2012; @kammann_nonlinear_2012; @li_incoherent_2015]. As a result of this incomplete spin relaxation of the excited carriers, changing the ellipticity of the pump breaks the symmetry of the condensate toward the same circular polarization as that of the pump. For pump circular polarizations far greater than 0.1 the condensate is formed deterministically in the same polarization state as that of the pump \[FIG. \[fig:pulsetrain\](d)\].
An interesting question here is why we observe the spontaneous buildup of circular polarisation, as opposed to the linear polarisation that is widely reported in the literature [@deng_condensation_2002; @kasprzak_bose-einstein_2006]. The key difference between the experiments presented in this work and other studies of polariton condensation lies in the excitation geometry. For our trapped condensates, the pump and condensate are spatially separated, which critically reduces the contaminating interactions between the condensate and reservoir. The large interaction between untrapped condensates and the unpolarized exciton reservoir results in spin-flip scattering of polaritons with reservoir excitons. If there is a depolarized reservoir on top of the condensate, the spin-flip scattering processes minimize any imbalance between circular components of the condensate. This minimization leads to quenching of the buildup of circular polarization, forcing the polaritons to condense only with linear polarization. Moreover it has been shown previously that, because of a smaller overlap with the reservoir, trapped condensates have a smaller linewidth than untrapped condensates [@askitopoulos_polariton_2013]. Our careful studies with temperature and our theoretical calculations (see Section \[sec:thermnoise\]), show how spin noise in the system results in spin flipping of the condensate. The spin flip rate scales exponentially with noise. Larger linewidth untrapped condensates have higher spin flip rates, which wash out circular polarization effects observed here.
![(a) Nonresonant linearly polarized weak probe overlapped with the condensate. (b) Average circular polarization degree vs power of the probe beam. The blue line is a guide to the eye.[]{data-label="fig:ResOnTop"}](figResOnTop){width="48.00000%"}
To show the crucial role of the reservoir excitons we place a weak nonresonant linearly-polarized probe beam on top of the condensate as shown in FIG. \[fig:ResOnTop\](a). The probe beam which has just a small fraction of the 4-spot pump power ($<0.025\; P_{th}$), induces a reservoir of excitons that overlap with the condensate but it does not stop the condensation or reduce the condensate density below the critical circular polarization density. We then measure the absolute average circular polarization degree in each realization, as a function of the weak probe power. As shown in FIG. \[fig:ResOnTop\](b), the circular polarization degree decreases monotonously as the probe power increases, demonstrating the quenching of circular polarization due to the influence of the overlapping reservoir. This measurement evidences the importance of the separation of the pump-induced reservoir and the trapped condensate in the observation of ferromagnetic condensates.
Four scenarios might explain the buildup of the stochastic circular polarization depending on populations of same- and opposite- (or cross-) spin polaritons:
a higher interaction energy for cross-spin than for same-spin polaritons in a condensate which is in thermal equilibrium,
a higher gain from the cross-spin reservoir,
density-dependent losses enhanced by cross-spin condensed polaritons, and
\[enum:wl\] linear polarization energy splitting accompanied by a dissipation rate splitting which destabilizes the linearly-polarized condensate (‘spin bifurcation’)
. As we will show now, our experimental data strongly suggest that scenario (\[enum:wl\]) is the correct explanation. In the first scenario (‘energy-minimization’), the condensate free energy is minimized when it acquires circular polarization. This situation could happen in a condensate in thermal equilibrium if the interaction energy of cross-spin polaritons is stronger than that of same-spin polaritons, meaning the coexistence of cross-polarized polaritons is not favored [@rubo_suppression_2006]. However, the interaction with opposite spin polaritons is well known to be weaker than, and opposite to, that of same-spin polaritons [@vladimirova_polariton-polariton_2010; @takemura_polaritonic_2014; @takemura_heterodyne_2014]. Moreover, being externally driven and having short lifetimes, polariton condensates are generally far from thermal equilibrium [@kasprzak_formation_2008]. We note that “energetical” mechanisms cannot explain why states with elliptical polarization (i.e. not fully circular) are formed. In the second scenario (‘cross-gain’), in order to acquire a circular degree of polarization, the condensate must experience larger gain from the cross-spin reservoir than from the same-spin reservoir. However, the scattering rate from the cross-spin reservoir into the condensate is measured to be significantly smaller than the same-spin [@lagoudakis_stimulated_2002]. The third scenario (‘cross-loss’) requires the condensate loss rate to increase when opposite spins are present. If polaritons are directly excited by light, observations have suggested biexciton formation can produce such enhanced losses [@paraiso_multistability_2010]. However, this is only significant when the relative spectral detuning of cavity and exciton is small ($<\SI{2}{\milli\electronvolt}$), which is far from the case here. We observe the spontaneous buildup of circular polarization throughout the entire $+2$ to detuning range. In the remaining scenario (‘spin bifurcation’), which we present in Section \[sec:theory\] for the first time, the buildup of circular polarization is caused by small differences of the energy and dissipation rates of two orthogonal linearly-polarized polariton modes, which is present even at $k=0$.
Strain-induced splitting of the linear components of polariton condensates has been demonstrated previously [@balili_huge_2010; @klopotowski_optical_2006]. In our sample this splitting varies depending on the position on the sample. We observe a linear polarization energy splitting of up to $\SI{100}[\sim]{\ueV}$ depending on the position of excitation on the membranes. Note that, all the effects reported here are also seen on unetched samples, so strain from patterning is not crucial. However, we observe a higher splitting at the edges of the membrane than in the middle, as there is more stress in the structure at the edges. Due to the curvature of the cavity stopband, any energy splitting is accompanied by a difference of the linewidth (dissipation rate), as explained in Appendix \[app:polsplit\]. This energy splitting between the two linear components combined with a difference in dissipation rates causes the polarization of the condensate to change from linear polarization to circular at a critical density (see Section \[sec:theory\]).
We emphasize that the stochastic circular polarization here cannot be explained in the framework of the optical spin Hall effect [@kavokin_optical_2005; @kammann_nonlinear_2012]. In our trapping geometry the condensate is formed at the ground state with ($\bar{k}=0,\;\delta
k=\SI{0.4}{\um^{-1}}$) \[FIG. \[fig:1\](c)\], where the transverse-electric and transverse-magnetic (TE-TM) splitting vanishes [@shelykh_semiconductor_2004]. The trap diameter here is 6 times smaller than the observed spin-ring patterns measured for a nonequilibrium condensate formed at much higher in-plane wave-vectors in the same sample [@kammann_nonlinear_2012]. Moreover, the geometry or the orientation of the trap does not affect the polarization state of the condensate. We also see the stochastic circular polarization with a ring-shaped trap and also in high-order spatial mode condensates [@cristofolini_optical_2013; @askitopoulos_robust_2014]. Finally, it should be noted that any theoretical picture that assumes the buildup of circular polarization arises only because of the geometrical arrangement of the pump, would necessarily fail to explain the most essential part of this work, which is the spontaneous symmetry breaking (stochastic behavior).
Spin Bifurcation Theory (Broken Parity)\[sec:theory\]
=====================================================
Our theory is a development of the theory of polariton weak lasing in two coupled condensation centers [@aleiner_radiative_2012] now for the case of the spin degree of freedom. Here, we have right and left circular polarizations instead of two separated condensates, and we also allow for the gain-saturation nonlinearity in the system.
The order parameter for an exciton-polariton condensate is a two-component complex vector $\Psi=[\psi_{+1},\psi_{-1}]^\mathrm{T}$, where $\psi_{+1}$ and $\psi_{-1}$ are the spin-up and spin-down wave functions. The components of the order parameter define the measurable condensate pseudospin $\mathbf{S}=(1/2)(\Psi^\dag\cdot\bm{\sigma}\cdot\Psi)$, and the normalized spin vector $\mathbf{\hat{s}}=\mathbf{S}/S$, where $\sigma_{x,y,z}$ are the Pauli matrices. The components of this vector contain information about the intensities and relative phases of the emitted light. The order parameter evolves according to the driven dissipative equation $$\begin{aligned}
\label{eq:main}
\begin{split}
{\mathrm{i}}\frac{d\Psi}{dt}=&-{\textstyle{\frac{\mathrm{i}}{2}}}g(S)\Psi-\frac{{\mathrm{i}}}{2}(\gamma-{\mathrm{i}}{\varepsilon})\sigma_x\Psi
\\&+{\textstyle{\frac{1}{2}}}\left[(\alpha_1+\alpha_2)S+(\alpha_1-\alpha_2)S_z\sigma_z\right]
\Psi,
\end{split}\end{aligned}$$ or in components:
$$\begin{aligned}
{2}
\begin{split}
\dot{\psi}_{+1}=&-{\textstyle{\frac{1}{2}}}g(S)\psi_{+1}
-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{-1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{+1}\vert^2+\alpha_2\vert\psi_{-1}\vert^2)\psi_{+1},
\end{split}\\
\begin{split}
\dot{\psi}_{-1}=&-{\textstyle{\frac{1}{2}}}g(S)\psi_{-1}
-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{+1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{-1}\vert^2+\alpha_2\vert\psi_{+1}\vert^2)\psi_{-1}.
\end{split}\end{aligned}$$
\[eq:maincomp\]
Here, $g(S)=\Gamma-W+\eta S$ is the pumping-dissipation balance, $\Gamma$ is the (average) dissipation rate, $W$ is the incoherent in-scattering (or ‘harvest’ rate), and $\eta$ captures the gain-saturation term with $S = (\vert
\psi_{+1}\vert^2+ \vert \psi_{-1}\vert^2)/2$ [@keeling_spontaneous_2008]. Here, this gain saturation depends on the total occupation of the condensate (treated more generally in Appendix \[app:varcross\]). It is assumed now that $X$ (horizontal) and $Y$ (vertical) linearly-polarized single-polariton states have different energies and dissipation rates. The energy of the $X$-polarized state is shifted by $-{\varepsilon}/2$, and the energy of the $Y$-polarized state by $+{\varepsilon}/2$. The dissipation rate from the $X$-polarized state is $\Gamma+\gamma$, while the dissipation rate from the $Y$-polarized state is $\Gamma-\gamma$ (see also Appendix \[app:polsplit\]). Finally, $\alpha_1$ is the repulsive interaction constant for polaritons with the same spin, and $\alpha_2$ is the interaction constant for polaritons with opposite spins.
From Eq. \[eq:main\] we obtain for the components of the pseudospin vector ($\alpha=\alpha_1-\alpha_2$):
\[eq:pseudospinEq\] $$\begin{aligned}
{3}
\begin{split}
\dot{S_x}=-g(S)S_x-\gamma S-\alpha S_z S_y,
\end{split}\\
\begin{split}
\dot{S_y}=-g(S)S_y+{\varepsilon}S_z+\alpha S_z S_x,
\end{split}\\
\begin{split}
\dot{S_z}=-g(S)S_z-{\varepsilon}S_y,
\end{split}\end{aligned}$$
and the related equation for the total spin $\dot{S}=-g(S)S-\gamma S_x$. There are two sets of solutions, which we call here the paramagnetic and ferromagnetic solutions.
#### Paramagnetic solutions.
These give simple condensation into either $X$ or $Y$ linearly-polarized states. The $Y$ state possesses the longest lifetime, and the condensation threshold is reached for this state first at $W_1=\Gamma-\gamma$. There is no parity breaking for this condensate: $S_y=S_z=0$, $S_x=-S$ with $S=(W-W_1)/\eta$, so that the occupations of $+1$ and $-1$ components are equal. However, this condensate solution becomes unstable for $W>W_2$. The values of the critical occupation $S_c$ and the critical pumping rate are $$S_c=\frac{\gamma^2+{\varepsilon}^2}{\alpha{\varepsilon}},\qquad W_2=W_1+\eta S_c.$$ Note that this instability is present also for equal dissipation rates, i.e. when $\gamma=0$. In this case, the system (Eq. \[eq:pseudospinEq\]a-c) describes the self-induced Larmor precession of the pseudospin vector. Incorporating energy relaxation (e.g., using small negative $\gamma$) then leads to the formation of the $X$-polarized condensate—an intuitively expected result.
#### Ferromagnetic solutions.
The key ingredient of our theory is the presence of the $\gamma>0$ parameter describing the variation of dissipation rates. This parameter allows the formation of the ‘weak lasing’ regime [@aleiner_radiative_2012], which is characterized by two important features: (i) the $X$-polarized condensate is also unstable, and (ii) when the $Y$-polarized condensate loses stability at the critical occupation $S_c$, it continuously transforms into one of the two ferromagnetic states. While Eqs. are parity symmetric, i.e., they are not affected by the interchange of left and right circular polarization, the new solutions are characterized by broken parity symmetry and by spontaneous formation of either left or right elliptical polarization. These solutions are
\[eq:Sz\_pos\] $$S_x=-\frac{g(S)}{\gamma}S, \qquad S_y=-\frac{g(S)}{{\varepsilon}}S_z,$$ $$S_z=\pm\frac{{\varepsilon}}{\gamma}\sqrt{\frac{\gamma^2-g(S)^2}{{\varepsilon}^2+g(S)^2}}\,S, \qquad
S=\frac{\gamma[{\varepsilon}^2+g(S)^2]}{\alpha{\varepsilon}g(S)},$$
where the positive root of the second equation in Eq. (\[eq:Sz\_pos\]b) should be taken. We note that while the sign of $S_x$ is always negative, $S_y$ and $S_z$ have opposite signs for the two solutions. This means that the left-circular component is accompanied by a diagonal component, and the right-circular by anti-diagonal. Moreover, if these components change for some reason, they mirror each other as long as the total condensate occupation stays fixed. We label these two solutions as the $s_\downarrow$ and $s_\uparrow$ spin states.
The spin-independent model for the gain saturation used in this Section is sufficient to describe the experimentally observed features. However, the spin relaxation in the reservoir can be slow [@li_incoherent_2015], and in this case the model should be modified to allow the saturation terms to depend on the individual occupations of the left- and the right-circular polarization components rather than the total occupation only. The parity breaking is still present after this modification; however, the stability of solutions becomes more complex. The ferromagnetic solutions can now become unstable and transform into periodic cycles [@rayanov_frequency_2015], the dynamics of the pseudospin can become irregular, and this can also result in the formation of the stable $X$-polarized condensate at high pumping powers. See Appendix \[app:varcross\] for more details.
Numerical calculations for the occupation of the two circular components of the wavefunction when $S<S_c$ (dotted lines) and when $S>S_c$ are shown in FIG. \[fig:theoryPD\](a). Here, the condensate is initialized with a small asymmetry in spin-up and spin down occupations (<1%). Below the critical occupation $S_c$, the condensate is linearly polarized, but when the occupation is increased above the threshold $S_c$, the condensate adopts one of two elliptically polarized configurations depending on the initial conditions. In the experiment, the stochastic behavior is due to random spin fluctuations at the onset of the condensation. In theory, we can reproduce it by randomly setting the initial conditions. Numerical calculations of the condensate polarization versus excitation power are shown in FIG. \[fig:theoryPD\](b). Directly at the condensation threshold the condensate is linearly polarized, but once it reaches the critical occupation ($P_c=1.3 P_{\mathrm{th}}$, marked by a dashed grey line), the linear component is quenched and circular polarization builds up. This behavior reproduces the experimental data, as shown in FIG. \[fig:theoryPD\](c). We observe an initial buildup and subsequent quenching of linear polarization with the continuing increase of circular polarization at $P_c=1.25P_{th}$ (marked by a dashed grey line, with total intensity marked by a dotted red line). Once circular polarization is achieved, the orientation of the condensate circular polarization becomes stochastic under linearly polarized pumping.
We can extend Eq. (\[eq:main\]) and account for 2D real-space degrees of freedom by using complex Ginzburg-Landau-type equations [@wouters_excitations_2007; @keeling_spontaneous_2008; @dreismann_coupled_2014], which in addition to the pump and decay also incorporate a repulsive potential due to the excitons in the pump spots and an energy relaxation [@wouters_energy_2010] for polaritons in the trap: $$\begin{gathered}
{\mathrm{i}}\frac{d\Psi}{dt}=-\frac{{\mathrm{i}}}{2} \left[ g(S)+ \gamma\sigma_x \right]\Psi \\
+(1-{\mathrm{i}}\Lambda)\Big\{
\frac{1}{2}\left[(\alpha_1+\alpha_2)S+(\alpha_1-\alpha_2)S_z\sigma_z\right]\Psi \\
- \frac{1}{2}{\varepsilon}\sigma_x\Psi-\frac{\nabla^2}{2m^*}\Psi+V_p\Psi \Big\},\end{gathered}$$ where $m^*$ is the effective mass of the polaritons. The harvest rate is given by $W=rP/\Gamma_R$, where $P$ is the spin-independent spatial profile of the excitation, $\Gamma_R$ is the decay rate of the exciton reservoir, and $r$ is the incoming rate of polaritons into the condensate. The gain saturation is given by $\eta=r^2 P/\Gamma_R^2$. The repulsive potential due to the interaction of polaritons with the exciton reservoir is given by $V_p={\textstyle{\frac{1}{2}}}g_r N + {\textstyle{\frac{1}{2}}}g_P P$, where $g_r$, and $g_P$ are the interaction constants of polaritons with the exciton reservoir and the pump spot respectively, and $N=g(S)/r$ is the density of the exciton reservoir. Here, $\Lambda\ll 1$ is a phenomenological constant that gives the energy relaxation. The density profile of the two circular components of the wave function in the steady state \[FIG. \[fig:theoryPD\](d)\], for the case of a trapped condensate in the middle of the 4 pump spots, exhibits a circular polarization degree of $\vert s_z \vert=0.69$. Note that with $\gamma=0$ and only polarization splitting (including TE-TM splitting), our 2D simulations do *not* show bistable condensation.
It is important to note the differences between the ferromagnetic states we discuss here and the magnetization transition in equilibrium cold atom systems [@sadler_spontaneous_2006; @stamper-kurn_spinor_2013]. First, the parity breaking bifurcation described above does not reduce the energy of the system (unlike for atoms). In fact the energy of elliptically polarized states is [*higher*]{} than that of linearly polarized states. Second, the in-plane components of the spin do not vanish completely. Third, we have a magnetized condensate with only two possible orientations, whereas in atomic systems ferromagnetic domains with continuous variable orientation are observed.
If the Hamiltonian and the initial state of a system are symmetric under the exchange of spin-up and spin-down components, but the final state is not, the parity symmetry is spontaneously broken. This is indeed the case here: We excite an equal population of spin-up and spin-down polaritons, which spontaneously condense, but form highly circularly polarized macroscopic states in the absence of any external magnetic field.
Resonant excitation\[sec:res\]
==============================
The GaAs substrate commonly used in the fabrication of GaAs microcavities is opaque at the emission wavelength ($\SI{\sim800}{\nano\meter}$) of the cavity polaritons. As a result, the back side of the cavity is resonantly inaccessible. Resonant excitation of the cavity from the front side has complications with backscatter from the laser, especially in high finesse cavities and at normal incidence, where the condensate emission mode is located. To circumvent this problem we chemically etch the substrate to form membranes of thickness and diameter \[see FIG. \[fig:1\](a)\]. For resonant excitation, we use a narrow-linewidth ($<\SI{2}{\GHz}$) CW laser, which is amplitude modulated with a second AOM. We call this resonant laser the ‘gate’. We use two photomultipliers and a fast oscilloscope to time resolve the left- ($\sigma_-$) and right-circular ($\sigma_+$) polarization intensity of the condensate emission. The resonant excitation laser, the nonresonant pump laser, the cameras and the oscilloscope are all synchronized, which allows us to vary the delay time and amplitudes of each laser pulse on demand.
Resonant initialization of spin states
--------------------------------------
![ Measured circular polarization of condensate vs pump ellipticity, for three different gate polarizations. Dashed lines mark the region where the condensate initializes stochastically in spin-up or spin-down states in each realization. \[fig:initialization\] ](figInitialization)
We can control the polarization of the trapped condensate with the gate laser. In this case, we additionally *resonantly* excite the condensate (which is generated by the four nonresonant pump spots) with a second laser from the backside of the microcavity membrane. This gate can be linearly, left-, or right-circularly polarized. FIG. \[fig:initialization\] shows the condensate circular degree of polarization versus that of the pump. In the green curve which shows the behavior when the gate is linearly polarized, we reproduce the same result as that in FIG \[fig:pulsetrain\](d). However, when a right (or left) circularly polarized gate is applied, the curve shifts to the left (or right). In other words, with a linearly polarized pump, the condensate initializes in a right (or left) circularly polarized state. The imbalance caused by the resonant gate cancels out with an opposite circularly polarized pump with a circular polarization degree of $\vert s_{z,\text{pump}} \vert\sim 0.1$.
Elliptically-polarized pump: coherent driving
---------------------------------------------
In a first experiment, we initialize a condensate in the spin-down state ($s_\downarrow$) by making the pump laser slightly left-circularly polarized (‘asymmetric pumping’). Once the condensate is created, we excite the sample resonantly from the back side with an oppositely circularly polarized ($\sigma_+$) gate. FIG. \[fig:res\](a) shows the intensity of $\sigma_+$ and $\sigma_-$ components of the condensate emission during this gating. We see a reduction in intensity for the component which is opposite to the gate laser polarization and an increase for the same spin polarization component. To account for this in the theory, we add a new term to Eq. \[eq:maincomp\], corresponding to the resonant laser:
$$\begin{aligned}
{2}
\begin{split}
\dot{\psi}_{+1}=&-{\textstyle{\frac{1}{2}}}g_{+1}(S)\psi_{+1}
-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{-1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{+1}\vert^2+\alpha_2\vert\psi_{-1}\vert^2)\psi_{+1}\\
&-{\mathrm{i}}A\,\Pi(t,t_0,\delta t)e^{-{\mathrm{i}}\omega_g t},
\end{split}\\
\begin{split}
\dot{\psi}_{-1}=&-{\textstyle{\frac{1}{2}}}g_{-1}(S)\psi_{-1}
-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{+1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{-1}\vert^2+\alpha_2\vert\psi_{+1}\vert^2)\psi_{-1},
\end{split}\end{aligned}$$
\[eq:mainCompRes\]
where $A\,\Pi(t,t_0,\delta t)=AH(t-t_0)H(t_0+\delta t-t)$ uses the Heaviside step function $H$ to give a square pulse with amplitude $A$ which starts at time $t_0$ and lasts for $\delta t$, and $\omega_g$ is the excitation frequency. To account for the elliptically-polarized pumping we modify $g(S)$ to $g_{\pm
1}(S)=\Gamma-W_{\pm 1}+\eta S$. Numerical calculations \[FIG. \[fig:res\](b)\] show the case $W_{-1}=1.09\;W_{+1}$, $A=5\times 10^{-4}
n$, where $n$ is the occupation of the condensate, and $\omega_g=-0.3 {\varepsilon}$. The dotted line marks the time average of the oscillations. The condensate pseudospin vector precesses around the stationary state pseudospin vector at a frequency of $\omega_L/2\pi\sim\SI{10}{\GHz}$ in a limit cycle \[see FIG. \[fig:res\](c)\]. In the case where the condensate is highly spin-polarized and the gate is at resonance ($\omega_g=0$), the oscillation frequency is equal to the self-induced Larmor precession frequency $\omega_L=\gamma\varepsilon/g$ (Appendix \[app:kramers\]). This sets the fastest possible spin dynamics in the system, and does not depend on the gate intensity. Here, the condensate pseudospin oscillates faster than our detection time resolution and consequently we only see the average effect in FIG. \[fig:res\](a). The coherent driving reported here strongly depends on the detuning of the gate laser frequency relative to that of the condensate. The resonance width at which we can drive the condensate is determined to be 10-, as explained in Appendix \[app:reswidth\].
{width="100.00000%"}
In the case of FIG. \[fig:res\](d) the intensity of the gate laser is increased by five times with respect to that in (a). Under these conditions, the time average of the circular component of the condensate emission becomes almost unpolarized. If the amplitude of the resonant excitation is large enough, the condensate pseudospin can cross over to the second attractor (the spin-up state) and form a large trajectory which encompasses both spin-up and spin down stationary states with a characteristic period doubling [@alexeeva_actively_2014] \[FIG. \[fig:res\](e,f)\]. The dotted lines in (e) mark the time average of the oscillations. FIG. \[fig:res\](g) shows the power dependence of the average circular polarization as a function of the intensity of the gate. As the oppositely polarized gate intensity is increased, we see the condensate average circular polarization converges to zero. Here, we have the gate resonant with the condensate. However, the coherent driving strongly depends on the detuning of the gate laser frequency to that of the condensate. The resonance width where we can drive the condensate is determined to be 10-, as explained in Appendix \[app:reswidth\]. That theory and experiment agree regarding the observed average polarization over the whole range of gate powers, and also the observation of a resonance (see Appendix \[app:reswidth\]) strongly suggests that our description in terms of coherent driving is valid.
In summary, the fixed points of broken parity symmetry ($s_\downarrow,s_\uparrow$) become unstable due to small perturbations and convert to limiting circles around stationary states. The precession is linear for small gate amplitudes but it becomes nonlinear for large amplitudes. This is manifested by oscillation of the condensate parameters, occupation and polarisation with time. In this linear regime, the gate pulse appears to act as if it induces an effective magnetic field, around which the condensate polarisation precesses. It is worth noting that this system can exhibit chaotic behavior with increased amplitude of the pulse. Increasing the amplitude first results in period doubling, and eventually leads to chaos (Feigenbaum scenario) [@alexeeva_actively_2014]. The ability to coherently control the spin of the condensate suggests its utility for computational operations.
Linearly-polarized pump: spin switching
---------------------------------------
We now explain the case when the nonresonant pump is linearly polarized. In this case there is no external ‘force’ to drive the condensate to a specific spin state. As a result, once the circular component of the condensate pseudospin crosses zero, it falls into the opposite spin state’s attractor. FIG. \[fig:resSwitch\](a) shows a realization which lasts for $\SI{4}{\micro\second}$ with the condensate first initialized in the spin down state ($s_\downarrow$). We resonantly excite the condensate with an oppositely polarized gate ($\sigma_+$). This causes the switching of the polarization of the condensate to the same polarization as that of the gate. The gate, which is $\SI{1.5}{\micro\second}$ in duration, is then turned off but the condensate remains in the switched polarization because the pump is linearly polarized and the symmetry is not explicitly broken. This shows that we are capable of manipulating the polarization of the condensate on demand, while also reinforcing our observation that the condensate picks a polarization spontaneously when it is formed. It should be noted that the state of the condensate does not change when the circular polarization of the gate is the *same* as that of the condensate.
If the symmetry breaking was somehow set by the parameters of the experiment, as in the previous example where the pump was slightly elliptical, the condensate would switch back to its original state after the gate beam was turned off. Instead, a very small gate field in the cavity can initiate coherent switching. The upper panel in FIG. \[fig:resSwitch\](a) shows the transmitted gate intensity when the pump is blocked. Indeed, the gate power before the cavity is , which is 50 times weaker than the pump power. However, only a small fraction of this resonant beam couples to the cavity in our setup. Therefore, a suitable comparison of the intensity of the gate to that of the condensate is to compare the transmitted intensity of the gate to the intensity of the condensate in the same direction. We find that the gate intensity is more than 60 times weaker than the condensate intensity, when the gate laser frequency is tuned to the bottom of the polariton dispersion (accounting for the blueshift of the condensate).
By estimating the occupation number of the condensate (see Appendix \[sec:particlenumber\]) we find that only 13 polaritons are enough to reverse the spin state of the condensate. The condensate switching time is less than (our detection limit), and is 10 times faster than the switching time of the AOM \[FIG. \[fig:resSwitch\](b)\]. This important fact shows that the condensate does not follow the optical gate adiabatically. Simulations of the spin-switching with minimum resonant gate intensity are shown in FIG. \[fig:resSwitch\](c). The polarization of the gate is opposite to that of the condensate and we have assumed symmetric pumping rates for the spin-up and spin down condensates i.e. $W_{+1}=W_{-1}$. The condensate polarization reverses within $\SI{\sim200}{\ps}$ once the gate is applied and remains in that state after the pulse is turned off during continued spin evolution \[FIG. \[fig:resSwitch\](d)\]. Switching requires a minimum gate intensity, to twist the condensate pseudospin onto the equator in the Poincaré sphere. This sets a threshold for the gate power. By measuring the gate flux, and using the switching time of $\SI{10}{\ns}$, an *upper* bound of the minimum energy for switching the state of the condensate is found to be $\SI{1E-15}[\sim]{J}$, comparable to state-of-the-art optoelectronic switches with similar speeds [@nozaki_sub-femtojoule_2010]. We emphasise, however, that the theoretical limit for the minimum switching energy is 50 times smaller because the spin dynamics of the system ($\sim\SI{200}{\ps}$) is 50 times faster than our detection limit. This polaritonic system is then an extremely low-power switch.
Multistability has indeed been demonstrated before in resonantly pumped condensates [@paraiso_multistability_2010; @cerna_ultrafast_2013]. However, there are several major differences between our system and that of the Deveaud group. In Deveaud’s experiments the physical process causing multistability is the nonlinear nonradiative losses in the polariton gas due to the formation of biexcitons. These losses are only significant when the polariton gas energy is close to the biexciton energy ($<\SI{2}{\milli\electronvolt}$) [@wouters_influence_2013]. In contrast here, the bistability that we observe is present $>\SI{10}{\milli\electronvolt}$ below the biexciton energy. There is no phase transition in Paraïso et al. work [@paraiso_multistability_2010] on multistability and symmetry is *not* spontaneously broken. In contrast, we observe spin symmetry breaking while the power thresholds of the left- and right-circularly polarized states are the same, allowing us to observe spontaneous magnetization. In the Deveaud multistable system, in order to switch the polarization one has to inject an opposite-spin polariton density equal to the density difference of spin-up and spin-down polaritons. In contrast, in our experiments, the condensate switches with a gate intensity 60 times weaker than the condensate. Theoretically, the gate intensity can be much weaker and the reason that we do not see switching at even weaker powers experimentally is due to spin fluctuations in the condensate, as discussed below. Finally, we note that other microstructured systems such as microdisk lasers can also show bistability. The whispering gallery modes in microdisk lasers can have clockwise or counterclockwise propagating lasing modes [@hill_fast_2004]. When the coupling between the two modes is small, a cross-gain saturation causes one of the modes to dominate. The system can therefore operate in “flip-flop” mode and the two modes can be excited and switched with weak optical pulses [@liu_ultra-small_2010].
Thermal noise: spin flipping\[sec:thermnoise\]
----------------------------------------------
Above the spin bifurcation occupation threshold ($S_c$), any small perturbation induces a ‘restoring force’, which drives the condensate toward the attractor once the perturbation is stopped. This restoring force keeps the condensate around the attractor for small spin fluctuations. However, for sufficiently large perturbations, the condensate can flip to the other attractor with the opposite circular polarization. In the experiment, for sample temperatures near the observed spin-polarized states remain stable for many seconds (longer than the stability of our experiment can be maintained). However, increasing the temperature above $T_c\simeq\SI{15}{\K}\pm1$ induces spin flips in the condensate during a measurement time window of $t_m=\SI{1.5}{\ms}$. The measured rate of the spin flipping beyond $T_c$ is a nonlinear function of the sample temperature as shown in FIG. \[fig:temp\](a). It is important to note that we do not have a real threshold for the occurrence of spin flipping here. In fact, the spin-flip rate increases exponentially with temperature right from $T=0$, until it becomes significant in the finite-time measurement window. We can account for this phenomenon by adding a thermally induced noise to our theory. This thermal noise $f(t)$, which is similar to the Johnson noise, is included in Eq. (\[eq:maincomp\]) to give Langevin-type equations:
\[eq:noise\] $$\begin{aligned}
{2}
\begin{split}
\dot{\psi}_{+1}=&-{\textstyle{\frac{1}{2}}}g(S)\psi_{+1}
-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{-1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{+1}\vert^2+\alpha_2\vert\psi_{-1}\vert^2)\psi_{+1}+f_{+1}(t),
\end{split}\\
\begin{split}
\dot{\psi}_{-1}=&-{\textstyle{\frac{1}{2}}}g(S)\psi_{-1}
-\frac{1}{2}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{+1}
\\&-{\textstyle{\frac{\mathrm{i}}{2}}}(\alpha_1\vert\psi_{-1}\vert^2+\alpha_2\vert\psi_{+1}\vert^2)\psi_{-1}+f_{-1}(t),
\end{split}\end{aligned}$$
where $f_{\sigma}(t)$ with $\sigma=\pm1$ is a realization of Gaussian random processes with zero mean $\langle f_\sigma(t)\rangle=0$ and $\delta$-like two-point correlation function $$\label{eq:noise2}
\langle f_\sigma(t) f_{\sigma'}(t')\rangle=0, \quad
\langle f_\sigma(t) f^*_{\sigma'}(t')\rangle=2 D\delta_{\sigma,\sigma'}\delta(t-t').$$ At finite temperature $T$ the intensity of the noise can be written approximately as $D={\textstyle{\frac{1}{2}}}(W+aT)$, with the $W$-contribution being a shot noise from the reservoir [@aleiner_radiative_2012] and the thermal part $aT$ defined by spin-flip polariton-phonon scattering.
The flip rate vs noise amplitude using stochastic simulations \[FIG. \[fig:temp\](b)\] reveals an Arrhenius-like increase at a critical threshold followed by a crossover to a linear regime. This model gives an excellent account of the dynamics \[FIG \[fig:temp\](a)\]. For temperatures beyond we reach the time resolution of our detection. As a result, we cannot completely span the crossover to the linear spin-flip regime in our experiment. A fit of the simulation results to the experimental data in FIG. \[fig:temp\](a) gives $a=\SI{.17}{\per\ps\per\K}$, which sets the dependence of spin flip rate on $D(T)$. We can then explore how this noise perturbs the spin system given by equations (\[eq:noise\]).
Inclusion of noise produces a spin flip rate that can overcome the effective spin potential barrier (see Appendix \[app:kramers\]). For the case in which the circular degree of polarization is high, the spin-flip process can be considered as a one-dimensional Kramers transition. The spin-flip rate $R_K$ can then be estimated as $$\label{eq:kramers_rate}
R_K=\frac{\sqrt{\varepsilon g(S)}}{2\pi}
\exp\left\{ -\frac{g(S) n}{4 D} \ln\left(\frac{{\varepsilon}}{g(S)}\right) \right\}.$$ We note that for $\varepsilon=\SI{30}{\ueV}$ and the condensate occupation $n=800$, the zero-temperature shot-noise spin-flip rate (set by $W$) is negligible for our observation timescales (). The critical temperature $T_c(t_m)$ given by $R_K(T_c) = 1/t_m$ depends dramatically on the measurement window time $t_m$. While the phonon-polariton interaction $a$ in our system gives $T_c(\SI{1.5}{\milli\s})=\SI{15}{\K}$, at lower temperatures the condensate spin lifetime rapidly exceeds the stability time of our experimental apparatus (many seconds). Modifying the phonon-polariton interaction $a$ thus has an enormous effect on the spin stability. Finally, we note that in a similar fashion to thermal noise, an overlapping reservoir can also induce spin noise in the condensate. The spin noise causes condensate spin flips, which result in the reduction of the time-averaged circular polarization. Theoretically, this can be studied by introducing a noise term similar to Eq. \[eq:noise2\], but instead of depending on temperature the noise intensity depends on the overlapping reservoir density [@read_stochastic_2009].
Concluding remarks\[sec:conc\]
==============================
In summary, we showed how spin can emerge spontaneously in nonresonantly-pumped polariton condensates. We found that for trapped condensates, in the case where the pump is linearly polarized, parity symmetry is spontaneously broken by spin fluctuations at the onset of condensation. Fluctuations are amplified by nonlinearities in the condensate formation due to the energy and lifetime splitting of the linear polarization components, producing a spin-up or spin-down condensate. The symmetry can be explicitly broken by applying a slightly elliptically polarized pump, which increases the likelihood of forming condensates with the same spin as the pump. In the case where the pump is linearly polarized, we switched the condensate state using a 60-fold weaker resonant gate pulse with an opposite circular polarization. This situation changes when the pump is elliptically polarized, where instead of switching, the condensate pseudospin precesses around stationary states in limit cycles. Finally, we showed how thermal excitations can induce spin flips with a rate that increases exponentially with sample temperature.
We demonstrated here one way to explicitly break symmetry utilizing elliptical polarization pumping geometries. One could also break the symmetry by introducing a magnetic field to split the energy of the spin-down and spin-up condensates. Alternatively, the pumping symmetry could be broken with spin current injection. These experiments thus exhibit rich physics with potential applications in sensing.
The observation of spontaneous discretized spin-polarized states also has interesting consequences in the physics of condensate lattices. The possibility of shared reservoirs, and a Josephson type tunneling [@lagoudakis_coherent_2010] between adjacent sites, could provide new phenomena previously unobserved in driven bosonic systems. Magnetic phase transitions, geometric frustration and spontaneous pattern formation of spin in lattices, domain formation, topological spin insulators, and topological defects are a few examples of magnetic systems that could be studied, all within a highly-controlled bosonic many-body system.
While the condensed polariton lattice resembles nanomagnet arrays [@jamet_magnetic_2001; @hai_long_2010], it has the inherent advantages of tunable nonlinearity, longer spin relaxation time, ps response, rapid optical addressing and manipulation, and adaptable scalability. The spin-polarized state at zero magnetic field is retained for many seconds, 10 orders of magnitude longer than the condensation time, making it a suitable candidate for optical spin-based memories.
Spin switching with only a fraction of the condensate density, which is a direct result of the nonlinearity in our system, can be used for low power optical and electrical sensing and spin switches. Finally, the possibility of coherent driving allows the realization of superpositions of spin-up and spin-down states, which are the key requirements for quantum information processing.
Acknowledgments {#acknowledgments .unnumbered}
===============
We acknowledge discussions with B. L. Altshuler and N. G. Berloff. This work was supported by EPSRC Grant No. EP/G060649/1, EP/L027151/1, EU Grant No. CLERMONT4 235114, EU Grant No. INDEX 289968, ERC Grant No. LINASS 320503, the Leverhulme Trust Grant No. VP1-2013-011, Spanish MEC (Grant No. MAT2008-01555), the Greek GSRT ARISTEIA Apollo program and Fundación La Caixa, and Mexican CONACYT Grant No. 251808. F. P. acknowledges financial support from EPSRC at the University of Cambridge and a Schrödinger grant at the University of Oxford. The data corresponding to all the figures in this paper can be found at <https://www.repository.cam.ac.uk/handle/1810/248036>
.
Experimental methods\[app:expmethods\]
======================================
The cavity’s top (bottom) distributed Bragg reflector (DBR) is made of 32 (35) pairs of Al$_{0.15}$Ga$_{0.85}$As/AlAs layers of /. Four sets of three GaAs quantum wells (QW) separated by thick layers of Al$_{0.3}$Ga$_{0.7}$As are placed at the maxima of the cavity light field. The 5$\lambda$/2 () cavity is made of Al$_{0.3}$Ga$_{0.7}$As. The microcavity sample is chemically etched from the substrate side to form diameter membranes allowing optical access from the back of the sample for resonant excitation \[FIG. \[fig:1\](a)\]. The sample shows condensation under nonresonant excitation [@tsotsis_lasing_2012]. The excitation laser is a single-mode CW Ti:Sapphire, which is amplitude modulated using an AOM with a rise time of . To pattern the pump intensity a spatial light modulator was used [@cristofolini_optical_2013].
Strain-induced linear polarization splitting\[app:polsplit\]
============================================================
The measured energy of the ground state $X$- and $Y$-polarized photoluminescence far below threshold is shown in FIG. \[fig:transmat\](a). The energy splitting of the linearly polarized modes varies across the sample surface, reaching its maximum at the edges and minimum at the center of the membranes. This observation suggests that the splitting is correlated to the level of strain across the microcavity structure, since the latter is expected to possess a similar spatial dependence: namely to be strongest at the boundary between etched and non-etched regions and relax towards the central parts of the membranes. Note that we observe all the same phenomena even in unetched samples, as strain is universally present from the III-V heterostructure growth.
Strain-induced splitting of the initially degenerate polariton states at $k=0$ into orthogonal linearly polarized modes has been demonstrated in previous works [@balili_huge_2010; @klopotowski_optical_2006]. Both the excitonic and the photonic parts of the polariton can be affected by strain to produce such an anisotropy. In the former case, the initial splitting of the bright exciton states due to exchange interactions are enhanced by strain-induced mixing of the heavy and light hole valence bands, thereby reducing the symmetry of the QW [@aleiner_anisotropic_1992; @ivchenko_heavy-light_1996; @balili_huge_2010]. In the latter case, strain induces a small birefringence in the cavity and/or DBRs, hence lifting the degeneracy between the $[110]$ and $[1\bar{1}0]$ axes [@klopotowski_optical_2006].
Because of the finite curvature of the cavity stopband, splitting the lower polariton into two orthogonal modes necessarily induces a difference of their linewidths as well. For the microcavity structures studied in this work the polariton modes are located on the low-energy side of the stopband \[FIG. \[fig:transmat\](b)\]. In this case the mode possessing higher energy will exhibit a narrower linewidth, since it is located closer to the stopband center, where the DBR reflectivity is at its maximum. Correspondingly, the lower energy mode will exhibit a larger linewidth, since it is located closer to the edge of the stopband, where the DBR reflectivity starts to drop. For an energy splitting of the order of , transfer matrix calculations predict a linewidth difference of approximately \[FIG. \[fig:transmat\](c)\].
This small difference in linewidth is not resolvable with our instruments. However, it should be noted that any nonzero linewidth difference, as long as it is negative sign relative to the energy splitting, eventually leads to the bifurcation of the circular polarization at a critical threshold \[FIG. \[fig:dEgamma\](a)\]. Moreover, if the ratio of the linewidth difference to energy splitting is kept constant (as we have $\gamma=0.1\varepsilon$ according to our transfer matrix simulations), the condensate becomes linearly polarized at high energy splittings \[FIG. \[fig:dEgamma\](b)\]. This is indeed what we observe at the edges of the membrane, where the energy splitting is as high as $\SI{100}{\ueV}$.
Variable cross spin saturation\[app:varcross\]
==============================================
For the case when the same-spin and cross-spin gain-saturation nonlinearities are different we have:
\[Evol2psi2\] $$\begin{aligned}
{2}
\begin{split}
\dot{\psi}_{+1}=&{\textstyle{\frac{1}{2}}}\left[w-{\textstyle{\frac{1}{2}}}(\mu|\psi_{+1}|^2
+(2\eta-\mu)|\psi_{-1}|^2)\right]\psi_{+1}\\
&-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{-1}
-{\textstyle{\frac{\mathrm{i}}{2}}}\left[\alpha_1|\psi_{+1}|^2+\alpha_2|\psi_{-1}|^2\right]\psi_{+1},
\end{split}\\
\begin{split}
\dot{\psi}_{-1}=&{\textstyle{\frac{1}{2}}}\left[w-{\textstyle{\frac{1}{2}}}(\mu|\psi_{-1}|^2
+(2\eta-\mu)|\psi_{+1}|^2)\right]\psi_{-1}\\
&-{\textstyle{\frac{1}{2}}}(\gamma-{\mathrm{i}}{\varepsilon})\psi_{+1}
-{\textstyle{\frac{\mathrm{i}}{2}}}\left[\alpha_1|\psi_{-1}|^2+\alpha_2|\psi_{+1}|^2\right]\psi_{-1},
\end{split}\end{aligned}$$
where $w=W-\Gamma$ and we have now two saturation parameters, $\eta$ and $\mu$. The saturation is controlled by individual occupations of circular components when $\mu=2\eta$, and the saturation is controlled by the total occupation when $\mu=\eta$. In general, $\eta\leqslant\mu\leqslant2\eta$. Equations above in the matrix form read $$\begin{aligned}
\label{EvolPsi}
\begin{split}
\frac{d\Psi}{dt}=&\frac{1}{2}\left[w - \eta S - (\mu-\eta) S_z\sigma_z\right]\Psi
-\frac{1}{2}(\gamma-{\mathrm{i}}\varepsilon)\sigma_x\Psi\\
&-\frac{\mathrm{i}}{2}\left[(\alpha_1+\alpha_2)S+(\alpha_1-\alpha_2)S_z\sigma_z\right]\Psi,
\end{split}\end{aligned}$$ and the equations for pseudospin components are
\[EvolSpin2\] $$\begin{aligned}
&& \dot{S}_x =(w-\eta S)S_x - \gamma S - \alpha S_z S_y, \\
&& \dot{S}_y =(w-\eta S)S_y + {\varepsilon}S_z + \alpha S_z S_x, \\
&& \dot{S}_z =(w-\mu S)S_z - {\varepsilon}S_y.\end{aligned}$$
Linearly polarized condensates (parity conserved)
-------------------------------------------------
These particular solutions are given by $S_y=S_z=0$, $S_x=\pm S$, and $S=(w\mp\gamma)/\eta$. $X$-polarized condensates (upper sign) can exist for $W>\Gamma+\gamma$. $Y$-polarized states (lower sign) appear for $W>\Gamma-\gamma$. Considering their stability with respect to small fluctuations: $S_y=y$, $S_z=z$, $S_x=\pm S_0+x$, and $S=S_0\mp x$, with $S_0=(w\mp\gamma)/\eta$, we have linearized equations
\[StabEqs\] $$\begin{aligned}
&& \dot{x}=-\eta S_0 x, \\
&& \dot{y}=\pm\gamma y+({\varepsilon}\pm\alpha S_0)z , \\
&& \dot{z}=(\pm\gamma -(\mu-\eta)S_0)z - {\varepsilon}y .\end{aligned}$$
Taking $x,y,z\propto e^{\lambda t}$ we see that fluctuations in $x$ always decay, while (\[StabEqs\]b,c) produce the equation for the Lyapunov exponent $\lambda$, $$\label{Lyapun}
(\lambda\mp\gamma)^2+(\mu-\eta)S_0(\lambda\mp\gamma)+{\varepsilon}({\varepsilon}\pm\alpha S)=0.$$
The stability of the $Y$-polarized condensate is lost when one root of this equation crosses zero. This corresponds to the critical occupation $S_c$ and critical pumping $W_2$, $$\label{W22}
S_c=\frac{\gamma^2+{\varepsilon}^2}{[\alpha{\varepsilon}-(\mu-\eta)\gamma]}, \qquad
W_2=\Gamma-\gamma + \eta S_c.$$
The stability of $X$ polarized state depends on the interrelation between $\gamma$ and $(\mu-\eta)S_0$. For $\mu=\eta$ this state is always unstable. However, if $\mu>\eta$ the stable $X$ polarized state can be formed for large enough condensate occupations (far above the threshold).
Elliptically polarized condensates (parity broken)
--------------------------------------------------
These solutions with $S_z\ne 0$ are given by
\[WLStates2\] $$\begin{aligned}
&&S_x=-\frac{1}{\alpha{\varepsilon}}\left[{\varepsilon}^2+(w-\eta S)(w-\mu S)\right], \qquad\\
&&S_y=\frac{(w-\eta S)}{{\varepsilon}}S_z, \qquad\\
&&S_z=\pm{\varepsilon}\sqrt{\frac{S^2-S_x^2}{{\varepsilon}^2+(w-\mu S)^2}}.\end{aligned}$$
Substitution into (\[EvolSpin2\]a) gives $$\begin{aligned}
\label{EqForS}
\begin{split}
&(\mu-\eta){\varepsilon}\left[{\varepsilon}^2+(w-\eta S)(w-\mu S)\right]\\
&+\alpha^2{\varepsilon}(w-\mu S)S+\alpha\gamma\left[{\varepsilon}^2+(w-\mu S)^2\right]=0.
\end{split}\end{aligned}$$ The positive root of this equation for $S$ should be taken. Also, it is necessary to satisfy the condition $|S_x|\leqslant S$, which gives $w\geqslant(W_2-\gamma)=w_c$. This means that the weak lasing solutions appear continuously from the $Y$-polarized solution at the critical pumping $W_2$.
The stability of weak lasing states can also be lost. Numerical analysis shows the following typical scenario of evolution of the condensate polarization state with increasing $w$ for $\mu>\eta$. First, the $Y$ linearly polarized state is formed. Then it transforms into a weak lasing, elliptically polarized state. The stability of the latter is also lost with increasing $w$, resulting in some irregular, quasi-chaotic dynamics and/or in the oscillatory motion of the pseudospin vector. Finally, for large $w$ the stable $X$ polarized state is formed.
Estimate for particle number\[sec:particlenumber\]
==================================================
The condensate particle number is experimentally measured by: $$\label{eq:particlen}
n=\frac{\Phi \tau}{ \vert C \vert^2},$$ where $\Phi$ is the photon flux, $\tau=\SI{10}{\ps}$ is the polariton lifetime, and $\vert C\vert^2=0.4$ is the photon Hopfield coefficient. The photon flux is measured by: $$\Phi=\frac{\alpha R}{\eta},$$ where $\alpha=3.5\;\mathrm{e^-/count}$ is the photoelectron sensitivity of the CCD, $\eta=0.0021$ is the total detection efficiency including the camera quantum efficiency and the total optical transmission efficiencies, and $R=\SI{1.9E10}{\per\second}$ is the spatially-integrated count rate of the CCD. Inserting these values in Eq. (\[eq:particlen\]) gives the particle number $n\simeq800$, at $P=1.7 P_{\text{th}}$.
Resonance width\[app:reswidth\]
===============================
We study the reduction of the opposite component of the condensate circular polarization to the gate laser \[marked by $\Delta s_-$ in FIG. \[fig:res\](d)\] as the ‘detuning’ of the gate varies, while the gate power remains constant. In order to change the detuning of the gate laser frequency with respect to the condensate, instead of changing the frequency of the laser, we tune the condensate frequency by changing the pump intensity. The trapped condensate ‘blueshifts’ as the pump intensity is increased, mainly due to the repulsive interaction between the polaritons. This contrasts with the case of untrapped condensates, where interactions of polaritons with the excitons in the reservoir is the source of blueshifts [@wouters_spatial_2008; @wertz_spontaneous_2010; @askitopoulos_polariton_2013]. In the 4 spot trapped geometry, we have a blueshift of and as a result we can tune the condensate energy accurately with respect to that of the gate. FIG. \[fig:resPeak\](a) shows $\Delta s_-$ with respect to the detuning of the gate laser. We observe a sharp resonance, with a full width at half maximum (FWHM) of . FIG. \[fig:resPeak\](b) shows the theoretical curve versus the gate detuning ($\hbar\omega_g$), which resembles a Lorentzian profile with a linewidth of . Theoretically, the linewidth of the resonance is defined by the noise in Eqs. . The FWHM of the Lorentzian resonance peak is $D/(1-s_z^2)n$. We note that the resonance frequency $\omega_c$ is slightly redshifted, due to the effect of the linear polarization splitting and the decay rate splitting, $$\omega_c=\frac{1}{2}\left[ (\alpha_1+\alpha_2) S - \frac{(\gamma S_y S_z + \varepsilon S
S_x)}{(S_x^2+S_y^2)} \right].$$
The Kramers flip rate\[app:kramers\]
====================================
From Eq. we can obtain the spin vector equations:
\[eq:LEqsS\] $$\begin{aligned}
&&\dot{S}_x= - g(S) S_x - \gamma S - \alpha S_z S_y + F_x(t), \\
&&\dot{S}_y= - g(S) S_y + {\varepsilon}S_z + \alpha S_z S_x + F_y(t), \\
&&\dot{S}_z= - g(S) S_z - {\varepsilon}S_y + F_z(t),
\end{aligned}$$
where the correlators of real-function noise $F_i(t)$ are $$\label{NoiseS}
\left<F_i(t)F_j(t^\prime)\right>=2DS\delta_{ij}\delta(t-t^\prime), \qquad i,j=x,y,z.$$
Here we consider limiting case when two parity breaking states are formed near the north and south poles of the Poincaré sphere, i.e., $|S_z|\gg|S_{x,y}|$. The spin components of fixed states in this limit are $S_{x0}\simeq -{\varepsilon}/\alpha$, $S_{y0}\simeq -\gamma/\alpha$, $S_z\simeq\pm S_0$, where $S_0$ is the root of $S=\gamma{\varepsilon}/\alpha g(S)$. In what follows we also denote $g_0=g(S_0)$ and by assumption $g_0\ll{\varepsilon},\gamma$. Being excited away from the fixed state, the spin exhibits fast self-induced Larmor precession and slow relaxation. The precession frequency is $\omega=\alpha
S_z$, so that $\omega=\gamma{\varepsilon}/g_0$ near the stationary states.
The spin should be driven by noise into the equatorial plane ($S_z=0$) in order to flip. This Kramers problem can be simplified if we perform averaging over fast precession of the spin vector. This treatment is valid as long as $|S_z|\gg|S_{x,y}|$. Consider the motion in the north hemisphere. We assume that the number of polaritons does not change during the flip, i.e., $S$ is fixed to $S_0$, and we consider the case of large occupations, $\ln S_0\gg 1$. Omitting the $g$-terms from Eqs. (\[eq:LEqsS\]a,b) we find that for a given value of $S_z>0$ the averages over one cycle of the other two components are $\left<S_x\right>=-{\varepsilon}/\alpha$ and $\left<S_y\right>=-\gamma S_0/\alpha S_z$. Then, from (\[eq:LEqsS\]c) we obtain the equation for slow evolution of $S_z$
\[SlowSz\] $$\frac{dS_z}{dt} = - g_0 S_z + g_0 \frac{S_0^2}{S_z} + F_z(t)
=-\frac{dU(S_z)}{dS_z}+F_z(t),$$ $$U(S_z)=g_0\left( {\textstyle{\frac{1}{2}}}S_z^2-S_0^2\ln S_z \right).$$
This expression for the effective potential $U(S_z)$ is not valid for small $S_z$, where it diverges logarithmically. The top of the barrier should be cut off when $S_z$ becomes comparable to $|\left<S_y\right>|$, that is for $S_z\simeq S_0\sqrt{g_0/{\varepsilon}}$. The value of potential on the top of the barrier is then $U_b\simeq -g_0 S_0^2\ln(S_0\sqrt{g_0/{\varepsilon}})$. The bottom of the well is positioned at $U_0=g_0 S_0^2({\textstyle{\frac{1}{2}}}-\ln S_0)$. As a result, the spin should overcome the barrier $$\begin{aligned}
\label{DeltaU}
\Delta U=U_b-U_0&=\frac{1}{2} g_0 S_0^2\left[\ln\left(\frac{{\varepsilon}}{g_0}\right)-1\right]
\nonumber \\
&\simeq \frac{1}{2} g_0 S_0^2 \ln\left(\frac{{\varepsilon}}{g_0}\right).\end{aligned}$$ Using the known result for the Kramers first passage time in the one-dimensional problem [@zwanzig_nonequilibrium_2001], we obtain the spin-flip rate $$\begin{aligned}
\label{KramersR}
R_K=\frac{R_0}{2\pi}\exp\left\{-\frac{\Delta U}{DS_0} \right\}
&=\frac{R_0}{2\pi}\exp\left\{-\frac{g_0 S_0}{2D} \ln\left(\frac{{\varepsilon}}{g_0}\right) \right\},\\ \nonumber
S_0&=\frac{\gamma{\varepsilon}}{\alpha g_0}.\end{aligned}$$ This expression assumes $g_0 S_0/D\gg 1$ and ${\varepsilon}\gg g_0$. The pre-exponent $R_0$ cannot be written exactly by this method, since we do not know the shape of the effective potential near the top of the barrier. It can be estimated as $R_0\simeq\sqrt{{\varepsilon}g_0}$.
Simulations and numerical parameters\[app:simparam\]
====================================================
The parameters used for all the simulations are as follows:\
0D simulations: $\eta=\SI{.01}{\ps^{-1}}$; $\Gamma=\SI{.1}{\ps^{-1}}$; $\hbar\varepsilon=\SI{30}{\ueV}$; $\gamma=0.1\varepsilon$; $\hbar\alpha_1=\SI{10}{\ueV}$; $\alpha_2=-0.5\alpha_1$\
2D simulations: $\hbar\alpha_1=\SI{3}{\ueV\um^2}$; $\alpha_2=-0.5\alpha_1$; $\hbar g_r=\SI{46}{\ueV\um^2}$; $g_P=g_R/4$; $\Lambda=0.1$; $m^*=5.1\times10^{-5}m_e$; $\gamma_R=\SI{10}{\ps^{-1}\um^2}$; $\hbar\varepsilon=\SI{7}{\ueV}$; $\gamma=0.2 \varepsilon$.
|
Moments of Impact
When 17 year old Claire is in a tragic car crash, her sister dies and her brother's brain is affected in a way so that he might never remember his old life. When Claire goes to therapy group she meets Greg the man who was driving the car that caused the crash. After being instructed by her therapy counselor to talk to meet Greg she discovers his brother Niall and a band known as one direction. She finds the five friends she never had and learns how to accept the crazy turns life has. But will her brother ever remember who she is??
30. Remember the Date
A huge grin took over my face as I walked into the kitchen to grab a Pepsi. I sat down on the couch where my brother was sitting watching some boring history show, but right now I didn't care, nothing could rain on my parade. “Aren’t you gonna complain and ask me to change the channel?” Sam asked confused. “Nope,” I said sipping my soda. “What’s up with you? And why are you so smiley” Sam was actually acting like a normal brother. A normal brother.. not like my confused memory lost brother. “Are you okay?” I asked suspiciously “Did your...” “No, my memory didn’t come back, I just decided to finally stop trying to remember. If it comes back it does, i’m just done trying. So why are you so happy?” “Remember that guy that came over the other day? Louis?” “Oh I see, it’s the guy, enough said.” he said turning his attention back to the tv show. I got up from the couch and started up the stairs when Sam yelled up the stairs at me “Don’t forget about tomorrow!” I searched my brain for anything that might be of importance. “What’s tomorrow again?” “The funeral,” he said nonchalantly. “Shoot” I muttered while a stream of cuss words went through my head. I had finally started to try and move away from the accident, to forget the horrific memories, but something always seemed to make them keep coming back. I shut the door to my room and texted Nikki and Syd. I knew I would be a mess tomorrow and they were the only ones I wanted to see. They were like my sisters, they always knew what to say and how to calm me down. |
It's been three weeks since Ingrid and I activated Star Control and the new robots in the Galactic Zone. Earlier today, I was working on a Nukatron when these damn kids came at us with their Thirst Zappers. Of course, they got soda all over the exposed hardware. The Nukatron lurched and pointed its nozzle right at one of the boys. I thought for sure he triggered the military protocol, and we were all dead. Turns out Star Control sensed the glitch, so we never had to find out. It shut down the Nukatron itself. God, I was so relieved. I still think having armed robots in the park is insane, but as far as I'm concerned, this Star Control's the real deal. |
1. Technical Field
Several aspects of the present invention relate to an electrophoretic display device, a method of manufacturing an electrophoretic display device and an electronic device, and more specifically relates to an electrophoretic display device, a method of manufacturing the electrophoretic display device, and an electronic device provided with the electrophoretic display device.
2. Related Art
It is generally known that, if electric fields are allowed to act on a dispersion system in which fine particles are dispersed in liquid, the fine particles move (or migrate) in the liquid by the Coulomb force. This phenomenon is referred to as electrophoresis. In recent years, an electrophoretic display device that displays desired information (images) using the electrophoresis draws attention as a new display device.
The electrophoretic display device is characterized by exhibiting display memory characteristics and broad viewing angle characteristics even at the time of stoppage of voltage application and by possessing a capability of performing high contrast display with reduced electricity consumption.
An electrophoretic display device is a non-luminous type (reflection type) display device. Therefore, the electrophoretic display device has characteristic that scarcely damage eyes as compared to a luminous type display device such as a cathode-ray tube display.
As such an electrophoretic display device, there is known a microcapsule-type electrophoretic display device that includes a pair of substrates each having an electrode, and a plurality of microcapsules arranged between the substrates and filled with a dispersion system in which electrophoretic particles (fine particles) are dispersed in a dispersion medium (JP A-2007-58151 is an example of the related art).
In the meanwhile, in principle, an electrophoretic display device is characterized by its reduced electricity consumption characteristic as described above. On the other hand, however, a phenomenon that leak current flows between electrodes is likely to occur. When such a phenomenon occurs, electric power is consumed due to the leak current. Therefore, there is a problem that electricity consumption increases.
That is to say, in the case where a voltage V to be applied to between the electrodes is constant, electricity consumption P of the electrophoretic display device is inversely proportional to resistance values R between the electrodes as represented by the following relation: P=V2/R.
Therefore, in a conventional electrophoretic display device, insulation property between electrodes is ensured by a binder having insulation property which is filled in spaces between the electrodes. However, metal ions and the like, which can not be removed from the binder, are contained in the binder.
Therefore, resistance values R of the binder are decreased due to the metal ions, so that there is a problem that electricity consumption P of the conventional electrophoretic display device is extremely increased.
Further, in order to suppress the electricity consumption P of the conventional electrophoretic display device from being increased, it may be conceived that a voltage V to be applied to between the electrodes is lowered. In this case, however, electric fields having sufficient intensity can not act on electrophoretic particles sufficiently so that it is impossible to move electrophoretic particles. |
Equation-of-motion coupled-cluster theory based on the 4-component Dirac-Coulomb(-Gaunt) Hamiltonian. Energies for single electron detachment, attachment, and electronically excited states.
We report in this paper an implementation of a 4-component relativistic Hamiltonian based Equation-of-Motion Coupled-Cluster with singles and doubles (EOM-CCSD) theory for the calculation of ionization potential, electron affinity, and excitation energy. In this work, we utilize the previously developed double group symmetry-based generalized tensor contraction scheme and also extend it in order to carry out tensor contractions involving non-totally symmetric and odd-ranked tensors. Several approximated spin-free and two-component Hamiltonians can also be accessed in this implementation. We have applied this method to the halogen monoxide (XO, X = Cl, Br, I, At, Ts) species, in order to assess the quality of a few other recent EOM-CCSD implementations, where spin-orbit coupling contribution has been approximated in different degrees. Besides, we have also studied various excited states of CH2IBr, CH2I2, and I 3 - (as well as single electron attachment and detachment electronic states of the same species) where comparison has been made with a closely related multi-reference coupled-cluster method, namely, Intermediate Hamiltonian Fock Space Coupled-Cluster singles and doubles theory. |
Dear traveler; welcome on our website, please sit comfortable and let us lead you through our offer.
Booking with us is more than just buying a trip - it means joining a group of people who are passionate about traveling, who will show you best possible places ...
We are passionate about travelling and we want to share our passion with you. The most important for us is your satisfaction - we know that our clients appreciate it. We guarantee that our offer is systematically and carefully checked and updated frequently to propose you the best value to prices for our services. Krakow is one of the most beautiful cities in Europe or even all over the world. Each part of a town have own unique charm and attraction. There are ‘must-see’ locations in all districts. There are so many places which are worth seeing that it could take a long time to properly enumerate all of them. One of the most interesting attractions is the Wieliczka Salt Mine. We want to arrange for you a trip to this magnificent place. If you were wondering about breathtaking trips through salt chambers you should visit Wieliczka Salt Mine. There is specific healing microclimate which has a beneficial results on improving breathing quality. Approximately 60 kilometers west of Krakow located is the largest concentration camp from II World War - Auschwitz Birkenau. We want to invite you on Auschwitz tours to see a true symbol of terror and holocaust with your own eyes. Enjoy discovering the most delightful and mysterious places with people who will organize professional tours tailored specifically for your expectations. By understanding your needs and requirements we are able to propose you the most convenient solution. We want to share with you what we are offering to tourists. Krakow and its neighbourhoods is one of the most charismatic places in Poland. We are always doing our best to show you all places that cannot be missed during your stay in Krakow. It will be a real pleasure for us to meet you in Krakow. |
<?php
/*
Plugin Name: SportsPress Next Team Preset
Plugin URI: http://themeboy.com/
Description: Add a Next preset to SportsPress league table column equations.
Author: ThemeBoy
Author URI: http://themeboy.com/
Version: 2.6.3
*/
// Exit if accessed directly
if ( ! defined( 'ABSPATH' ) ) exit;
if ( ! class_exists( 'SportsPress_Next_Team_Preset' ) ) :
/**
* Main SportsPress Next Team Preset Class
*
* @class SportsPress_Next_Team_Preset
* @version 2.6.3
*/
class SportsPress_Next_Team_Preset {
/** @var bool The link events setting. */
public $link_events = true;
/**
* Constructor
*/
public function __construct() {
// Define constants
$this->define_constants();
$this->link_events = get_option( 'sportspress_link_events', 'yes' ) === 'yes' ? true : false;
// Filters
add_filter( 'sportspress_equation_options', array( $this, 'add_options' ) );
add_filter( 'sportspress_equation_presets', array( $this, 'presets' ) );
add_filter( 'sportspress_equation_solve_for_presets', array( $this, 'solve' ), 10, 3 );
add_filter( 'sportspress_table_options', array( $this, 'add_settings' ) );
}
/**
* Define constants.
*/
private function define_constants() {
if ( !defined( 'SP_NEXT_TEAM_PRESET_VERSION' ) )
define( 'SP_NEXT_TEAM_PRESET_VERSION', '2.6.3' );
if ( !defined( 'SP_NEXT_TEAM_PRESET_URL' ) )
define( 'SP_NEXT_TEAM_PRESET_URL', plugin_dir_url( __FILE__ ) );
if ( !defined( 'SP_NEXT_TEAM_PRESET_DIR' ) )
define( 'SP_NEXT_TEAM_PRESET_DIR', plugin_dir_path( __FILE__ ) );
}
/**
* Add additional options.
*
* @return array
*/
public function add_options( $options ) {
$options[ 'Presets' ]['$nextteam'] = __( 'Next Team', 'sportspress' );
return $options;
}
/**
* Add preset
*
* @return array
*/
public function presets( $presets ) {
$presets[] = '$nextteam';
return $presets;
}
/**
* Solve preset
*
* @return mixed
*/
public function solve( $input, $equation, $post_id ) {
if ( strpos( $equation, '$nextteam' ) !== false ) {
$args = array(
'post_type' => 'sp_event',
'numberposts' => 1,
'posts_per_page' => 1,
'post_status' => 'future',
'meta_query' => array(
array(
'key' => 'sp_team',
'value' => $post_id,
'compare' => 'IN',
),
),
'order' => 'ASC',
);
if ( get_option( 'sportspress_table_next_team_filter_league', 'no' ) === 'yes' ) {
$leagues = get_the_terms( get_the_ID(), 'sp_league' );
if ( ! isset( $league_ids ) ) $league_ids = array();
if ( empty( $league_ids ) && $leagues ):
foreach( $leagues as $league ):
$league_ids[] = $league->term_id;
endforeach;
endif;
$league_ids = sp_add_auto_term( $league_ids, get_the_ID(), 'sp_league' );
if ( isset( $league_ids ) ) {
$args['tax_query'][] = array(
'taxonomy' => 'sp_league',
'field' => 'term_id',
'terms' => $league_ids
);
}
}
$events = get_posts( $args );
if ( $events ) {
$event = reset( $events );
$teams = array_filter( (array) get_post_meta( $event->ID, 'sp_team', false ) );
if ( ( $key = array_search( $post_id, $teams ) ) !== false ) {
unset( $teams[ $key ] );
} else {
return '-';
}
$team_id = reset( $teams );
if ( ! $team_id ) return '-';
if ( has_post_thumbnail( $team_id ) ) {
$logo = get_the_post_thumbnail( $team_id, 'sportspress-fit-icon' );
$icon = '<span class="team-logo">' . $logo . '</span>';
} else {
$icon = sp_team_abbreviation( $team_id, true );
}
if ( $this->link_events ) {
return '<a title="' . $event->post_title . '" href="' . get_post_permalink( $event->ID, false, true ) . '">' . $icon . '</a>';
} else {
return '<span title="' . $event->post_title . '">' . $icon . '</a>';
}
} else {
return '-';
}
} else {
return $input;
}
}
/**
* Add settings.
*
* @return array
*/
public function add_settings( $settings ) {
$settings[] = array(
'title' => __( 'Next Team', 'sportspress' ),
'desc' => __( 'Filter by League', 'sportspress' ),
'id' => 'sportspress_table_next_team_filter_league',
'default' => 'no',
'type' => 'checkbox',
);
return $settings;
}
}
endif;
new SportsPress_Next_Team_Preset();
|
Glen in a recent post (Mon, 25 Nov 1996 19:27:26) cited "the change in
family in a microscopic single celled creature which was observed to
suddenly become a multicellular life form." In the post he refers to
Talk Origins post of an alga, Chlorella pyrenoidosa (vulgaris) that
changed its form to "being in the genus Coelosphaerium, which is in a
different family from Chlorella" (Quote from Boxhorn). Sorry folks not
everything, even on the venerable Talk Origins is good science, and this
WOULD NOT be a good example to cite for speciation. It is not Glenn's
fault (he can hardly be expected to know algae genera). In fact I don't
even recall the genus, Coelosphaerium, and I TAed phycology once at the
U. of Illinois. But I do know how easy it is to contaminate cultures
and that I lot of the colonial (better term than multicellular) forms
can have unicellular stages.
But when I looked up the genus Coelosphaerium in my phycology (algae)
text, I found that it was not only a different family - it was a blue
green. This would have implied a kingdom switch from a eukaryot (having
a nucleus) to a prokaryot. While more devolution, that would be an
earth shaking change, which if provable could be published in Science
and not posted to folks that don't know algae (most protozoa folks don't
either - so maybe the researchers thought it just changed its form). It
was most likely a case of contamination. I raise some algae for class
and it is not that easy to get unialgal cultures and keep them that way.
I have had several of
mine get contaminated by blue greens. Might also mention that many of
the marine algae have a life cycle which has two radically different
forms. In one form they can be a filamentous structure and in another
part of their life cycle a different enough form that sometimes the same
alga was originally classified as two different genera. A good example
of this is some of the large Kelps, big brown algae, that have a
gametophyte stage (1N) that is filamentous and microscopic. |
Q:
Chinese Flag is not changing in the language switcher
On my website: if i switch to Chinese language the flag is not changing in the language switcher? The other languages are working fine. E.g. if you switch to French, its showing the French flag...
This is the language.phtml i am using:
<?php if(count($this->getStores())>1): ?>
<div class="polyglot-language-switcher" data-grid-columns="1" data-anim-effect="fade" data-open-mode="click" data-anim-speed="0.1" >
<ul style="display: none">
<?php foreach ($this->getStores() as $_lang):?>
<li><a href="<?php echo $_lang->getCurrentUrl() ?>" title="<?php echo $this->htmlEscape($_lang->getName()) ?>" data-lang-id="<?php echo $this->htmlEscape($_lang->getCode()) ?>"><img src="<?php echo $this->getSkinUrl('images/flags/' . $_lang->getCode() . '.png');?>" alt=""> <?php echo $this->htmlEscape($_lang->getName()) ?></a></li>
<?php endforeach;?>
</ul>
</div>
<?php endif; ?>
A:
Digging through your javascript files I found this piece
$j('.polyglot-language-switcher').polyglotLanguageSwitcher({
selectedLang: function () {
return $j('html').attr('lang');
}
});
Which basically uses the lang attribute of the HTML tag to set the current language. Testing this on several stores the language is always set correctly.
<html lang="en" id="top" class="no-js"> for English,
<html lang="en" id="top" class="no-js"> for French... But for Chinese <html lang="zh" id="top" class="no-js">
And since you're using the code CN but the language is ZH it doesn't match.
ZH is the ISO2 language code that Magento uses while the language switcher uses the store codes you've provided. The quickest and cleanest solution is to simply change the storecode to ZH. Any other solution would require a hard coded rewrite of the code
|
Modulation of macrophage functionality induced in vitro by chlorpyrifos and carbendazim pesticides.
The immune response is the first defense against pathogens; however, it is very sensitive and can be impacted on by agrochemicals such as carbamate and organophosphate pesticides widely present in the environment. To understand how pesticides can affect immune cell function in vitro, this study investigated the effects of chlorpyrifos (CPF) and carbendazim (CBZ), the most commonly used pesticides worldwide, on murine immune cell (i.e. macrophage) functions, including lysosomal enzyme activity and pro-inflammatory cytokines (IL-1β and TNFα) and nitric oxide (NO) production by isolated mouse peritoneal macrophages. This study showed for the first time that CPF and CBZ dose-relatedly reduced macrophage lysosomal enzyme activity and LPS-induced production of IL-1β, TNFα and NO. In general, the effects caused by CPF appeared more pronounced than those by CBZ. Collectively, these results demonstrated that CPF and CBZ exhibited marked immunomodulatory effects and could act as potent immunosuppressive factors in vitro. This inhibition of macrophage pro-inflammatory function may be an integral part of the underlying mode of action related to pesticide-induced immunosuppression. |
The MIT Technology Review has a plan — or three — to take down Bitcoin.
Writing in an article titled “Let’s Destroy Bitcoin,” tech writer Morgan Peck presents three scenarios that she believes could lead to Bitcoin’s eventual demise.
The first option is a “government takeover,” whereby governments create their own digital currencies — dubbed “Fedcoins” — which will allegedly “improve upon the efficiencies of Bitcoin,” presumably reducing or even eliminating demand for decentralized cryptocurrencies.
Another of MIT’s strategies to take down Bitcoin involves the “tokenization of everything.” In this scenario, economic activity evolves into a hyper-efficient mass-barter system, in which virtually every company releases its own cryptocurrency and an automated system allows users to seamlessly trade their “FacebookCoins” for “ToyotaCash” depending on which asset they need to complete a transaction.
“Think of this as an incredibly efficient barter system,” says Campbell Harvey, a finance professor at Duke University. “Barter is generally inefficient, but if you have a network and you tokenize the goods and services and enable it with a blockchain, it can become very efficient.”
The author’s most unique strategy to take down Bitcoin involves social media conglomerate Facebook masterminding a stealth takeover of the cryptocurrency.
In this scenario, Facebook launches a multi-pronged attack on the cryptocurrency’s current implementation.
First, the company creates a proprietary, third-party Bitcoin wallet and integrates it throughout Facebook’s product suite, a scheme designed to trick users into giving the company outsized control of the Bitcoin ecosystem.
Peck explains:
“For those who already use Bitcoin, the experience is so vastly superior to what they’ve previously experienced that they immediately migrate their funds to their Facebook wallet. Those who don’t yet own any bitcoins, or have never heard of them, could be given the option of earning some on the site, either by watching advertisements or by writing Facebook posts for others to see.”
Meanwhile, the company would secretly launch a mining operation, which it could perhaps augment by allowing users to opt-in to a Coinhive-style mining script in exchange for an ad-free browsing experience.
Once Bitcoin has firmly entered the mainstream and become inseparable from Facebook’s product suite, the company could wield its influence to quietly fork Bitcoin and force its users — most of whom are ignorant of the software’s technical details — to adopt the new version, which will be structured however the company sees fit.
Could one of these scenarios come to fruition, leaving Bitcoin as currently structured by the wayside? Peck certainly seems to think so. I, however, have my doubts. Here’s a follow-up post in which I explain why I believe these strategies are far-fetched.
Featured image from Shutterstock. |
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One of the most common misconceptions about veganism or plant-based diets is that they're expensive or hard to manage.
A dreaded and regular question for 'full time vegans' is, "but what do you even eat?".
But when you've been doing it a little while, you'll discover that there's actually loads of foods you can enjoy.
Most importantly, without breaking the bank over the 'vegan' tag often placed, which have a fun habit of increasing the price of things by about a third.
We've put together a list of 25 things commonly sold in stores, which are what's known as 'accidentally vegan', you might be surprised as to how much of your diet is plant based already, or if you are vegan and didn't know you could eat these - well, you're welcome!
Note: Please always be sure to double-check the ingredients before purchasing anything on this list, as manufacturers are at liberty to change their ingredients at any time.
Cadbury's Drinking Chocolate
(Image: Daily Mirror)
Most of the big name fizzy drinks available in supermarkets are vegan-friendly, with just a few exceptions, namely Lilt, Lilt Zero, Kia-Ora and Schweppes Orange Squash, which all potentially carry traces of fish gelatin.
However, if it’s a hot drink you’re after and a delicious sweet treat fix, then we have good news – there are plenty of hot chocolate drinks that happen to be vegan. Mixed with warm almond milk, soy milk or even boiling water, they taste rich and creamy without the need for dairy.
Freddo's hot chocolate and Cadbury's Drinking Chocolate are two of the best known brands.
Crumpets
(Image: Handout)
Stop the press. Crumpets are vegan.
We've got Warburtons as the main image, but most store branded packs are plant based.
After all, real bread is made with just four ingredients: flour, water, yeast and salt. Although they have other added preservatives, crumpets are fundamentally the same concept.
Bread
(Image: Publicity Picture)
As said above, real bread is made with just the four core ingredients.
If you look out for quality bread from the bakery it makes an excellent vegan option.
Although you should beware some enriched breads like brioche or buns contain butter and egg yolks, but there are plenty of vegan alternatives.
Chicken flavoured noodles
(Image: Waitrose & Partners)
You wouldn't think it, but a lot of noodles are vegan. A lot aren't, and have milk powder in as a thickening agent.
But chicken flavoured noodles, especially a lot of the ethnic brands and super noodles don't use the dreaded dairy as an ingredient inclusion.
Veganism isn't all salads as some would like you to believe, comfort, treat and lazy eating is a huge part of it too!
Bisto gravy
(Image: Publicity Picture)
One of our favourite discoveries is that instant vegan gravy is a thing (thanks, Bisto!) - but onion and vegetable gravy Tesco own brand is also vegan.
You just can't beat a veggie sausage, mash, peas and gravy dinner on a rainy day.
Lotus Biscoff Biscuit Spread
(Image: HANDOUT)
Lotus Biscoff Biscuits are vegan and is now available as a spread, and when it came out it was an absolute toast game changer.
Lots of fruit jams are vegan too, but Biscoff on bread was a dish we never knew A perfect alternative to chocolate spread or peanut butter if they're not your thing.
Create a delicious, unique sweet spread with this best kept secret.
Garlic bread (pizza bread or slices)
(Image: The People)
It might not seem like it but some garlic breads are totally suitable for a herbivore human.
Some have butter as the spread, but a lot use a margarine/oil based garlic spread.
One that we particularly like you can pick up at your local essentials shop, Safeway's garlic bread. It's like a pizza, only better.
Jelly
(Image: Getty Images)
Jelly often has gelatin in it, for those who don't know what gelatin or gelatine is, it's a translucent, colourless, flavourless food ingredient, derived from collagen taken from animal body parts.
If that doesn't float your boat, but jelly does, Sainsbury's raspberry jelly is gelatin free, and even has real raspberries in it - so it's a bit like one of your five a day.
(We said a bit)
Bournville dark chocolate
(Image: Publicity Picture)
Aside from Bournville, Cadbury doesn't offer many vegan options. But this one kind of makes up for it with it's creamy delicousness.
At Easter, the chocolate company released Bournville chocolate buttons, which was incredible to be totally honest.
Crisps - Pringles, Walkers, Twiglets
(Image: Handout)
As with seemingly everything, lots of crisps have milk powder in them, unless they're cheese or sour cream flavour though, literally who knows why.
But believe it or not, a lot of meaty flavoured crisps are actually entirely meat free, which makes them a great choice for vegans who every now and then get a craving for something a little on the edge.
Crisps that are totally okay include: Pringles Original - BBQ Sauce, Texas BBQ, Paprika and Smokey Bacon flavour, Twiglets, Bacon Hoola Hoops, McCoy’s Thai Sweet Chicken, Sainsbury’s bacon crispies, Sainsburys Taste The Difference sea salt and peppercorn crisps, Sainsbury’s meaty variety crisps, M&S fish ‘n’ chip crisps, Doritos Chilli Heatwave and salted original and Walkers Ready Salted, Salt and Vinegar, Prawn Cocktail and Worcester Sauce crisps.
Biscuits - chocolate bourbons, Oreos, Fox's Party Rings
(Image: Daily Record)
People who have a problem with veganism will try and tell you you can't eat biscuits. But they're wrong, so so wrong.
One of the biggest surprises for us was chocolate bourbons, custard cremes aren't usually okay (there is a Tesco brand you can eat though), but vegan biscuit treats include: Lotus Original Caramel Biscuits, Fox's Ginger Crinkle Crunch Biscuits, Fox's Dark Chocolate Chunkie Cookies, Fox's Party Rings, Bourbon Biscuits, Oreos, Nairn's Biscuits – Dark Chocolate Chip Oat, Stem Ginger Oat, Mixed Berries Oat, Fruit & Spice Wheat Free and Crawford's Pink Wafers.
Unfrosted Pop Tarts (blueberry, strawberry and brown sugar - cinnamon)
The two main non-vegan ingredients found in most Pop-Tarts are milk, which can also be found in the form of whey, and gelatin.
Sadly, every frosted Pop-Tarts flavor contains gelatin in the frosting, but there are still three very delicious, unfrosted Pop-Tart flavors that are vegan-friendly.
These include: blueberry, strawberry and brown sugar-cinnamon, which are all on PETA's list of "accidentally vegan" foods.
Cereal - Weetabix, Shreddies, Asda blueberry wheaties
(Image: Daily Record)
As a vegan, you can still have your breakfast cereal in a morning, instead of using cow milk, switch to a plant milk instead: oat, soy, almond, rice, coconut, hemp, cashew.
Unfortunately, like with most things, not all cereals are vegan.
Easy ingredients to look out for are of course milk and honey but however, vitamin D can also be a red flag.
Many companies, including Kellogg’s, source their vitamin D from lanolin. This is grease from sheep’s wool, therefore not vegan.
But lots like Weetabix and Shreddies are proudly vegan, even the frosted ones and ones with chocolate.
Smiley face potatoes
(Image: Birmingham Post and Mail)
According to McCain's web site, “Mealtime is fun time with McCain SMILES® Fun Shaped Potatoes. ... SMILES, like basically all fries, are vegan.
These squishy happy potato faces will not only make you happy with their happiness, but they don't require milk or butter or whatever - so they're commonly guilt free.
And even though they're a kids treat - they can be yours too!
Sweets - Starburst, Love Hearts, Flying Saucers, Skittles, Turkish Delight
(Image: Daily Mirror)
Some sweets recipes actually contain animal and insect-derived ingredients like carmine (also called Cochineal – a red colouring derived from beetle shells!), beeswax and gelatine.
Thankfully though there are plenty of sweets that you are probably eating that are on the market today that are vegan friendly. You can find all these vegan sweets in Tesco, Asda, Sainsburys and other major UK supermarkets.
They include: Starburst, Millions, Haribo – Sour Rainbow Strips, Flying Saucers, Love Hearts, Jelly Tots, Sherbet Fountain, Skittles, Goody Good Stuff and Fruit Sherbets.
Pasta
(Image: Getty Images)
You may have heard that pasta is not vegan because it may contain egg as a listed ingredient. But those are usually 'fresh' pastas.
But generally, pasta contains no animal-derived ingredients and most packaged pasta—including spaghetti, rotini, and any other type is 100 percent vegan.
Marmite
(Image: PA)
As it says on the Marmite websites 'frequently asked questions' this spread is "perfectly suitable for vegetarians and vegans".
The question is: "Does Marmite™ have any meat in it?"
To which the company answer: "Absolutely not – Marmite™ is a meat-free product and always has been. It’s perfectly suitable for vegetarians and vegans. We couldn’t possibly let anyone miss out on our much-loved spread."
Coop/Asda/Morrison's jam and custard donuts
Quite a few supermarket doughnuts are actually vegan. Shiny ones like Krispy Kremes aren't, they have milk in their glazing and egg in their recipe.
But Morrison's, Coop and Asda to name a few are animal free in their jam and custard doughnuts. Be sure to check though, and ask a staff member if you're not sure!
Ritz Crackers
Despite having cheese on the packaging, Ritz Original Crackers are vegan, as are some of the brand's other flavours.
On the ingredients list are "natural flavor" and "natural smoke." - so there are no hidden animal products to be found here.
Ritz Crackers and cup of tea? Yes please!
Nature Valley Granola Bars
The majority of the crunchy granola bars are vegan.
The flavors include Apple Crisp, Peanut Butter, Cinnamon, Pecan Crunch, Roasted Almond, and Maple Brown Sugar.
Oats 'n Honey flavor isn't listed, because most vegans choose to steer clear of honey.
Popcorn
Unless it says 'butter coated' or 'honey' or something similar, popcorn is cooked in oil (or in the microwave) and even when it's sweet it's vegan.
Those bags of Propercorn, sweet and salty and just plain salty are just popcorn and seasoning so you can go to the cinema or Tesco and munch on these addictive and moreish snack.
Salted pretzels
(Image: Daily Mirror)
If you go to Aunt Anne's and ask for a pretzel with no dairy, they'll brush it with an oil based spread that is equally delicious and arguably not as heavy.
But an awesome snack are these little dried pretzels, especially the Sainsbury's ones. For £1.20 you can pick up a 150g bag to pick up whilst watching a bit of late night netflix.
Pot noodles
(Image: Daily Mirror)
This may be a bit left wing, but a few Pot Noodle's have no animal product ingredients in them.
This includes: Beef & Tomato, Bombay Bad Boy, Sweet & Sour, Brazilian BBQ Steak, Chilli Beef, Chinese Chow Mein, Piri Piri Chicken, Sticky Rib. All totally vegan, so student and low key eating can still totally be a thing.
Cup-a-soup
(Image: Daily Mirror)
Many cup-a-soups have milk powder in to thicken them up. Even loads of tomato soup, which came as a huge surprise to us anyway!
However not all of them are. Including a lot of Batchelors soups, some Heinz and brands such as Amy's Kitchen.
This is another one where if you shop in the ethnic or own brand paper soup packet section, they tend not to have anything untoward in it.
Betty Crocker Cake Mix
(Image: Daily Mirror)
Did you know that many boxed cake mixes are vegan?
It’s easy to slightly alter the directions on the packet by using egg replacers, which you can pick up online or in natural grocery stores.
Lots of pre-made icings and toppings are vegan too.
Does this list surprise you? Did we miss any 'accidentally vegan' treats that you love? Let us know in the comments! |
World Reacts Harshly to NHL's Cancellation
The House of Lords was among the bodies summoned in emergency session yesterday.
After intense negotiations between the NHL and the NHL Player's Association broke down, the prospect for hockey in the near future seem dim. The cancellation of the National Hockey League's season has caused ripple effects across the world. While a feeling of apathy toward professional ice hockey has pervaded the United States, nations across the globe are taking decisive action to handle the crisis.
The British House of Lords was summoned into an emergency session yesterday, when it became apparent that there would be no hockey in 2004-2005.
"This is an extremely rare move for this House," said the Earl Marshal, the Duke of Norfolk. "Never since the dawn of the Second World War have We, the Lords Spiritual and Temporal, felt such a compelling national interest to warrant such a bold step."
The Duke proceeded to choke down his crumpet and efface the tea stains from his ermine.
The French Estates General, which has not met at all since it was officially disbanded by King Louis XVI in 1789, assembled today in Paris to condemn the NHL's decision. A groundswell of bitterness towards America is expected, many observers of Franco-American affairs fear, yet it is not felt believed that the antipathy will become so intense that any food items will need to be renamed. Some members took the rare opportunity to suggest yet another Revolution, claiming, "It's been a God damned long time. We're overdue."
The governments of Chile, Saudi Arabia, Denmark, and Nepal have all declared a period of official State Mourning. Various Eastern European nations, including Romania, Latvia, Estonia, and Belarus, have placed their militaries at the highest state of alert. The United Nations Security Council issued a strong Resolution denouncing the NHL's decision. The Security Council was unwilling to enforce its Resolution, which evoked hearty laughs from across the NHL. It took no further action on the matter.
Egypt, Sri Lanka, and Austria have withdrawn their ambassadors and cut off all diplomatic ties with the United States as long as the hockey season is stalled.
Faced with such bold international reaction, embattled NHL Commissioner Gary Bettman commented, "This all seems a little over the top, but at least it's nice to know that somebody cares."
Make Michael M. Pepe's day - give this story five thumbs-up (there's no need to register, the thumbs are just down there!)
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Q:
Eliminate non-visible characters perl
I have a perl variable that is being read in from another script's STDOUT:
$var = `someScript.sh`
print $var <---- Prints "somestring"
However, the variable contains more than "somestring". There are 15 more characters on the front of the variable (special and not-special but hidden) that don't show when I print.
length($var) <--- Returns a number 10-15 larger than "somestring" has chars
I can eliminate the special characters like so:
$var =~ s/[^[:print:]]+//g
But it appears that there are also non-special characters that are revealed once the special characters have been removed:
print $var <---- Displays "0;<hostname>somestring"
(where <hostname> is the system hostname)
Is there a way to eliminate both the special characters AND the non-special characters that were being hidden? I want to be able to use $var as the key of a hash, and then reference it by "somestring"
$hash{$var} = 123
print $hash{'somestring'}
Thoughts?
A:
Can we assume that the characters you want to remove are before the non-printable characters ?
If so, maybe something like
$var =~ s/.*[^[:print:]]+//;
could work ?
|
INDEPENDENCE: The Cavaliers signed undrafted rookie Seth Curry to a 10-day contract on Friday, at least temporarily giving the Cavs five players from the 2013 draft.
Curry is the younger brother to Steph, the Warriors’ All-Star point guard. Their father, Dell, played one season with the Cavaliers in the late 1980s.
Curry has spent most of this season in the Development League, averaging 19.1 points and 5.9 assists for the Santa Cruz Warriors. He is widely considered an accomplished shooter despite making just 36-percent of his 3-pointers this season in the D-League (43 percent shooter overall).
He has been playing point guard with the Warriors, which the Cavs believe has impacted his percentages. He’s only 6-foot-1, but the Cavs are intrigued with his shooting ability and will play him off the ball alongside guys like Jarrett Jack and Dion Waiters.
Curry is the third player from Duke on the Cavs’ roster (joining Kyrie Irving and Luol Deng). In fact, Curry replaced Irving in Duke’s starting lineup when Irving went down with a toe injury his freshman season.
Curry joined his brother with the Golden State Warriors for training camp, but was among the last players cut. He spent time with the Memphis Grizzlies this season and appeared in one game for them, but otherwise has spent the bulk of the season in the D-League.
He was a D-League All-Star this season and has scored at least 20 points in 21 games.
The Cavs’ injury situation could get Curry on the court quickly. They dressed just nine healthy players for Thursday’s loss to the Oklahoma City Thunder. Injuries to guys like C.J. Miles, Irving and Deng create a need for a shooter.
To make room on their roster, the Cavs released Shane Edwards on the final day of his 10-day contract. He returned to the Canton Charge of the D-League, but he is again an NBA free agent. |
Q:
Silverlight/WPF - Can you have a different ItemTemplate depending on a base type of the item?
I am binding an ObservableCollection to a ListBox in Silverlight. The list can contain multiple Person or Vehicle objects which both derive from DomainObject. I would like to be able to have a different template for Person and Vehicle, but show them both in the same list. What is the best way to do this?
A:
DataTemplateSelector is not available in silverlight but there are a few resources around showing examples of how to implement it in a control.
Resource 1
Resource 2
|
A former construction company owner who delivered cash to Mafia leaders spent his third day in front of the Charbonneau Commission Wednesday.
On the stand Wednesday, Nicolo Milioto continued his display of ignorance, claiming that he had no idea what the Italian word 'capo' meant, and also saying that he did not understand English.
Milioto has testified that he doesn't know what the Mafia is, and that despite seeing Mafia leaders like Nick Rizzuto Sr. daily for decades, he had no idea what Rizzuto did for a living.
Milioto, also known as Mr. Sidewalk for his company's dominance of that industry in and around Montreal, said his only mistake was to act as a go-between for cash exchanges.
Milioto was caught on surveillance tape delivering tens, if not hundreds of thousands of dollars to Rizzuto Sr. during several exchanges. On the stand Milioto said he never asked what the money was for, and assumed it was all for the Catolica Eraclea community organization named after his home village in Sicily.
He also said that the only events occurring at Café Consenza, well known for its alleged Mob ties, were social activities linked to Catolica Eraclea.
“They're good people that I liked talking to,” he said. “They respect me, I respect them. Nothing more.”
He also said his wife and daughter didn’t worry about his relationship with suspected Mobsters, because, “My wife is a good Italian, she doesn't ask questions,” he said.
He said he didn’t bring his family to the social club to meet others from his Sicilian village, because it wasn’t a place for women.
“Sicilian bars, they're for men only. They're like taverns for Quebecers,” he said.
The commission was more interested in Milioto’s business dealings with the city of Montreal, Wednesday, claiming he was part of a system of collusion, despite his many proclamations of innocence.
Several witnesses, including city staff and competitors clearly identified Milito’s construction company Mileva as part of a close circle that divided up contracts for sidewalks.
Milioto was shown phone records proving he was in close contact with competitors before calls for tenders were opened.
It was a coincidence, he said.
“Was he calling me to say hello? I don’t know,” he said.
He was then shown more phone records, this time with another competitor and fellow Sicilian, Lino Zambito. Zambito's 56 calls, each less than a minute long, coincided with public tenders for sidewalk projects, evidence showed.
Despite there being no clear answer from Milioto, the commission noticed common trends among companies doing all the sidewalks in Montreal: the Consenza Club and Catolica Eraclea.
“We've got savoir-faire. These are people who get up early to go to work,” he said, adding that other Itlaian communities might not have the same get-up-and-go.
The commissioners evidently do not believe Milioto's protestations of innocence and ignorance, and asked what he gained from spending years shuttling money from construction company owners to a man who was publicly identified as the head of a criminal organization.
"I don't think I found advantages or disadvantages," said Milioto.
As for Rizzuto's character, Milioto said he was a good man, and he never saw the mafia leader as anything but a decent human being.
"I didn't see it, despite what everyone was saying... For myself I saw the man, the person," said Milioto. |
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---
abstract: 'The combination of elliptical deformation of streamlines and vorticity can lead to the destabilisation of any rotating flow via the elliptical instability. Such a mechanism has been invoked as a possible source of turbulence in planetary cores subject to tidal deformations. The saturation of the elliptical instability has been shown to generate turbulence composed of non-linearly interacting waves and strong columnar vortices with varying respective amplitudes, depending on the control parameters and geometry. In this paper, we present a suite of numerical simulations to investigate the saturation and the transition from vortex-dominated to wave-dominated regimes. This is achieved by simulating the growth and saturation of the elliptical instability in an idealised triply periodic domain, adding a frictional damping to the geostrophic component only, to mimic its interaction with boundaries. We reproduce several experimental observations within one idealised local model and complement them by reaching more extreme flow parameters. In particular, a wave-dominated regime that exhibits many signatures of inertial wave turbulence is characterised for the first time. This regime is expected in planetary interiors.'
author:
- Thomas Le Reun
- Benjamin Favier
- 'Adrian J. Barker'
- Michael Le Bars
title: Inertial wave turbulence driven by elliptical instability
---
The elliptical instability is a fundamental mechanism of importance in a wide range of fluid phenomena. Originally described in the context of strained vortices [@bayly_three-dimensional_1986], it has been studied in various situations such as in vortex dipoles and in wakes. More generally, it has been proposed as a general process to transfer energy to smaller scales in turbulence (see [@kerswell_elliptical_2002] and references within). It is important for geophysical fluid dynamics because it can drive flows in planetary cores subjected to tidal deformations [@lacaze_elliptical_2005; @le_bars_coriolis_2007; @le_bars_tidal_2010; @le_bars_flows_2015]. It has been invoked to explain the magnetic field of the early Moon [@le_bars_impact-driven_2011] and the Earth [@andrault_deep_2016]. This instability develops in rotating fluids when the streamlines are deformed into ellipses. Its linear growth, due to the resonance of two inertial waves with the elliptical basic flow is well described both theoretically [@craik1989; @le_dizes_three-dimensional_2000; @kerswell_elliptical_2002; @cebron_libration-driven_2014] and experimentally [@lacaze_elliptical_2005; @le_bars_coriolis_2007; @le_bars_tidal_2010; @Eloy2000]. The non-linear saturation of the elliptical instability remains poorly understood but it is the relevant regime to describe vortex core breakdown [@SCHAEFFER2010] as well as dissipation and magnetic field generation in planetary cores [@Kerswell1998]. Simulations and experiments of the elliptical instability exhibit a variety of non-linear behaviours depending on the values of the control parameters (the ellipticity of the streamlines and the viscosity) and on the geometry. The saturation of the instability can lead to either sustained flows [@barker_mag_2014; @grannan_experimental_2014; @favier_generation_2015] or cyclic behaviours between laminar and turbulent states [@Malkus1989; @Eloy2000; @barker_non-linear_2013; @Barker2016], reminiscent of the “resonant collapse” of inertial waves observed by McEwan [@McEwan1970]. The presence or absence of geostrophic modes appears to be important, but the diversity remains to be explained in detail. Indeed, each inertial wave excited by elliptical instability of the base flow can be itself unstable to a triadic resonance with another pair of inertial waves [@kerswell_secondary_1999]: these secondary instabilities have been observed both numerically [@mason_nonlinear_1999; @favier_generation_2015] and experimentally [@Eloy2003]. Whether these multiple resonances asymptotically lead to a wave turbulence regime [@galtier_weak_2003; @bellet_wave_2006], similar to the recently observed regimes with flexural waves in plates [@miquel2011], gravity-capillary waves [@aubourg2015] and internal waves [@brouzet_energy_2016], remains to be seen. Barker and Lithwick [@barker_non-linear_2013], in their local model of the elliptical instability, nonetheless showed that strong geostrophic flows emerge during the saturation and disrupt the inertial wave resonances, leading instead to growth and decay cycles. This competition between dominant geostrophic modes and inertial waves is reminiscent of the duality observed in rotating turbulence where, on one hand, geostrophic flows are widely observed [@godeferd_structure_2015] and, on the other hand, inertial waves have been shown to survive on top of the turbulent background [@yarom_experimental_2014; @clark_di_leoni_quantification_2014; @campagne_disentangling_2015; @favier_space_2010]. Conversely to experiments and numerical simulations of rotating turbulence, where energy is injected arbitrarily into both vortices and inertial waves through an external artificial forcing, the elliptical instability provides a natural mechanism that initially injects energy into a few inertial waves only, whose properties can be theoretically predicted.
{width="0.25\linewidth"}
We focus here on the instabilities growing from a base flow made of solid body rotation at frequency $\Omega$ plus an elliptic deformation rotating at frequency $n$. Both solid-body rotation and deformation are aligned with the vertical axis. In the frame rotating with the deformation, the base flow $ {\boldsymbol}{U}_b $ reads [@barker_non-linear_2013]: $$\label{eq:forcing}
{\boldsymbol}{U}_b = - \gamma \beta
\begin{bmatrix}
\sin(2\gamma t) & \cos(2\gamma t) & 0 \\
\cos(2\gamma t) & -\sin(2\gamma t) & 0 \\
0 & 0 & 0
\end{bmatrix}
\begin{bmatrix}
x \\
y\\
z\\
\end{bmatrix} = {\boldsymbol}{A}(t) {\boldsymbol}{x}$$ where we have introduced $\gamma ~\equiv ~ (\Omega- n)$ and $\beta$ the ellipticity. This base flow can be seen as a local model of a periodically strained vortex [@le_dizes_three-dimensional_2000] or of a tidally deformed planetary core [@barker_non-linear_2013] and is a non-linear inviscid solution of the Navier-Stokes equations written in the rotating frame. It is responsible for the parametric sub-harmonic excitation of two inertial waves with frequencies close to $\gamma$ provided $\vert\gamma\vert < 2 \Omega$ [@le_bars_flows_2015]. The dynamics of the perturbation ${{\boldsymbol}{u}}$ around the base flow ${\boldsymbol}{U}_b$ is governed by the following set of equations: $$\begin{aligned}
\label{eq:perturb_OI}
{\partial}_t {\boldsymbol}{u} + ({\boldsymbol}{U_b}.{\boldsymbol}{\nabla}) {\boldsymbol}{u} + ({\boldsymbol}{u}\cdot{\boldsymbol}{\nabla}) {\boldsymbol}{U_b} +& ({\boldsymbol}{u} \cdot {\boldsymbol}{\nabla}) {\boldsymbol}{u} + 2 {\boldsymbol}{\Omega} \times {\boldsymbol}{u} \\
&=- {\boldsymbol}{\nabla} \Pi + \nu {\boldsymbol}{\nabla}^2 {{\boldsymbol}{u}}& \nonumber\\
\label{eq:incomp}
{\boldsymbol}{\nabla}\cdot {\boldsymbol}{u}~ &= ~0 \end{aligned}$$ where $\Pi$ is the modified pressure, ensuring the incompressibility of the dynamics, and $\nu$ is the constant kinematic viscosity. We assume that the flow is homogeneous, thus enabling us to carry out pseudo-spectral direct numerical simulations of equations (\[eq:perturb\_OI\])-(\[eq:incomp\]) in a so-called periodic shearing box. This is achieved using the <span style="font-variant:small-caps;">Snoopy</span> code introduced by Lesur [@lesur_impact_2007] and adapted to the study of the elliptical instability by Barker [@barker_non-linear_2013]. The perturbed flow is solved in a cubic box of size $L$ with periodic boundary conditions in all three directions. Lengths and time are normalised by $L$ and $\Omega^{-1}$ respectively. Simulations are initiated from a broad-band noise for wave numbers $4 \le k/(2\pi) \le 20$, though we obtain the same results if we instead adopt white noise. The control parameters are the normalised differential rotation $\gamma/\Omega$, the ellipticity $\beta$, which can be regarded as an input Rossby number, and the local Ekman number based on the box size $E \equiv \nu/(\Omega L^2)$. In the following, we choose $\beta = 5 \times 10^{-2}$, $10^{-6} \le E \le 10^{-5}$ and $\gamma/\Omega$ is set to $1.5$. The spatial resolution is up to $512$ grid points in each direction (see details in Supplementary Materials). Contrary to previous global DNS [@favier_generation_2015; @Cebron2010], we focus on values of $\beta$ as small as possible . The value of $E$ is a compromise between our desire to make the flow fully turbulent but have the simulation well resolved. This number is usually between $10^{-15}$ and $10^{-10}$ in planetary cores essentially because of their massive size (see Supplementary Materials, which includes Refs [@Cebron2010; @cebron_elliptical_2012], for further information). The ratio $\gamma/\Omega$ is set sufficiently high to avoid time-scale separation between the forcing and rotation. The growth rate of the elliptical instability is an increasing function of $\gamma\beta$ [@kerswell_elliptical_2002]; the value 1.5 produces rapid turbulent saturation and ensures the selection of a mode with reasonably small wavelength compared to $L$. Other forcing frequencies have been considered (see *e.g.* Supplementary Materials for $\gamma/\Omega=1$) and the results are qualitatively unchanged.
{width="0.68\linewidth"}
Snapshots of the evolving flow are displayed in Figure \[raw\_results\], with the kinetic energy of the fluctuating velocity field, decomposed into the geostrophic and the residual non-geostrophic 3D components. As previously shown in [@barker_non-linear_2013], we first observe the exponential growth of a few planar waves (Figure \[raw\_results\].a) whose wave number $k_{\rm{res}}/(2\pi )$ is between $6$ and $7$, thus ensuring a reasonable scale separation between the small-scale resonating waves and the size of the periodic box. The growth rate of the instability is consistent with theoretical estimates [@craik1989; @le_dizes_three-dimensional_2000] taking into account the bulk viscous damping. The geostrophic component grows at twice the instability growth rate, which confirms that it is driven by the direct nonlinear interactions of the resonant inertial waves, and not by a secondary instability [@kerswell_secondary_1999]. While the nonlinear interactions of inertial waves cannot lead to geostrophic modes with asymptotically low Rossby [@Greenspan1969], this is not true for our simulation at finite Rossby number. In the saturated phase, Figure \[raw\_results\].b reveals the emergence of strong columnar vortices aligned with, and invariant along the axis of rotation, as observed in [@barker_non-linear_2013 Fig. 5]. The energy stored in the geostrophic modes is comparable to the energy in the rest of the flow. Similarly to what is observed in forced rotating turbulence [@Campagne2014; @yarom_experimental_2014] or rapidly-rotating thermal convection [@stellmach2014; @favier2014; @guervilly2015], a non-local inverse cascade of the geostrophic modes takes place until, at $t \simeq 120$ rotations onwards, one single large-scale vortex, or condensate, remains (Figure \[raw\_results\].c). Consequently, the kinetic energy of the non-geostrophic component drops by two orders of magnitude.
Although they are the primary structures during the exponential growth phase of the instability, the latter result shows that inertial waves are no longer the main contribution to the flow during the late stages of the saturation. Following [@yarom_experimental_2014; @clark_di_leoni_quantification_2014], we analyse how the kinetic energy is located around the dispersion relation of inertial waves given by where $\omega$ is the dimensionless frequency and $\theta$ is the angle between the wave vector and the rotation axis. This is achieved by computing the spatio-temporal Fourier transform $\hat{{{\boldsymbol}{u}}}({{\boldsymbol}{k}},\omega)$ of the velocity field ${{\boldsymbol}{u}}({{\boldsymbol}{x}},t)$ and summing contributions associated with the same angle $\theta$. The spectral energy $|\hat{{{\boldsymbol}{u}}}(\theta,\omega)|^2$ resulting from this approach is displayed in Figure \[fig:fr0\_reldisp\]. During the growth phase ($t=10$ to $t= 30$ in Figure \[raw\_results\]), most of the energy is localised on the dispersion relation at the frequencies $\pm\gamma/\Omega$ (Figure \[fig:fr0\_reldisp\] a.), as expected from the temporal resonance condition with the base flow frequency $2\gamma$ [@le_bars_flows_2015; @kerswell_elliptical_2002]. In the early times of the saturated phase ($t= 50$ to $t= 105$ in Figure \[raw\_results\]), the geostrophic flow grows in amplitude and departure from the dispersion relation is observed while the energy remains localised close to frequencies around $\gamma/\Omega$ (Figure \[fig:fr0\_reldisp\]b). We interpret this result as follows: the base flow excites one particular frequency (fixed by the initial resonance condition with the base flow) while the wave vectors adapt themselves to interact with the growing geostrophic modes, whose energy is localised at $\theta\approx\pi/2$. The geostrophic flow is dominantly cyclonic, as commonly observed in rotating turbulence [@godeferd1999; @smith_near_2005], and the increased apparent vorticity induces a shift toward larger values of $\theta$. As the geostrophic vortices grow in amplitude, in phase c. (from $t=140$ onwards in Figure \[raw\_results\]) no inertial wave can be clearly identified (Figure \[fig:fr0\_reldisp\]c). Correspondingly, the non-geostrophic kinetic energy decreases, as observed in Figure \[raw\_results\]. After a viscous timescale, the geostrophic correction to the base flow is eventually dissipated leading to another resonance, and so on (more details about these cycles can be found in [@barker_non-linear_2013]).
{width="0.49\linewidth"} {width="0.49\linewidth"}
In the following, we question the universality of these results. Our simulations are designed to study locally the properties of the flow in a wider container. As the geostrophic modes are invariant along the rotation axis, they should connect with boundaries. This interaction induces a secondary flow known as Ekman pumping, which acts as a bulk friction on these modes. As is routinely done in quasi-geostrophic models of rapidly-rotating fluids [@schaeffer_quasigeostrophic_2005], and in confined inertial wave turbulence [@scott2014], an additionnal term is therefore added to the dynamics of the geostrophic part of the flow $ {{\boldsymbol}{u}}_{\mathrm{G}} $, which reads (in appropiate units) as [@pedlosky_geophysical_1987]: Here $h$ is the height of the container along the rotation axis. In Fourier space, (\[friction\]) is tantamount to adding a term $- f_r E^{1/2} \hat{{{\boldsymbol}{u}}}({{\boldsymbol}{k}})$, for modes with $k_z = 0$. Several additionnal reasons exist for controlling the growth of geostrophic modes. First, columnar vortices are typically not observed in global simulations. Instead, geostrophic modes emerge as steady axisymmetric flows, which do not necessarily inhibit the instability mechanism [@favier_generation_2015] (but see \[20\]) Moreover, the inverse cascade shown in Figure \[raw\_results\] inevitably leads to vortices of extent similar to the size of the box, which is unphysical. The same issue arises in two-dimensional turbulence, where it is solved adding large-scale friction [@boffetta_two-dimensional_2012]. Lastly, additionnal physics such as imposing a background magnetic field [@barker_mag_2014; @guervilly2015], can also be responsible for precluding the emergence of large scale geostrophic flows. The friction coefficient $f_r$, which stands for the ratio $L/h$, is left here as a parameter to control the relative importance of the geostrophic modes in the saturated flow. We expect other mechanisms of specific dissipation (see *e.g.* magnetic [@guervilly2015; @barker_mag_2014], quadratic, scale-dependant) to lead to similar results.
The simulations hereafter are carried out with $f_r = 10^{-2}$ and $f_r =1$. We now set the Ekman number $E$ to $3 \times 10^{-6}$ and the resolution to $512^3$. These extreme parameters could not be reached previously since the transition from phase b. to c. (see Figure \[raw\_results\]) was then too difficult to resolve. For comparison, the simulations with friction corresponding to Figure \[raw\_results\] can be found in Supplementary Materials.
As displayed in Figure \[fig:fr12\], both relatively strong ($f_r = 1$) and weak ($f_r = 10^{-2}$) selective damping of the geostrophic modes leads to significant reduction of the geostrophic energy, but it does not affect the total energy, which remains similar to what was obtained previously in the early saturation phase (denoted as b. in Figure \[raw\_results\]). Moreover, the energy is maintained throughout the simulation. The kinetic energy of the flow is now sharply located around the dispersion relation, not only at the resonance frequency, but at many frequencies consistent with the dispersion relation of inertial waves. Other mirroring locations of the energy can be noticed (see dashed line in Figure \[fig:fr12\]); they are understood as non-resonant interactions between the waves and the base flow with frequencies $ -2\cos \theta + 2 \gamma/\Omega$. Energy focusing along the dispersion relation was observed in [@yarom_experimental_2014] but in their case energy was injected randomly into the system. In our case, all the waves excited at frequencies different from the resonant frequency must be produced by nonlinear resonant interactions, hence energy focusing around the dispersion relation provides strong evidence to support the existence of inertial wave turbulence driven by elliptical instability. We further investigate the creation of small scales when the geostrophic modes are sub-dominant by plotting the Rossby number as a function of the wavenumber $k$ computed as $Ro(k) = k E(k)^{1/2} / \Omega $, $E(k)$ being the isotropic energy spectrum. This is displayed in Figure \[fig:spatial\_spectra\] and suggests that for asympotically low Ekman numbers, $Ro(k)$ is constant and less than unity beyond the resonant scale. Hence, non-linear interactions are weak and rotation affects all scales; this result is completely different from the Zeman phenomenology of forced rotating turbulence [@godeferd_structure_2015], according to which isotropic Kolmogorov-like turbulence should be recovered at small scales.
To conclude, our results not only clarify the various saturation regimes of the elliptical instability observed in experiments and numerical simulations, but also provide a new approach to disentangle wave and vortices in any situation involving rotating turbulence. Depending on the relative importance of the geostrophic flows, one can observe intermittent behaviour, or quasi-stationary states close to inertial wave turbulence, provided that the input Rossby number (or equivalently $\beta$) is low enough. As shown here, the fundamental quantity to be considered is therefore the ratio between geostrophic flows and 3D modes, which depends on the specifics of the considered system, and has been mostly neglected when comparing different rotating turbulence configurations. In previous experiments and simulations in spherical or ellipsoidal geometries, the geostrophic modes resulting from the non-linear interactions of inertial waves manifest themselves as zonal flows, *i.e.* mean steady axisymmetric flows pervading the fluid interior [@noir_experimental_2012; @morize_experimental_2010; @grannan_submitted; @grannan_experimental_2014; @favier_generation_2015] (see [@lin_precession-driven_2016] however). Their amplitudes tend to be proportional to $\beta^2E^{-\alpha}$ with $\alpha$ ranging from $0$ to $2$ [@morize_experimental_2010; @sauret_tide-driven_2014] depending on the excitation frequency. Since the amplitude of the RMS velocity scales like $\beta$ [@barker_non-linear_2013; @grannan_submitted], the ratio of the geostrophic zonal flows to the 3D modes is therefore proportional to $\beta E^{-\alpha}$. As the elliptical instability grows provided $\beta > E^{1/2}$ [@le_bars_tidal_2010], we conclude that for $\alpha<1/2$ there exists a regime where inertial wave turbulence is expected at low $\beta$ and $E$ — see right pannel of Figure \[fig:spatial\_spectra\]. Inertial wave turbulence can therefore be expected in planetary cores and more generally in rotating turbulent flows. This new turbulence regime has to be studied in detail in order to understand both dynamos [@moffatt_1970; @bardsley_davidson_2016] and dissipation driven by the elliptical instability. In the general framework of rotating fluid turbulence, our study indicates that mechanisms controlling the growth of geostrophic modes completely determine the nature of turbulence between quasi two-dimensional and wave turbulence.
We acknowledge support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 681835-FLUDYCO-ERC-2015-CoG). We also acknowledge support from IDRIS (Institut du Développement et des Ressources en Informatique Scientifique) for computational time on Turing (Projects No. 100508 and 100614) and from the HPC resources of Aix-Marseille Université (Projects No.15b011 and 16b020) financed by the project Equip@Meso (No. ANR-10-EQPX-29-01) of the program Investissements d’Avenir supervised by the Agence Nationale pour la Recherche. AJB is supported by a Leverhulme Trust Early Career Fellowship.
|
BUFFALO, NY - MARCH 21: Arizona Coyotes Defenseman Oliver Ekman-Larsson (23) looks on during the Arizona Coyotes and Buffalo Sabres NHL game on October 21, 2018, at KeyBank Center in Buffalo, NY. (Photo by John Crouch/Icon Sportswire via Getty Images)
After locking down superstar defenseman Oliver Ekman-Larsson for eight more years, and keeping the rest of their top six defensemen from last season, the Arizona Coyotes are feeling confident in their defense heading into the 2018-19 regular season.
The popular saying among the world of sports is that defense wins championships, and it looks as if Arizona Coyotes GM John Chayka is sticking to that saying by staying the course with their top six defensemen on the roster as the Coyotes look to make a significant jump in the upcoming season.
The first step was to sign the teams top two defensemen, Oliver Ekman-Larsson and Niklas Hjalmarsson, to lengthy contracts. Ekman-Larsson signed to an eight-year contract, while Hjalmarsson signed to a two-year contract for the Coyotes.
According to an article on the Arizona Coyotes website that was written by Dave Vest, Ekman Larson said “I’m very happy. I love living in Arizona and playing for the Coyotes so it was a no-brainer for me. I didn’t really think about leaving or going anywhere else. I’ve been focused on staying in Arizona. That’s where I want to play. I think we have something good coming.”
Ekman Larson currently ranks second in the Coyotes franchise for goals scored by a defenseman (102). With the length of his contract, it is clear that the Coyotes have plenty of faith in him as a leader for the team, and fully expect him to break future records.
Being forced to play only 48 games with the Coyotes last season due to an injury, Hjalmarsson will be looking to make a large impact for the team if he is able to stay healthy during the duration of the season.
Having won three Stanley Cups, Hjalmarsson will be playing a large part if the Coyotes are looking to improve on their previous season for the upcoming 2018-19 season, with the ultimate goal of returning to the Stanley Cup Playoffs.
With Ekman Larson and Hjalmarsson signed to their new contracts, the Coyotes continue the trend of having experienced defensemen with Jason Demers and Alex Goligoski filling up the rest of the top two pairings on the blue line.
Previously slated to play on the top pairing with Ekman-Larsson, Hjalmarsson will more than likely be placed on the second defensive pairing with Goligoski, with Demers filling the top pairing with Ekman-Larsson.
Last but certainly not least, the bottom pairing looks like it will be Jacob Chychrun and Kevin Connauton. During the regular season, this bottom pairing may shift from time to time with newly acquired defenseman Jordan Oesterle filling into the roster during the season.
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Coupled with a revamped offense, the Coyotes will be looking to continue to utilize a fast-paced system that is spread throughout the entire Coyotes lineup. If one thing is certain, be prepared to see plenty of quick breakout plays, and smooth transitions up the ice that will all start with the Coyotes defense. |
A healthy and homely land for all race Now infected with deadly diseases Of war,killings,rhythm of guns and bombs Dropping in the ears of mother and child Unpleasant tones that presses play on heart... |
Q:
Setting Scroll View's zoomScale and hitting back button crashes program
I was trying to make a program where you click an image and it segues to show it on full screen, scaled so that there is no whitespace around (CS 193P assignment 4 task 7 for anyone who knows it). View controllers are embedded in navigation controller. It turns out that the program crashes with EXC_BAD_ACCESS (code = EXC_I386_GPFLT) when I hit the back button in the navigation bar.
I found out that I can prevent this crash by scrolling to the top of the image and then going back. Another way to completely prevent it is to comment out the line that sets scrollView's zoomScale. Here's the code I used for loading and handling the image:
import UIKit
class ImageViewController: UIViewController, UIScrollViewDelegate {
@IBOutlet weak var scrollView: UIScrollView! {
didSet {
scrollView.contentSize = imageView.frame.size
scrollView.delegate = self
scrollView.minimumZoomScale = 0.03
scrollView.maximumZoomScale = 5.0
}
}
func viewForZoomingInScrollView(scrollView: UIScrollView) -> UIView? {
return imageView
}
var imageURL: NSURL? {
didSet {
image = nil
if view.window != nil {
fetchImage()
}
}
}
private func fetchImage() {
if let url = imageURL {
let qos = Int(QOS_CLASS_USER_INITIATED.value)
dispatch_async(dispatch_get_global_queue(qos, 0)) {
let imageData = NSData(contentsOfURL: url)
dispatch_async(dispatch_get_main_queue()) {
if url == self.imageURL {
if imageData != nil {
self.image = UIImage(data: imageData!)
} else {
self.image = nil
}
}
}
}
}
}
private var imageView = UIImageView()
private var image: UIImage? {
get { return imageView.image }
set {
imageView.image = newValue
imageView.sizeToFit()
scrollView?.contentSize = imageView.frame.size
scrollViewDidScrollOrZoom = false
autoScale()
}
}
private var scrollViewDidScrollOrZoom = false
private func autoScale() {
if scrollViewDidScrollOrZoom {
return
}
if let sv = scrollView {
if image != nil {
sv.zoomScale = max(sv.bounds.size.width / image!.size.width, sv.bounds.size.height / image!.size.height)
sv.contentOffset = CGPoint(x: (imageView.frame.size.width - sv.frame.size.width) / 2, y: (imageView.frame.size.height - sv.frame.size.height) / 2)
scrollViewDidScrollOrZoom = false
}
}
}
func scrollViewDidEndZooming(scrollView: UIScrollView, withView view: UIView!, atScale scale: CGFloat) {
scrollViewDidScrollOrZoom = true
}
func scrollViewDidScroll(scrollView: UIScrollView) {
scrollViewDidScrollOrZoom = true
}
override func viewDidLoad() {
super.viewDidLoad()
scrollView.addSubview(imageView)
}
override func viewWillAppear(animated: Bool) {
super.viewWillAppear(animated)
if image == nil {
fetchImage()
}
}
override func viewDidLayoutSubviews() {
super.viewDidLayoutSubviews()
autoScale()
}
}
I tried to make a simple application which segues into ImageViewController from a View Controller that has only a button and is embedded in navigation controller, and the crash is still the same. Here's the code I used in the first view controller:
class FirstViewController: UIViewController {
let url = NSURL(string: "https://developer.apple.com/swift/images/swift-og.png")
override func prepareForSegue(segue: UIStoryboardSegue, sender: AnyObject?) {
if segue.identifier == "Show Full Image" {
let ivc = segue.destinationViewController as! ImageViewController
ivc.imageURL = url
}
}
}
What causes this and am I doing something wrong here? I'm using Xcode 6.3 beta 3.
A:
It seems that the problem is actually with the scrollView's delegate, as I was able to fix this with adding
override func viewWillDisappear(animated: Bool) {
super.viewWillDisappear(animated)
scrollView.delegate = nil
}
|
crpX mutants of Escherichia coli K12: specific regulatory effects of altered cyclic AMP receptor proteins.
We attempted to correlate structural modifications of the adenosine 3',5' cyclic monophosphate (cAMP) receptor protein (CAP), to changes in some of its in vivo regulatory functions such as (i) stimulation of the lactose operon expression and (ii) control of adenylate cyclase activity. A radioimmunological procedure was used to study the structure of CAP synthesized by three mutants (crpX) grown under various conditions, in the presence or absence of endogenous or exogenous cAMP. In one mutant CAP appears to be sensitive to thermal inactivation. In another mutant CAP is particularly sensitive to degradation in the absence of cAMP; this degradation is enhanced by high temperature and during stationary phase of growth, and prevented by the addition of glucose. Functional alterations of CAP were not found to follow structural changes strictly. In the crpX mutants and in strains carrying the crp+ or other crp allele, the stimulation of the lactose operon expression and the modulation of the in vivo rates of cAMP synthesis appear to vary in parallel, favoring an indirect mechanism of regulation of adenylate cyclase by CAP. |
A Systematic Review of the Prevention and Treatment of Prescription Drug Misuse.
This is a review and evaluation of the current clinical guidelines and empirical literature in relation to the Department of Defense (DoD) policies and directives regarding prescription drug misuse (PDM). Sources were 11 clinical guidelines and consensus statements, 20 DoD Directives and the published literature from 2000 to 2012. Articles were included if they specifically focused on the prevention or treatment of PDM. DoD directives were evaluated in relation to the clinical guidelines and the relevant research literature. Empirical evidence supporting the directives was limited. There is little empirical evidence for the prevention and treatment of PDM and the majority of published guidelines and studies focus on prescription opioids. Important limitations include the lack of information about appropriately identifying and managing persons at risk for PDM. More research is needed to identify and recommend effective mechanisms for the prevention and treatment of PDM. |
Jackson Prep baseball alumni continue to shine
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With this year’s college baseball conference play starting up, many notable Jackson Prep alumni are taking the field for Division-I teams. These standouts include Gene Wood, Parker Caracci, Jake Mangum, and Noah Hughes, all of which are sophomores and play for schools in the southeastern conference.
Gene Wood continues his college career this year with the University of Alabama baseball program. Last year, Alabama finished fifth in the SEC West with a conference record of 15-15 and an overall record of 32-26. Although Gene played shortstop in high-school, the crimson tide have utilized him in both infield and outfield positions because of his athleticism and ability to adapt. Gene’s most noteworthy moment so far this season was his appearance on SportsCenter’s Top Ten Plays after an impressive diving catch in one of Bama’s games.
Both Noah Hughes and Jake Mangum play for Mississippi State University, who won the SEC regular season baseball title in 2016. As freshmen, these former prep stars contributed to MSU’s stellar season, in which Hughes made eight relief appearances and achieved his first save and Mangum earned a starting position in right field as well as won the SEC batting title, SEC freshman of the year award, Boo Ferriss Award, and First Team All-SEC honors, and other accolades. State ended its regular season at 21-9 in conference play and 44-18 as a whole. This year both Hughes, who underwent season ending Tommy John surgery last year, and Mangum return to the State roster. Noah Hughes is steadily recovering from his injury but will sit out this season to ensure maximum recovery. Also, Jake has started pitching for Mississippi State this year. So far, Mangum has pitched in three games and achieved his first win.
At Ole Miss, Parker Caracci is grayshirted this year. Similar to a redshirt, a grayshirt is put on players of teams who wish to sit out players for a year. This year is used as training and preparation time, and often grayshirts/redshirts are players with big potential. Ole Miss currently sits at 15-9 overall and maintains an even 3-3 conference record. |
Manufacturers
Add Me!
Good Smile Company is going to release the figma 356 Red ( レッド ) action figure from the popular game/anime series “Pokémon” ( ポケットモンスター ). Will be released in December 2017. Around 130mm tall, 6,296 yen.
You can order him here:
Good Smile Company Online Shop Limited Ver.
Pokemon Center Online Shop Limited Ver.
GOODSMILE ONLINE SHOP Purchase Bonus
Purchases of figma Red from the GOODSMILE ONLINE SHOP will include a Pikachu (Winking Face) as a bonus! Bonus will be sent together with your product. Designs shown here is for illustrative purposes only. The final product may differ.
Pokémon Center, Pokémon Store & Pokémon Center Online Bonus
Preorders from the Pokémon Center, Pokémon Store or Pokémon Center Online will include a Pikachu as a bonus!
Pokémon Center Online Product Page: https://www.pokemoncenter-online.com/
Bonus will be provided together with your product. Pikachu’s facial expression differs from the GOODSMILE ONLINE SHOP Purchase Bonus. Designs shown here is for illustrative purposes only.
——Description from Manufacturer——
The legendary trainer is joining the figma series!
The main character of the Pokémon Fire Red and Leaf Green games, the legendary Pokémon trainer ‘Red’ is joining the figma series!
The smooth yet posable figma joints allow you to act out a variety of different scenes.
A flexible plastic is used in specific areas, allowing proportions to be kept without compromising posability.
He comes with a standard face plate with a confident look as well as a shouting face plate for battle scenes.
The figma comes with the first partner Pokémon: Bulbasaur, Charmander and Squirtle.
A backpack as well as a Poké Ball are also included for various poses.
An articulated figma stand is included, which allows various poses to be taken.
——GOODSMILE ONLINE SHOP——
This product is available for preorder at the GOODSMILE ONLINE SHOP.Preorders will be open from 13th June 2017 (Thu) from 12:00JST until the 3rd August 2017 (Thu) at 12:00JST. |
Toms
Seasonal Classic Slip On
Light Grey Canvas
The original Classic Slip On espadrille in light grey canvas with stitched detail, elastic 'V' for easy on and off and the blue TOMS logo on the heel.
- Canvas upper
- Suede insole
- Mixed rubber sole
- TOMS insoles are marked with US sizing
About TOMS
During a trip to Argentina in 2006 American Traveller Blake Mycoskie befriended children in Argentina and found they had no shoes to protect their feet. To help the children he met, he created Toms a footwear brand that would match every pair of shoes purchased with a pair of new shoes given to a child in need. One for One.
Rated 4 out of
5 by
Anna212 from
Lovely shoeAbsolutely love this shoe, very summery and cute however the color is more of a nude than a grey and probably better suited to summer wear as can dirty easily but other than that really nice shoe and matches just about anything :)
Date published: 2016-09-10
Rated 5 out of
5 by
Cashton19 from
Such comfortable shoesI've worn these jogging / walking / shopping and they are so comfortable. Want another pair but can't decide what colour yet
Date published: 2016-06-08
Rated 4 out of
5 by
jess6207 from
Really comfyNice colour, good fit, classic style. Really glad I bought these. |
Effects of ethyl alcohol on human peripheral lymphocytes.
Chronic alcoholics are more susceptible to infection and have increased incidences of certain types of carcinomas. One explanation for this may be suppressed immune responses secondary to ethyl alcohol consumption. This project was initiated to study the effect of ethyl alcohol on lymphocyte responses in vitro by monitoring tritiated thymidine uptake. Lymphocytes were incubated in the presence of phytohemagglutinin-P, concanavalin A, and pokeweed mitogen. The response of normal lymphocytes was noted after mitogen stimulation in the presence of ethyl alcohol in graded doses. Ethyl alcohol levels greater than or equal to 50 mg/dL suppressed tritiated thymidine uptake of normal lymphocytes for phytohemagglutinin-P and concanavalin A. Since ethyl alcohol exposure in concentrations consistent with blood levels that may be attained during routine ingestion significantly decreased lymphocyte blastogenesis, it is speculated that chronic ethyl alcohol ingestion may alter immune surveillance sufficiently to be responsible in part for the increased incidence of infection and/or neoplasms seen in alcoholic subjects. |
New Delhi [India], Mar 12 (NewsVoir): In an endeavour to laud womanhood, Migsun Kaushalam, a skill development vertical of prestigious Migsun Group has pledged to provide placement linked skill development training to at least 12,000 female candidates from rural areas for the target allocated to it.
To initiate this, Migsun Kaushalam has already established two women-only residential training centres in District Bilaspur and Raigarh of the Chhattisgarh State each in housekeeping trade.
Designed for the socio-economic development of people, mainly women from vulnerable and disaster hit communities; this program embodies the approach of eradicating poverty amongst the most neglected segment of society.
Migsun Kaushalam ventured into Skill Development domain in the year 2017 and work under various government of India programmes.
Migsun Kaushalam aims to target both rural and urban youths with focus on SC, ST, OBC, minority and women.
Within a short span of less than a year, Migsun Kaushalam now has its footprints in the state of Uttar Pradesh, Madhya Pradesh, Chhattisgarh, Jharkhand and coming up in the State of Gujarat and Karnataka as well.
For honing of skills, it has setup the training centre infrastructure which is in line with the requirements laid down by NSDC.
Candidates also undertake an on-job training to help them understand the environment in which they are going to work. The said setup is also validated by the concerned department of the state government and central government appointed Training Support Agencies.
"It gives me immense happiness to announce that Migsun Kaushalam has pledged to provide placement linked skill development training to the women, who are the most important part of the society. Often it is seen that women can handle managerial positions better than men because they are temperamentally calmer and able to multi-task, if they are supported and trained. The placement linked skill development training will empower rural women, not only that it will also redefine their lifestyle," said Managing Director, Migsun, Yash Miglani.
The primary focus of it is to provide placement to all its trained candidates.
For the said reason, Migsun Kaushalam has tied up with various regional and national level organizations, target training industry specific ventures and placement consultancies so that 100 percent job is provided to each trained candidates with more than 3 offers / interviews to each trained candidate.
It has hired the best trainers from the industry who have adequate training experience with industry relevant qualification and are TOT certified by the industry / relevant sector skill council, so that the quality training is provided to the enrolled candidates and the candidates can get the promised job.
"I am very thankful to Migsun Kaushalam for providing me with the skill development training. Now I am able to support my family financially and send my children to school," said Pushpa who is enrolled in their training programme. (NewsVoir)
Chennai (Tamil Nadu)[India] Jan 21 (Newsvoir): Preethi Kitchen Appliances with Food Consulate entered the Guinness Book of World Records for building a 41.8 feet tower with 18,818 cupcakes and smashed the previous record held by a South African organisation for 35 feet tower.
The Supreme Court on Monday asked the National Green Tribunal (NGT) to consider whether to widen the scope of scrutiny into compliance of all car manufacturers with the emission norms, as German auto major Volkswagen has challenged a punitive action of the tribunal.
Smule Mirchi Cover Star is India’s biggest cover artist hunt that offers the winner a once-in-a-lifetime opportunity to perform at the 11th Mirchi Music Awards in Mumbai in front of the Bollywood’s biggest music celebrities, a truly incomparable experience for anyone who loves and follo
Mumbai (Maharashtra) [India] Jan 21 (Newsvoir): NeoGrowth, the pioneer in digital lending for SMEs in India and Paisabazaar.com, India’s largest online marketplace for With this alliance, NeoGrowth and Paisabazaar.com have increased their POS-based loan business by 100 per ce
New Delhi [India], Jan 21 (BusinessWire India): FlowerAura and Ola, in the last week of 2018, launched a campaign titled "Gift Health - Gift Plants" under which FlowerAura gifted plants to all Ola customers taking a ride from T1 and T3 of IGI Airport on December 28 and 29.
Gurugram [Haryana] (India), Jan 21 (NewsVoir): Vineet Nanda joined CHD Developers as Director, Strategy, Sales, Marketing and Customer Experience today. He is a game changer and a turnaround specialist with over three decades of proven track record in manufacturing and real estate sectors.
New Delhi [India], Jan 20 (ANI): The Central Board of Direct Taxes (CBDT) on Sunday refuted reports regarding en masse issue of prosecution notices to small companies for TDS default, terming them as "completely misleading and full of factual inaccuracies."
California [United States], January 20 (ANI): Google Maps has rolled out its speed limit feature available for all Android and iOS users in more regions including the United States, Denmark and the United Kingdom. |
/*
Copyright (c) 2010, Yahoo! Inc. All rights reserved.
Code licensed under the BSD License:
http://developer.yahoo.com/yui/license.html
version: 3.3.0
build: 3167
*/
YUI.add('selector-native', function(Y) {
(function(Y) {
/**
* The selector-native module provides support for native querySelector
* @module dom
* @submodule selector-native
* @for Selector
*/
/**
* Provides support for using CSS selectors to query the DOM
* @class Selector
* @static
* @for Selector
*/
Y.namespace('Selector'); // allow native module to standalone
var COMPARE_DOCUMENT_POSITION = 'compareDocumentPosition',
OWNER_DOCUMENT = 'ownerDocument';
var Selector = {
_foundCache: [],
useNative: true,
_compare: ('sourceIndex' in Y.config.doc.documentElement) ?
function(nodeA, nodeB) {
var a = nodeA.sourceIndex,
b = nodeB.sourceIndex;
if (a === b) {
return 0;
} else if (a > b) {
return 1;
}
return -1;
} : (Y.config.doc.documentElement[COMPARE_DOCUMENT_POSITION] ?
function(nodeA, nodeB) {
if (nodeA[COMPARE_DOCUMENT_POSITION](nodeB) & 4) {
return -1;
} else {
return 1;
}
} :
function(nodeA, nodeB) {
var rangeA, rangeB, compare;
if (nodeA && nodeB) {
rangeA = nodeA[OWNER_DOCUMENT].createRange();
rangeA.setStart(nodeA, 0);
rangeB = nodeB[OWNER_DOCUMENT].createRange();
rangeB.setStart(nodeB, 0);
compare = rangeA.compareBoundaryPoints(1, rangeB); // 1 === Range.START_TO_END
}
return compare;
}),
_sort: function(nodes) {
if (nodes) {
nodes = Y.Array(nodes, 0, true);
if (nodes.sort) {
nodes.sort(Selector._compare);
}
}
return nodes;
},
_deDupe: function(nodes) {
var ret = [],
i, node;
for (i = 0; (node = nodes[i++]);) {
if (!node._found) {
ret[ret.length] = node;
node._found = true;
}
}
for (i = 0; (node = ret[i++]);) {
node._found = null;
node.removeAttribute('_found');
}
return ret;
},
/**
* Retrieves a set of nodes based on a given CSS selector.
* @method query
*
* @param {string} selector The CSS Selector to test the node against.
* @param {HTMLElement} root optional An HTMLElement to start the query from. Defaults to Y.config.doc
* @param {Boolean} firstOnly optional Whether or not to return only the first match.
* @return {Array} An array of nodes that match the given selector.
* @static
*/
query: function(selector, root, firstOnly, skipNative) {
root = root || Y.config.doc;
var ret = [],
useNative = (Y.Selector.useNative && Y.config.doc.querySelector && !skipNative),
queries = [[selector, root]],
query,
result,
i,
fn = (useNative) ? Y.Selector._nativeQuery : Y.Selector._bruteQuery;
if (selector && fn) {
// split group into seperate queries
if (!skipNative && // already done if skipping
(!useNative || root.tagName)) { // split native when element scoping is needed
queries = Selector._splitQueries(selector, root);
}
for (i = 0; (query = queries[i++]);) {
result = fn(query[0], query[1], firstOnly);
if (!firstOnly) { // coerce DOM Collection to Array
result = Y.Array(result, 0, true);
}
if (result) {
ret = ret.concat(result);
}
}
if (queries.length > 1) { // remove dupes and sort by doc order
ret = Selector._sort(Selector._deDupe(ret));
}
}
return (firstOnly) ? (ret[0] || null) : ret;
},
// allows element scoped queries to begin with combinator
// e.g. query('> p', document.body) === query('body > p')
_splitQueries: function(selector, node) {
var groups = selector.split(','),
queries = [],
prefix = '',
i, len;
if (node) {
// enforce for element scoping
if (node.tagName) {
node.id = node.id || Y.guid();
prefix = '[id="' + node.id + '"] ';
}
for (i = 0, len = groups.length; i < len; ++i) {
selector = prefix + groups[i];
queries.push([selector, node]);
}
}
return queries;
},
_nativeQuery: function(selector, root, one) {
if (Y.UA.webkit && selector.indexOf(':checked') > -1 &&
(Y.Selector.pseudos && Y.Selector.pseudos.checked)) { // webkit (chrome, safari) fails to find "selected"
return Y.Selector.query(selector, root, one, true); // redo with skipNative true to try brute query
}
try {
return root['querySelector' + (one ? '' : 'All')](selector);
} catch(e) { // fallback to brute if available
return Y.Selector.query(selector, root, one, true); // redo with skipNative true
}
},
filter: function(nodes, selector) {
var ret = [],
i, node;
if (nodes && selector) {
for (i = 0; (node = nodes[i++]);) {
if (Y.Selector.test(node, selector)) {
ret[ret.length] = node;
}
}
} else {
}
return ret;
},
test: function(node, selector, root) {
var ret = false,
groups = selector.split(','),
useFrag = false,
parent,
item,
items,
frag,
i, j, group;
if (node && node.tagName) { // only test HTMLElements
// we need a root if off-doc
if (!root && !Y.DOM.inDoc(node)) {
parent = node.parentNode;
if (parent) {
root = parent;
} else { // only use frag when no parent to query
frag = node[OWNER_DOCUMENT].createDocumentFragment();
frag.appendChild(node);
root = frag;
useFrag = true;
}
}
root = root || node[OWNER_DOCUMENT];
if (!node.id) {
node.id = Y.guid();
}
for (i = 0; (group = groups[i++]);) { // TODO: off-dom test
group += '[id="' + node.id + '"]';
items = Y.Selector.query(group, root);
for (j = 0; item = items[j++];) {
if (item === node) {
ret = true;
break;
}
}
if (ret) {
break;
}
}
if (useFrag) { // cleanup
frag.removeChild(node);
}
}
return ret;
},
/**
* A convenience function to emulate Y.Node's aNode.ancestor(selector).
* @param {HTMLElement} element An HTMLElement to start the query from.
* @param {String} selector The CSS selector to test the node against.
* @return {HTMLElement} The ancestor node matching the selector, or null.
* @param {Boolean} testSelf optional Whether or not to include the element in the scan
* @static
* @method ancestor
*/
ancestor: function (element, selector, testSelf) {
return Y.DOM.ancestor(element, function(n) {
return Y.Selector.test(n, selector);
}, testSelf);
}
};
Y.mix(Y.Selector, Selector, true);
})(Y);
}, '3.3.0' ,{requires:['dom-base']});
|
Byron Bay is a coastal town located in North-East NSW, approximately 800km north of Sydney. It is a popular tourist destination, renowned for its surf beaches and laid-back culture.
Byron Bay court house is situated on Middleton Street in the heart of the town centre.
There are two airports nearby, including Ballina 30 minutes south and Coolangatta (Gold Coast)60 minutes to the north. There is a train station served by NSW Countrylink and a bus depot in the centre of town. |
Grain boundary stability governs hardening and softening in extremely fine nanograined metals.
Conventional metals become harder with decreasing grain sizes, following the classical Hall-Petch relationship. However, this relationship fails and softening occurs at some grain sizes in the nanometer regime for some alloys. In this study, we discovered that plastic deformation mechanism of extremely fine nanograined metals and their hardness are adjustable through tailoring grain boundary (GB) stability. The electrodeposited nanograined nickel-molybdenum (Ni-Mo) samples become softened for grain sizes below 10 nanometers because of GB-mediated processes. With GB stabilization through relaxation and Mo segregation, ultrahigh hardness is achieved in the nanograined samples with a plastic deformation mechanism dominated by generation of extended partial dislocations. Grain boundary stability provides an alternative dimension, in addition to grain size, for producing novel nanograined metals with extraordinary properties. |
Q:
cbind columns of varying length, filtering observations that do not share a common index in R
I have 6 time series objects stored in their own dataframe, each with an index from 2000-01-01 to 2010-01-01, however, the observations differ for each object. For clarification, whilst each object might have an observation for 2005-01-01, one object might not have an observation for 2010-02-01, whilst all 5 others do.
I want to use cbind to bind them all together, however, as each object has a differing length I can't (and the fact I want to find the time-varying correlations between each object). Basically I want to find a way to only bind 'complete cases' across all 6 objects, and slot them into their respective index spot.
I am thinking of creating a data frame with a time index ranging from 2000-01-01 to 2010-01-01, binding them to their respective time index (this is the part I don't know how to do), and then using complete cases to remove the observations that don't share a common index. If there is a better way to do this, clarification is also appreciated!
Thank you!
A:
One way to do this would be:
1
Create a data frame with the full time range from 2000-01-01 to 2010-01-01. For this you can use seq().
2
Use dplyr::left_join() to join your various data frames onto this reference data frame (make sure to give your reference data frame as the first argument of left_join()).
Edit to explain comment:
left_join needs to "know", how to join the data frames together. You have two options:
you can give the same name for your reference data frame's date column (so, for instance, if your 6 data frames's date variable is called "Date", your reference data frame's only column should also be called "Date")
or, if you called it something else (say, "Reference" for instance), you need to add a by argument: left_join(df_ref, df1, by = c("Reference", "Date"))
|
<LinearLayout
xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:tools="http://schemas.android.com/tools"
android:layout_width="match_parent"
android:layout_height="match_parent"
android:orientation="vertical">
<include
layout="@layout/toolbar"
android:id="@+id/toolbar"
android:layout_width="match_parent"
android:layout_height="@dimen/dp_56"/>
<FrameLayout
android:layout_width="match_parent"
android:layout_height="match_parent">
<ListView
android:id="@+id/todo_list_listview"
android:layout_width="match_parent"
android:layout_height="match_parent"/>
<include
android:id="@+id/todo_list_empty_view"
layout="@layout/empty_view"/>
<ImageButton
android:id="@+id/todo_list_add_imagebutton"
android:layout_width="@dimen/dp_56"
android:layout_height="@dimen/dp_56"
android:layout_gravity="right|bottom"
android:layout_marginBottom="@dimen/dp_16"
android:layout_marginRight="@dimen/dp_16"
android:tint="@android:color/white"
android:src="@drawable/ic_add"
android:background="@drawable/oval"
android:elevation="@dimen/floating_button_elevation"
android:stateListAnimator="@anim/oval_elevation"/>
</FrameLayout>
</LinearLayout>
|
In my early days of living in Beijing in the fall of 2002, I found a cheap way to improve my Chinese: riding in a taxi for hours each night so I could chat with the drivers, who offered an inexpensive master class in regional dialects. One night that December, as a cab dropped me off at my apartment, I was in a delirious haze. Soon the coughing began. I slept more than I was awake, always with a feverish dream.
I checked into a hospital. The doctors said that X-rays showed my lungs were badly occluded. The usual treatment of steroids failed to help much. I wanted to go back to the U.S., but the doctors said it wouldn’t be wise to travel.
Within a week I began to recover my strength. Two weeks later, I was in New York, and Beijing was grappling with the first wave of severe acute respiratory syndrome, or SARS, infections. That summer, I received a polite email from the hospital where I had been treated: They were collecting data on all cases of “atypical pneumonia” — like the sort that had stricken me, an otherwise healthy 34-year-old — in the earliest weeks of SARS. Would I like to be tested?
Living in Beijing during SARS — and for more than a decade afterward — has put a sharp edge on the sensations of this strange moment, when another new coronavirus is sickening thousands of people.
What is apparent first is the ways in which China has changed since 2003. The mass mobilization of millions of people, the enterprises fired up like a single machine to make badly needed products, the transport planes full of military doctors and nurses with experience treating SARS and other viruses. All this is new.
To watch a few minutes of Chinese TV news each night or scroll through my Douyin short-video feed (also unimaginable in 2003) offers a sort of transport, a sci-fi leap into a white jumpsuited, mask-wearing nation on a war footing. Young nurses post videos of themselves cutting off their hair so they can fit into containment suits for 20-hour shifts. The president, touring the capital, gets his temperature checked dutifully at each stop. Parents wait outside in cold lines with coughing children.
When you see the human scale and fearful speed of the national reaction in China, two things linger longest in mind. First, the coronavirus of 2020 will be a defining event in the Chinese popular, political and social consciousness. In this it resembles 2008, when China had to manage the Summer Olympics and then, immediately, a shocking global financial crisis. China will see herself differently after this; so will the world. Much like 9/11 in the U.S., this is an event that will color the mental landscape of a generation.
There’s a second thing you can’t help wondering as you watch: What if this outbreak had occurred in Houston? Would we have quarantined the city? Limited travel? Forced people to have their temperatures checked twice a day?
This isn’t an abstract question. Not because the coronavirus is going to arrive at scale in the U.S. soon — it’s too early to know whether that will happen — but because we all live now in an age of high-speed connected networks we barely understand and struggle to manage. And contagions are a feature of this new world. Fake news, fear, nationalism and disease spread faster than ever now.
In 2015, writing in the New England Journal of Medicine, Bill Gates warned that “of all the things that could kill more than 10 million people around the world, the most likely is an epidemic.” And, he observed, we’re not prepared.
What’s really playing out in China and the world now is not just the human story of a medical epidemic. It’s also a chapter in our generation’s defining struggle with the unnerving perils of a connected age. The Cold War era was one of isolation. The Age of Globalization that followed envisioned simple, easy, hopeful connections. Our new age, though, is one of competing demands: between privacy and constant connection. The coronavirus is a test. And not just for China.
I never took that blood screening the hospital proposed to see if I have SARS antibodies. Watching this new epidemic has made me want to go do so, out of a sense of sympathy and maybe a feeling, too, of curiosity.
Adam Smith observed in 1759 that even a sympathetic European would be more disturbed by the loss of his little finger than by the destruction of China in an earthquake. But in our connected age? Your earthquake is my earthquake. Your virus is my virus. So, as tempting as it is to unplug, to put up walls, to “decouple” from other nations or whip up old racist tropes, this is exactly what we must not do. The problems we face and that the Chinese face today are really the same problem: how to cope with the murderous demands of our complex, networked new world.
Ramo is co-chief executive and vice chairman of Kissinger Associates. He is the author of “The Seventh Sense: Power, Fortune and Survival in the Age of Networks.” |
Kansas committee changes records bill
TOPEKA, Kan. (AP) – A Kansas Senate committee has made major changes to a measure that sought to make it easier for the public to get documents used to justify police searches and arrests.
As originally written, the bill would have presumed that affidavits to obtain search and arrest warrants are open record after the warrants are executed. Lawyers would have to prove such documents should be sealed or redacted. Kansas is one of the few states that seal probable-cause affidavits.
But in the Senate Judiciary Committee Sen. Greg Smith on Thursday came up with amendments that would separate out the arrest warrant affidavits and continue to seal them as in current law.
The Topeka Capital-Journal reports Rep. John Rubin, who sponsored the original bill, said Thursday he’ll work to debate the changes. |
Q:
How do I "print" an image to a ASP.NET update panel page?
I create a chart, and save it in the path server.mappath("/images/chart/chartname.png"), and if I go to the path, the image is there, and I can open it on my computer, but what I would really like to do is display the image on the page after I create it, preferably asynchronously. I've tried putting a asp:image control in the update panel and changing the url, but that doesn't work. I've tried a bunch of different ways, if someone could point me to the right direction, that would be great. I won't post any code simple because what I have so far IS working. Once I start attempting to print the image I'll post snippets if I have answers.
Edit: Here is some code
The button event that starts the whole thing:
Protected Sub btnCreate_Click(sender As Object, e As EventArgs) Handles btnCreate.Click
Dim worker As New backgroundWorker
'Check input
worker.RunWorker({})
Session("worker") = worker
Timer1.Enabled = True
End Sub
This starts the worker, which generates the chart fine, and starts the timer which is used to update the panel. Eventually in that code, this happens
Dim imgpath As String = Server.MapPath("images/chart/test.png")
chart.SaveImage(imgpath, ChartImageFormat.Png)
chartImg.ImageUrl = "~/images/chart/test.png"
Now, I know that the panel is being updated after this code is executed, because I output some messages to a multiline textbox, and they do appear. All these controls are also in the contentTemplate of the updatePanel.
A:
Setting the ImageUrl property of an ASP.Net image control, while within and update panel, should do the trick without having to use Javascript, although that method can be very efficient. UpdatePanels tend to be "heavy", that is the ScriptManager, UpdatePanel, and ASP.Net ViewState tend to send a lot of information back and forth via their AJAX methods. You can see what I mean by using Fiddler to watch your web traffic.
That being said, I was able to achieve the desired effect in the following manner. I have two static images, Image1.jpg and Image2.jpg, but it should work with your dynamically generated image, as long as the URL is correct.
Here's the text of my ASPX page:
<form id="form1" runat="server">
<asp:ScriptManager ID="ScriptManager1" runat="server">
</asp:ScriptManager>
<div>
<asp:UpdatePanel ID="UpdatePanel1" runat="server" UpdateMode="Conditional">
<ContentTemplate>
<asp:Image ID="Image1" runat="server" ImageUrl="~/Image1.jpg" Width="300"></asp:Image><br />
<asp:Button runat="server" ID="btnSwitchImage" Text="Switch" />
</ContentTemplate>
</asp:UpdatePanel>
</div>
</form>
And here is the code-behind:
public partial class WebForm1 : System.Web.UI.Page
{
protected void Page_Load( object sender, EventArgs e )
{
btnSwitchImage.Click += new EventHandler( btnSwitchImage_Click );
}
void btnSwitchImage_Click( object sender, EventArgs e )
{
Image1.ImageUrl = "~/Image2.jpg";
}
}
As long as the button and image controls are within the UpdatePanel's ContentTemplate everything should be relayed via AJAX. Once again, use Fiddler to confirm this.
If this example works for you but you still can't get your application working try posting some code in your question. It might help everyone analyze the problem directly.
|
Q:
Java Development Workflow with Text-Editor and Commandline
I want to get started with Java! I have a bit of experience with C/C++ and Python development. For this i'm mainly using Emacs (a text editor) and the commandline, thus not using a heavier weight IDE for those kind of things.
I don't want to adapt my workflow to suit an IDE, but I don't know the Workflow (write, build, test) in Java so I thought about asking here. Searching the Web didn't give me good results.
Can someone give me the the basic workflow when developing Java with my requirements? I use Linux for all my programming.
Are my requirements/wishes even practical or should i consider using something like IDEA or Eclipse?
Can someone point me to documentation or blog posts about this topic or documents, that give a quick overview and/or examples on how to get started with Java (something for programmers with a little experience in other languages)?
A:
For this I'm mainly using Emacs (a text editor) and the commandline,
thus not using a heavier weight IDE for those kind of things.
An IDE has many advantages over a text editor, mainly when navigating, debugging and refactoring code, but it is not required. Actually, working without an IDE is useful to understand the underlying technologies. My advice would be: Start without an IDE, and when everything works, try out some IDEs to see how they help you.
Can someone give me the the basic workflow when developing Java with
my requirements?
The basic workflow is (for any compiled language):
write source code
build
run
In the case of Java, that means:
1 Writing source code
You write .java files in a text editor, observing the right filesystem layout (file name = class name, directory corresponds to package etc.). You already have that covered.
2 Compiling the code
You compile the code using a Java compiler, possibly building a JAR or WAR file (depending on the type of application you are writing). You can do that manually by directly invoking javac (see for example Java - compile from command line - external jar ), but you should really use a build tool. The best tool to get started is probably Apache Maven or Gradle.
The basic idea is the same with both Maven and Gradle: You write a build file, which essentially describes your project and how to compile it (a POM file in the case of Maven, a build.xml for Gradle), then you can build by just invoking the build tool. The build tool takes care of all the nitty gritty like invoking javac etc. Most importantly, both also perform dependency resolution, meaning they can automatically download and use libraries that you use in your code.
3 Running
Finally, you run the program from the command line. How to do that depends on the type of program: A simple executable (or a Spring Boot application) can by run using java -jar myprog.jar, a WAR file must be deployed to a Servlet container (such as Apache Tomcat).
I hope this gives a general overview of How do I develop without an IDE?. For more details, look for specific questions here on Stackoverflow (or elsewhere), read the docs, and if all fails ask a more specific question here :-).
|
Q:
A real matrix whith rows generating $U$ and columns generating $V$
Let $n \in \mathbb{N}$, and $U,V$ two linear subspaces of $\mathbb{R}^n$ of the same dimension. Could one always make a matrix $A \in \mathbb{M}^{n \times n}(\mathbb{R})$ such that $spanA = U$ and $spanA^T = V$?
I find it hard to find a counterexample. I know that for any $n \in \mathbb{N}$, there is such a matrix if $\dim U = \dim V \in \{0,n\}$, we could just take $0,I$ as matrices. Moreover, if $U,V$ are lines, that means $U = \mathbb{R}v$ and $V = \mathbb{R}w$ for some nontrivial vectors $v,w$, then the matrix below works.
$$
\left( \ w_1v \ | \ w_2v \ | \ \cdots \ | \ w_nv \ \right)
$$
Here $w_i$ are coordinates of the vector $w$, and each entry represents a column this way.
Then I took two subspaces of dimension two in $\mathbb{R}^3$, namely
$$
U \quad = \quad
span \left\{
\left( \begin{array}{ccc}
1 \\
0 \\
0
\end{array} \right)
,
\left( \begin{array}{ccc}
0 \\
1\\
0
\end{array} \right)
\right\}
\qquad
V \quad = \quad
\left( \begin{array}{ccc}
0 \\
1\\
0
\end{array} \right)^\perp
$$
The matrix we need here is
$$
\left( \begin{array}{ccc}
1 & 0 & 0 \\
-1 & 1 & 0 \\
0 & -1 & 0 \end{array} \right)
$$
I find it hard to deal with the general case. Could you give me some help to establish the statement, or give a counterexemple?
A:
Let $m$ be the dimension of $U$ and $V$. Let $M_U$ be an $n\times m$ matrix whose columns are a basis of $U$ and $M_V$ be an $n \times m$ matrix whose columns are a basis of $V$.
Now $U = \{M_U \vec{x} : \vec{x} \in \mathbb{R}^m \}$ and $V = \{M_V \vec{x} : \vec{x} \in \mathbb{R}^m \}$.
We wish to find a matrix $A$ such that
$$
\begin{align*}
U &= \{M_U \vec{x} : \vec{x} \in \mathbb{R}^m \} = \{A \vec{x} : \vec{x} \in \mathbb{R}^n \}, \\
V &= \{M_V \vec{x} : \vec{x} \in \mathbb{R}^m \} = \{A^T \vec{x} : \vec{x} \in \mathbb{R}^n \}.
\end{align*}
$$
We note that $\{ M_V^T \vec{x} : \vec{x} \in \mathbb{R}^n\} = \mathbb{R}^m$, because the rank of $M_V^T$ is $m$ and it has $m$ rows. Thus
$$
U = \{M_U \vec{x} : \vec{x} \in \mathbb{R}^m \} = \{M_U M_V^T \vec{x} : \vec{x} \in \mathbb{R}^n \}.
$$
But this immediately suggests that $A=M_U M_V^T$, because $\mathrm{span}(M_U M_V^T) = U$. By symmetry, also $\mathrm{span}(M_V M_U^T) = V$, and because $A^T=M_V M_U^T$, we are done.
|
Q:
in case of an f:viewParam bound to a converter, why do we need the Converter#getAsString
Say I have the following f:viewParam definition:
<f:metadata>
<f:viewParam name="cust-id" value="#{CustomerCEVController.customer}"
converter="#{customerConverter}" converterMessage="Unknown customer, please use a link from within the system."
required="true" requiredMessage="cust-id f:viewParam not present"
/>
</f:metadata>
I navigate to the intended page with a "?cust-id=2342" parameter in the URL and so the role of the getAsObject method in the converter is to obviously instantiate the Customer field in the backing bean (e.g. by doing a DB query based on the cust-id value).
What's not very clear to me is why we need the getAsString method and how it is employed. This is not a question about the role of the getAsString in converters in the usual case, i.e. in the binding between the .xhtml view UI elements and the backing bean where their role is straightforward. I 've also read here that we can treat the f:viewParam as a UI input element for GET parameters but the role of the converter in the opposite direction doesn't make sense to me.
A:
The getAsString() is indeed not used in case of <f:viewParam>, but an existing converter can be reused for other components where getAsString() is really been used.
E.g.
<h:outputText value="#{CustomerCEVController.customer}" converter="#{customerConverter}" />
or
<h:selectOneMenu value="#{CustomerCEVController.customer}" converter="#{customerConverter}">
<f:selectItems value="#{data.customers}" />
</h:selectOneMenu>
It's up to you whether to implement getAsString() as per its contract or not. If you don't, then your converter would not be reuseable for other components at all.
|
# Copyright 1999-2017 Gentoo Foundation
# Distributed under the terms of the GNU General Public License v2
EAPI=6
inherit gnustep-base
DESCRIPTION="Default X11 back-end component for the GNUstep GUI Library"
HOMEPAGE="http://www.gnustep.org"
SRC_URI="ftp://ftp.gnustep.org/pub/gnustep/core/gnustep-back-${PV}.tar.gz"
LICENSE="LGPL-2.1"
SLOT="0"
KEYWORDS="amd64 ppc sparc x86 ~amd64-linux ~x86-linux ~x86-solaris"
IUSE="opengl xim"
RDEPEND="${GNUSTEP_CORE_DEPEND}
=gnustep-base/gnustep-gui-${PV%.*}*
opengl? ( virtual/opengl virtual/glu )
x11-libs/libICE
x11-libs/libSM
x11-libs/libX11
x11-libs/libXext
x11-libs/libXi
x11-libs/libXmu
x11-libs/libXt
x11-libs/libXft
x11-libs/libXrender
>=media-libs/freetype-2.1.9
!gnustep-base/gnustep-back-art
!gnustep-base/gnustep-back-cairo"
DEPEND="${RDEPEND}"
S=${WORKDIR}/gnustep-back-${PV}
src_configure() {
egnustep_env
myconf="$(use_enable opengl glx)"
myconf="$myconf $(use_enable xim)"
myconf="$myconf --enable-server=x11"
myconf="$myconf --enable-graphics=xlib"
econf $myconf
}
|
Write a Review
MOON GIRL AND DEVIL DINOSAUR TP VOL 02 COSMIC COOTIES
She's been so busy worrying about the Terrigen Cloud turning her Inhuman, Lunella Lafayette might instead fall prey to...Cosmic Cooties?! Because when a new boy moves to town from far, far away, he's oddly interested in her. Meanwhile, the most wanted T. rex in NYC is running out of places to lie low - a problem that won't get any easier when our darling duo undergo a body swap! It's a big change-up that will see Luna spending a freaky Friday (or whatever day it happens to be) as Devil Dinosaur, and vice versa! Will Luna evade capture? Will DD get a passing grade? And who exactly is Moon Girl's new 9-year-old archnemesis, Kid Kree? Luna's got a huge future in the Marvel Universe, if only she can survive the present! Collecting MOON GIRL AND DEVIL DINOSAUR #7-12.Rated T |
State Notebook
October 29, 2007|- Dave Curtis and - Ted Hutton
GATORS
Gators' O-line breaks down
Entering Saturday, UF's offensive line had posted solid statistics all season. The Gators, who start two seniors and two juniors up front, had allowed just five sacks in seven games, including tests against Tennessee, Auburn and LSU.
But Georgia hurried and harrassed QB Tim Tebow most of Saturday afternoon in Jacksonville, sacking him six times in beating the Gators 42-30.
"Georgia did a good job mixing up blitzes," Tebow said afterward. "I should have made a few better protections calls, and we should have picked up a few more guys and gotten the ball out."
"People used to have to deal with us," Bowden said. "We were there. Every Saturday. ... [They were] aiming at Florida State. Now here it is the other way around.
"We're aiming at them."
It's a strange feeling for the Seminoles and Bowden. For so long they were the team with national title hopes and Heisman Trophy candidates, the ones with the red circle on their backs. Nowadays, though, they're just trying to grow up and grow quickly.
Bowden's players will now attempt to progress fast enough to challenge some of the best in the country. Even though they beat Duke, which loses so often that victories against it are difficult to gauge, FSU has gained confidence.
"We've got some work to do," nose guard Budd Thacker said. "We're going to get in practice this week, take care of some things."
OWLS
OT bites Owls this time
After going into overtime for the second straight week against a Sun Belt opponent, coach Howard Schnellenberger said he expects more close games.
"We have not dominated anybody that we have played, and that tells us where we are and it will be that way for the balance of this year," Schnellenberger said Sunday, the day after the Owls (4-4, 3-1) lost their first conference game 33-30 to Louisiana-Monroe in the third overtime.
In two of its three wins FAU had to come back from 10-point deficits, and the same was true against the Warhawks (3-5, 3-2), though the Owls weren't able to escape. ...
FAU's defense has given up more than 400 yards in seven straight games, and opponents are averaging 428.1 yards against the Owls. It's also been susceptible to the big play, such as Saturday when ULM's Calvin Watson got free for the winning 31-yard touchdown run.
"We didn't play it right and that has been our problem on defense," Schnellenberger said. |
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A Conversation with Joshua Weinstein, Director of “Menashe” , the Only Yiddish Film in Sundance
It was a delightful surprise during this Sundance Film Festival. Usually, the idea of a film with a non-professional cast depicting a small story inside a close-knit community may not be so appealing, but the freshness and authenticity with which first-time director Joshua Weinstein infuses Menashe overcomes those hurdles. The film takes us inside an ultra-orthodox community in Borough Park, Brooklyn, where the titular character, a lower-class Hasidic Jew, tries to raise his son and it received warm applause at the festival. A professional cinematographer and a veteran of documentaries, Weinstein spoke with us about the difficulties of getting inside a community that does not go to the cinema or celebrate movies, and how finding the right cast (notably Menashe Lustig, who is a respected comedian in that community) was key to an honest portrayal and an enjoyable film.
This is a very close community where cameras are not necessarily well appreciated. So how did you manage to film in that neighborhood?
It was very challenging. We would lose locations and we would lose actors. The supermarket that we shot in, I think we ended up using three supermarkets to make one. People don’t want the camera and don’t want to compromise or bend, just like in the film. We shot on the street and huge crowds would come and observe us. For the most part, people were interested and excited and they wanted to be involved with the film and they were fascinated by it. And that was the story. And the producers I worked with were great, trying tirelessly and double checking on locations and what was coming, and with extras, and it looks on screen as if every moment was just a miracle that we caught, and it is so difficult to execute that and it really was a miracle. It takes a lot of work to make things be so authentic.
You could have done this movie with professional actors in a different place. Why did you want to do almost an anthropological film in a way?Well, to me the most important thing for the film was this, if you are not going to have stars, if you are not going to have big action sequences, it’s authenticity. You can’t fake that and there is no number that will gain that for you, it has to be there. You have to really be in a real Rabbi study, you have to have real beards. There’s no faking, it’s all real people. You couldn’t find faces like this, the faces are incredible. The body types are incredible. And you had to do it in this way, because any other way would have been fake, and then it’s not worth doing.
What were the preconceptions that you may have had before making the film and what did you learn after being in this community for so long?I think most of us, when we look at the ultra Orthodox Jewish people, it’s off-putting, they want to remain closed off and they want to remain completely a world apart, but at the same time because they want their independence, they appear to us cold. They appear that they don’t want to even be with the outside world. So I remember I would visit these communities and we would go look around at the big festivals like one where it’s like Jewish Halloween and everyone is dressed in their costumes and parade in the street. I would walk around and people are so kind and so generous. It was during these moments that I got to go in their homes and I realized how warm, funny and interesting they were. And that’s why I knew I had to make a film, not from the outside point of view, but from the inside looking out.
A scene from Menashe.
photo by federica valabrega
How difficult was it to find these actors because one of the things that impressed me from the movie is even if they are not professionals, they are very solid, I would say all of them. Did you use some of them from the Yiddish theater too?No. Not one of these people were a professional actor. And the reason why, so 99.9 percent of real Orthodox Jews was going to be used in the movie. So we were only able to cast about 30 people to be in the movie, and a little bit more came in, but only 30 of them I thought were excellent. And I just let them rehearse, this was an actor’s movie and I just cared so deeply about making them comfortable and even though some scenes were planned out, we allowed them to ad-lib a little bit. We didn’t make marks that they had to sit on and the film has a handheld feel. A lot of times we had handheld cameras and we had more coverage to make it easy.
How much did you learn making the movie about the different styles they use to dress?It’s so fascinating. As you know, of the ultra Orthodox, this is only one of the groups we are talking about. And then within Hasidism, there are over 40 groups that are Hasidic. But each of the groups, they listen to their Rabbi dictate what the clothes that they wear are. In the outside world, you would think it all looks the same, but actually every group has a little bit different jackets and a little bit different hats, a little bit different socks. And they pick up on these cues about the different socks and jackets, and it’s funny, because it’s the length of the coat, it’s the sheen on the coat, it’s the pattern on the coat and they are all black. And to the outside world they all look the same, but there are actually differences for every sect about what type of garb they wear.
Many people think Yiddish it’s a dying language, but that is not the case right?
It is but it’s only used among very religious people. And outside of it, the rest of the Jews, it’s definitely a small minority who speak it. I have heard numbers that there’s only like a few thousand of people who are speaking Yiddish in their practice. So yes, it is alive. But most people that speak it daily would never watch this movie.
What is your own connection to Yiddish?
Both my mom and dad’s side came from outside Warsaw in Poland, and so with all my great-grandparents, Yiddish was their spoken language. So it was incredible because we did post-production of the movie in Warsaw and it was my first time going there after my family left 100 years ago. And just to be there in this place where Yiddish Cinema was huge. There was incredible movies being made there and incredible books and incredible plays. Yiddish was the language of modern Judaism, up until the creation of Israel. It is a shame because so many works were not translated and not known to us anymore.
Hollywood Foreign Press Association (HFPA)
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/**
* \file ati_pcigart.c
* ATI PCI GART support
*
* \author Gareth Hughes <gareth@valinux.com>
*/
/*
* Created: Wed Dec 13 21:52:19 2000 by gareth@valinux.com
*
* Copyright 2000 VA Linux Systems, Inc., Sunnyvale, California.
* All Rights Reserved.
*
* Permission is hereby granted, free of charge, to any person obtaining a
* copy of this software and associated documentation files (the "Software"),
* to deal in the Software without restriction, including without limitation
* the rights to use, copy, modify, merge, publish, distribute, sublicense,
* and/or sell copies of the Software, and to permit persons to whom the
* Software is furnished to do so, subject to the following conditions:
*
* The above copyright notice and this permission notice (including the next
* paragraph) shall be included in all copies or substantial portions of the
* Software.
*
* THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
* IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
* FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL
* PRECISION INSIGHT AND/OR ITS SUPPLIERS BE LIABLE FOR ANY CLAIM, DAMAGES OR
* OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE,
* ARISING FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER
* DEALINGS IN THE SOFTWARE.
*/
#include "drmP.h"
# define ATI_PCIGART_PAGE_SIZE 4096 /**< PCI GART page size */
static int drm_ati_alloc_pcigart_table(struct drm_device *dev,
struct drm_ati_pcigart_info *gart_info)
{
gart_info->table_handle = drm_pci_alloc(dev, gart_info->table_size,
PAGE_SIZE);
if (gart_info->table_handle == NULL)
return -ENOMEM;
return 0;
}
static void drm_ati_free_pcigart_table(struct drm_device *dev,
struct drm_ati_pcigart_info *gart_info)
{
drm_pci_free(dev, gart_info->table_handle);
gart_info->table_handle = NULL;
}
int drm_ati_pcigart_cleanup(struct drm_device *dev, struct drm_ati_pcigart_info *gart_info)
{
struct drm_sg_mem *entry = dev->sg;
unsigned long pages;
int i;
int max_pages;
/* we need to support large memory configurations */
if (!entry) {
DRM_ERROR("no scatter/gather memory!\n");
return 0;
}
if (gart_info->bus_addr) {
max_pages = (gart_info->table_size / sizeof(u32));
pages = (entry->pages <= max_pages)
? entry->pages : max_pages;
for (i = 0; i < pages; i++) {
if (!entry->busaddr[i])
break;
pci_unmap_page(dev->pdev, entry->busaddr[i],
PAGE_SIZE, PCI_DMA_BIDIRECTIONAL);
}
if (gart_info->gart_table_location == DRM_ATI_GART_MAIN)
gart_info->bus_addr = 0;
}
if (gart_info->gart_table_location == DRM_ATI_GART_MAIN &&
gart_info->table_handle) {
drm_ati_free_pcigart_table(dev, gart_info);
}
return 1;
}
EXPORT_SYMBOL(drm_ati_pcigart_cleanup);
int drm_ati_pcigart_init(struct drm_device *dev, struct drm_ati_pcigart_info *gart_info)
{
struct drm_local_map *map = &gart_info->mapping;
struct drm_sg_mem *entry = dev->sg;
void *address = NULL;
unsigned long pages;
u32 *pci_gart = NULL, page_base, gart_idx;
dma_addr_t bus_address = 0;
int i, j, ret = 0;
int max_ati_pages, max_real_pages;
if (!entry) {
DRM_ERROR("no scatter/gather memory!\n");
goto done;
}
if (gart_info->gart_table_location == DRM_ATI_GART_MAIN) {
DRM_DEBUG("PCI: no table in VRAM: using normal RAM\n");
if (pci_set_dma_mask(dev->pdev, gart_info->table_mask)) {
DRM_ERROR("fail to set dma mask to 0x%Lx\n",
(unsigned long long)gart_info->table_mask);
ret = 1;
goto done;
}
ret = drm_ati_alloc_pcigart_table(dev, gart_info);
if (ret) {
DRM_ERROR("cannot allocate PCI GART page!\n");
goto done;
}
pci_gart = gart_info->table_handle->vaddr;
address = gart_info->table_handle->vaddr;
bus_address = gart_info->table_handle->busaddr;
} else {
address = gart_info->addr;
bus_address = gart_info->bus_addr;
DRM_DEBUG("PCI: Gart Table: VRAM %08LX mapped at %08lX\n",
(unsigned long long)bus_address,
(unsigned long)address);
}
max_ati_pages = (gart_info->table_size / sizeof(u32));
max_real_pages = max_ati_pages / (PAGE_SIZE / ATI_PCIGART_PAGE_SIZE);
pages = (entry->pages <= max_real_pages)
? entry->pages : max_real_pages;
if (gart_info->gart_table_location == DRM_ATI_GART_MAIN) {
memset(pci_gart, 0, max_ati_pages * sizeof(u32));
} else {
memset_io((void __iomem *)map->handle, 0, max_ati_pages * sizeof(u32));
}
gart_idx = 0;
for (i = 0; i < pages; i++) {
/* we need to support large memory configurations */
entry->busaddr[i] = pci_map_page(dev->pdev, entry->pagelist[i],
0, PAGE_SIZE, PCI_DMA_BIDIRECTIONAL);
if (entry->busaddr[i] == 0) {
DRM_ERROR("unable to map PCIGART pages!\n");
drm_ati_pcigart_cleanup(dev, gart_info);
address = NULL;
bus_address = 0;
goto done;
}
page_base = (u32) entry->busaddr[i];
for (j = 0; j < (PAGE_SIZE / ATI_PCIGART_PAGE_SIZE); j++) {
u32 val;
switch(gart_info->gart_reg_if) {
case DRM_ATI_GART_IGP:
val = page_base | 0xc;
break;
case DRM_ATI_GART_PCIE:
val = (page_base >> 8) | 0xc;
break;
default:
case DRM_ATI_GART_PCI:
val = page_base;
break;
}
if (gart_info->gart_table_location ==
DRM_ATI_GART_MAIN)
pci_gart[gart_idx] = cpu_to_le32(val);
else
DRM_WRITE32(map, gart_idx * sizeof(u32), val);
gart_idx++;
page_base += ATI_PCIGART_PAGE_SIZE;
}
}
ret = 1;
#if defined(__i386__) || defined(__x86_64__)
wbinvd();
#else
mb();
#endif
done:
gart_info->addr = address;
gart_info->bus_addr = bus_address;
return ret;
}
EXPORT_SYMBOL(drm_ati_pcigart_init);
|
Rooker as the gravelly voice of the gun-toting Rocket Raccoon: He worked with director James Gunn on the 2006 horror-comedy Slither and again on the 2010 superhero comedy Super. “He is a very loyal director. He is a very loyal writer, when it comes to working with people that he knows and loves,” the actor says. “He really appreciates the efforts that each actor puts into these roles.”
And if the studio would require someone to don a form-fitting motion-capture suit for the role, Mark Ruffalo-style, Rooker has experience from his work on the video game Call of Duty: Black Ops II. Clearly, Marvel needs look no further for Rocket Raccoon.
The actor concedes that his return to The Walking Dead this season as racist meth addict Merle Dixon leaves him little time for other projects, but he makes it clear he’d find room on his schedule for Guardians of the Galaxy.
“I’m really crazy busy with The Walking Dead right now. But you know what? Write this up. Tweet the fuck out of it,” Rooker says. “If the fans want me as Rocket Raccoon, Marvel will listen to you guys, I think, sometimes. … Perhaps I will be lucky and blessed enough to go in there, and go at it with Mr. Gunn again, who knows?”
Officially announced in July at Comic-Con International, Guardians of the Galaxy is reportedly “about a U.S. pilot who ends up in space in the middle of a universal conflict and goes on the run with futuristic ex-cons who have something everyone wants.” Although the Guardians have boasted a large and changing roster over the past four decades, the concept art Marvel debuted at Comic-Con features Rocket Raccoon; Drax the Destroyer, the human resurrected in the body of an alien to combat Thanos; Groot, the extraterrestrial tree monster; Star-Lord, the interplanetary police officer; and Gamora, the most dangerous woman in the universe.
Part of Marvel’s second wave of films, Guardians of the Galaxy is set to open Aug. 1, 2014.
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Comments
Greg Ellis’ cockney raccoon from Avengers:EMH and MvC3 just sounds right to me, so I’m afraid I cant support this
THANOS
This would be perfect! The cockney accent was just shoe horned in with MvC3 but never felt right to me. I think Rooker would be great and would work great with the directors vision.
Tyler
Rooker for the Win. This guys Voice would be perfect if you ask me. Make it happen Marvel
Dekko
“Rooker Raccoon?” Sounds good!
That Guy
I’ve actually been assuming that Nathan Fillion would wind up as Rocket Raccoon, given his own relationship with Gunn, his own geek cred, and the fact that you can’t seem to have a Marvel casting discussion without his name coming up. Plus, he’s on record as saying he’s cold to the idea of playing Ant-Man, so that “obvious” road is probably out.
That said…this is an interesting idea.
Mark_whittington0608
The cockney accent made no sense as A) we don’t have racoons on the UK and B) it’s was said to be done as a reference to the Beatles song Rocky Racoon, but the Beatles were Liverpudlian.
Adam Walker
nah. I’m sure Andy Serkis will end up being Raccoon.
Wanna bet?
That Other Guy
Fillion would make a better Starlord
Brawl2099
This is totally perfect. Please make this happen!
http://www.facebook.com/people/Richard-Casey/623640256 Richard Casey
I get where you’re coming from, but talking, bipedal, gun totting racoons also don’t exist, ao the accent thing is a weird line to tow. But rooker? Cant really hear it, I’d much rather hear an actual voice actor crafting a voice to fit the character. Just PLEASE, PLEASE PLEASE don’t give the mo cap job to Serkis. He’s great and all, but come on, he’s not right for everyone’s favourite anthropomorphized mercenary racoon with a tree for a best friend. |
Inter- and intra-individual variation in resting oxygen consumption in post-larvae of the giant freshwater prawn, Macrobrachium rosenbergii (De Man).
In a study of the factors that influence metabolic rate in the giant freshwater prawn Macrobrachium rosenbergii, resting oxygen consumption (ROC) was measured in 90 post-larvae ranging in size from 0.1 to 2.8 g. As in many other animal species, ROC was strongly negatively related to body weight. A stressful event (anaesthesia with or without tagging) caused a sharp increase in the ROC that disappeared over a time scale of hours. As has been demonstrated for other species of crustaceans, ROC was highest in prawns in the pre-moult stage. Individual differences in ROC among prawns handled in the same way and in the same moult stage persisted over a period of hours, but not over days. It remains unclear, therefore, whether early differences in resting metabolic rate can explain the conspicuous differences in growth rate that are found in this species during the first few weeks of life and that profoundly influence subsequent life history events. |
About this Deal
Grab some gourmet grub to go. Bacon Peanut Brittles are a blend of peanuts, maple syrup, bacon, and spices, tossed and roasted into addictively crunchy bites. They satisfy modern gourmet palates and pay homage to memories of a home-cooked classic |
‘Blockchain vs traditional banks' has been the topic of harsh debate since crypto first became big news. From the outside, the situation is typical for such issues: two irreconcilable enemies, barking at each other non-stop, without the slightest possibility that either look at things from a rational viewpoint.
But, as usual, the entities around which the whole argument revolves are actually getting along with one another pretty well. How come? The thing is that the blockchain/banks relationship is complex and cannot be treated as a matter of one replacing the other. Rather, this is a gradually evolving merger with many different aspects — some of which we consider below.
Defining your terms
There is blockchain, and there are cryptocurrencies. They are not the same thing and mean something quite different, despite being closely related. Most those who advocate the ‘blockchain-will-kill-banks’ position don’t know the difference. Cryptocurrencies are forms of tokenized money distributed via a decentralized ledger (blockchain). Blockchain won’t kill banks, because it is a technology that anyone can use and integrate into their product for their own advantage. That is just what many banks are already doing. For example, Japanese and Korean banks are testing blockchain systems for payments and transactions. Spanish bank Santander has estimated the savings of banks using blockchain at $20 billion a year.
But why are banks doing this in the first place? Like other centralized systems, banks are facing certain problems: scalability, throughput, security and speed issues. Eventually, they won’t be able to process the data correctly and on time. Blockchain is an obvious solution. We’ve already talked about how blockchain will influence business: the banks of the future will become centralized businesses, with an existing structure, that utilize co-developed/outsourced blockchain instruments. While remaining centralized in structure, they will alter their business and management schemes by implementing blockchain solutions, exclusively designed for the company’s needs.
As far as existing cryptocurrencies are concerned, there’s a competition between them and the banks, but a reasonable one. The banks realize cryptocurrencies are here to stay. Banks have no other option but to build a bridge to cryptocurrency networks, since the interests of customers will inevitably prevail. This process will go slowly (approximately 10 to 15 years) but will intensify after most of the banking world has switched to blockchain solutions. That is a good thing both for users and businesses because banks and cryptocurrencies will become more and more tied to one another through seamless connections.
You’ll be able to choose between P2P-payments and traditional banking, which already won’t be traditional since the banks are gradually adopting blockchain solutions. Again, it is important to underline that the banks are not developing cryptocurrencies and running ICOs (though some are making serious attempts in that direction). Reasonable banks are adopting a technology that is totally coinless, or with coins meant for utility use only. Banks simply seek decentralized blockchain solutions to improve their services, increase security levels and slash operational costs.
Bank-issued crypto
Yet some banks are now developing their own ‘public’ cryptocurrencies. Why? To some bankers, crypto looks attractive simply for the juicy market caps, which make them drool all over their white collars. But in the end, it is very unlikely that branded cryptocurrencies, meaning bank-issued equity tokens, will become a consideration. You have to put an enormous effort into developing a high-quality new form of digitized money on the blockchain that will truly stand out. Even now most large corporations that adopt blockchain solutions are hiring contractors for the purpose, and these solutions are more about speed and throughput than the creation of new tokenized money. Then, there’s the fundamentally different philosophy behind banks, which do not seek “financial anarchy” - and that is what cryptocurrencies represent for die-hard bankers. They find blockchain attractive for its practical applications, and they might even tolerate crypto like BTC or ETH, but they will never allow the ethics of cryptocurrencies (in their popular understanding) into their world.
Finally, the nature of banking has nothing to do with equity tokens. It's like ICO issuers who say they need a token just because they want to, even though there’s no need for one. Some say a cryptocurrency owned by a bank will attract more customers who don’t want to open an account, but that notion is false since the whole process of opening a bank account will be swift and smooth thanks to the implementation of identity authentication on the blockchain. Really smart banks do want to be up-to-date and technologically advanced, but they also don’t want to play games in which all good seats are already taken. That will simply lead to a huge waste of money and time.
Any phenomenon has its nuances, and you have to pick the features that are good for you whilst excluding those that are useless. That’s what clever bankers are doing. For instance, six large banks have teamed up to create an internal cryptocurrency — a utility settlement coin — to settle transactions between each other faster and more securely. It is fundamentally different from what CitiBank is trying to do in its attempts to create a crypto product for popular demand. Others are not inventing anything new, simply going with existing solutions, offered, for example, by Ripple. Time will tell which decision is more efficient and viable: building decentralized systems from the ground up or implementing ready-made solutions.
What the future holds
There are obvious trends emerging now, which will intensify in the future:
Development of more seamless connections between crypto and banks.
Adoption of blockchain solutions by banks that will improve their services, reduce operational costs, and play a huge role in building connections with cryptocurrency systems like Waves, Bitcoin, etc.
The two processes above will lead to improved legislation and supervision (for example, right now The Bank of England, the U.K.'s central banking authority, is developing a proof-of-concept (PoC) examining how to maintain privacy over a distributed ledger-based network while still allowing regulatory overview of the data).
Attempts by banks to create branded cryptocurrencies of their own, aimed at competing with already established and widely recognized crypto, will eventually fade. Fewer banks will use their own equity tokens.
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/***************************************************************************
* *
* This program is free software; you can redistribute it and/or modify *
* it under the terms of the GNU General Public License as published by *
* the Free Software Foundation; either version 3 of the License, or *
* (at your option) any later version. *
* *
***************************************************************************/
#include "SettingsLog.h"
#include "WulforUtil.h"
#include "dcpp/SettingsManager.h"
#include <QDir>
#include <QFileDialog>
using namespace dcpp;
SettingsLog::SettingsLog(QWidget *parent) :
QWidget(parent)
{
setupUi(this);
init();
}
void SettingsLog::init(){
lineEdit_LOGDIR->setText(_q(SETTING(LOG_DIRECTORY)));
groupBox_MAINCHAT->setChecked(BOOLSETTING(LOG_MAIN_CHAT));
lineEdit_CHATFMT->setText(_q(SETTING(LOG_FORMAT_MAIN_CHAT)));
lineEdit_FILE_CHATFMT->setText(_q(SETTING(LOG_FILE_MAIN_CHAT)));
groupBox_PM->setChecked(BOOLSETTING(LOG_PRIVATE_CHAT));
lineEdit_PMFMT->setText(_q(SETTING(LOG_FORMAT_PRIVATE_CHAT)));
lineEdit_FILE_PMFMT->setText(_q(SETTING(LOG_FILE_PRIVATE_CHAT)));
groupBox_DOWN->setChecked(BOOLSETTING(LOG_DOWNLOADS));
lineEdit_DOWNFMT->setText(_q(SETTING(LOG_FORMAT_POST_DOWNLOAD)));
lineEdit_FILE_DOWNFMT->setText(_q(SETTING(LOG_FILE_DOWNLOAD)));
groupBox_UP->setChecked(BOOLSETTING(LOG_UPLOADS));
lineEdit_UPFMT->setText(_q(SETTING(LOG_FORMAT_POST_UPLOAD)));
lineEdit_FILE_UPFMT->setText(_q(SETTING(LOG_FILE_UPLOAD)));
groupBox_FINISH_DOWN->setChecked(BOOLSETTING(LOG_FINISHED_DOWNLOADS));
lineEdit_FINISH_DOWNFMT->setText(_q(SETTING(LOG_FORMAT_POST_FINISHED_DOWNLOAD)));
lineEdit_FILE_FINISH_DOWNFMT->setText(_q(SETTING(LOG_FILE_FINISHED_DOWNLOAD)));
checkBox_FILELIST->setChecked(BOOLSETTING(LOG_FILELIST_TRANSFERS));
checkBox_STAT->setChecked(BOOLSETTING(LOG_STATUS_MESSAGES));
checkBox_SYSTEM->setChecked(BOOLSETTING(LOG_SYSTEM));
checkBox_REPORT_ALTERNATES->setChecked(BOOLSETTING(REPORT_ALTERNATES));
groupBox_SPYLOG->setChecked(BOOLSETTING(LOG_SPY));
lineEdit_SPYFMT->setText(_q(SETTING(LOG_FORMAT_SPY)));
lineEdit_FILE_SPYFMT->setText(_q(SETTING(LOG_FILE_SPY)));
groupBox_CMD_DEBUG->setChecked(BOOLSETTING(LOG_CMD_DEBUG));
lineEdit_CMD_DEBUGFMT->setText(_q(SETTING(LOG_FORMAT_CMD_DEBUG)));
lineEdit_FILE_CMD_DEBUGFMT->setText(_q(SETTING(LOG_FILE_CMD_DEBUG)));
toolButton_BROWSE->setIcon(WulforUtil::getInstance()->getPixmap(WulforUtil::eiFOLDER_BLUE));
connect(toolButton_BROWSE, SIGNAL(clicked()), this, SLOT(slotBrowse()));
}
void SettingsLog::ok(){
SettingsManager *sm = SettingsManager::getInstance();
QString path = lineEdit_LOGDIR->text();
if (!path.isEmpty() && !path.endsWith(QDir::separator()))
path += QDir::separator();
sm->set(SettingsManager::LOG_DIRECTORY, _tq(path));
sm->set(SettingsManager::LOG_MAIN_CHAT, groupBox_MAINCHAT->isChecked());
sm->set(SettingsManager::LOG_FORMAT_MAIN_CHAT, _tq(lineEdit_CHATFMT->text()));
sm->set(SettingsManager::LOG_FILE_MAIN_CHAT, _tq(lineEdit_FILE_CHATFMT->text()));
sm->set(SettingsManager::LOG_PRIVATE_CHAT, groupBox_PM->isChecked());
sm->set(SettingsManager::LOG_FORMAT_PRIVATE_CHAT, _tq(lineEdit_PMFMT->text()));
sm->set(SettingsManager::LOG_FILE_PRIVATE_CHAT, _tq(lineEdit_FILE_PMFMT->text()));
sm->set(SettingsManager::LOG_DOWNLOADS, groupBox_DOWN->isChecked());
sm->set(SettingsManager::LOG_FORMAT_POST_DOWNLOAD, _tq(lineEdit_DOWNFMT->text()));
sm->set(SettingsManager::LOG_FILE_DOWNLOAD, _tq(lineEdit_FILE_DOWNFMT->text()));
sm->set(SettingsManager::LOG_UPLOADS, groupBox_UP->isChecked());
sm->set(SettingsManager::LOG_FORMAT_POST_UPLOAD, _tq(lineEdit_UPFMT->text()));
sm->set(SettingsManager::LOG_FILE_UPLOAD, _tq(lineEdit_FILE_UPFMT->text()));
sm->set(SettingsManager::LOG_FINISHED_DOWNLOADS, groupBox_FINISH_DOWN->isChecked());
sm->set(SettingsManager::LOG_FORMAT_POST_FINISHED_DOWNLOAD, _tq(lineEdit_FINISH_DOWNFMT->text()));
sm->set(SettingsManager::LOG_FILE_FINISHED_DOWNLOAD, _tq(lineEdit_FILE_FINISH_DOWNFMT->text()));
sm->set(SettingsManager::LOG_CMD_DEBUG, groupBox_CMD_DEBUG->isChecked());
sm->set(SettingsManager::LOG_FORMAT_CMD_DEBUG, _tq(lineEdit_CMD_DEBUGFMT->text()));
sm->set(SettingsManager::LOG_FILE_CMD_DEBUG, _tq(lineEdit_FILE_CMD_DEBUGFMT->text()));
sm->set(SettingsManager::LOG_SYSTEM, checkBox_SYSTEM->isChecked());
sm->set(SettingsManager::LOG_STATUS_MESSAGES, checkBox_STAT->isChecked());
sm->set(SettingsManager::LOG_FILELIST_TRANSFERS, checkBox_FILELIST->isChecked());
sm->set(SettingsManager::LOG_SPY, groupBox_SPYLOG->isChecked());
sm->set(SettingsManager::REPORT_ALTERNATES, checkBox_REPORT_ALTERNATES->isChecked());
}
void SettingsLog::slotBrowse(){
QString dir = QFileDialog::getExistingDirectory(this, tr("Choose the directory"), lineEdit_LOGDIR->text());
if (!dir.isEmpty()){
dir = QDir::toNativeSeparators(dir);
if (!dir.endsWith(QDir::separator()))
dir += QDir::separator();
lineEdit_LOGDIR->setText(dir);
}
}
|
Loss of heterozygosity and DNA aneuploidy in colorectal adenocarcinoma.
This study evaluated the relationship between DNA aneuploidy and loss of heterozygosity (LOH) at different genetic loci in colorectal adenocarcinoma. A total of 112 patients with surgically removed colorectal adenocarcinoma in Taipei Veterans General Hospital from January 1999 to July 2001 were included in this study. The pattern of DNA ploidy was determined with DNA flow cytometry, and the LOH of various genetic loci was determined with fluorescence polymerase chain reaction and denaturing gradient gel electrophoresis. The relationship between DNA ploidy, LOH of various genetic loci, and clinicopathologic variables was analyzed with the chi(2) test with Yates' correction as well as by multivariate binary logistic regression analysis. Seventy-one (63.4%) of the 112 carcinomas had DNA aneuploidy. The DNA aneuploidy was not associated with any clinicopathologic variable. Ninety-one tumors (81.3%) exhibited LOH in at least one genetic locus. In the univariate analysis, the DNA aneuploidy was associated with LOH of Tp53-penta, D8S254, D5S346, and high-frequency LOH (P =.001, P =.016, P =.041, and P <.001, respectively). In the multivariate analysis, the most significant factor influencing DNA aneuploidy was D8S254, followed by Tp53-penta, high-frequency LOH, and D5S346. DNA aneuploidy is strongly associated with LOH at specific genetic loci. |
Q:
c arrays output error
Can someone please explain why this algorithm
for (i = 0;i<5;i++)
{
for(j = 0;j<5;j++)
{
b[j] = a[i];
break;
}
}
gives strange output while this
for (i = 0;i<5;i++)
{
b[i] = a[i];
}
works perfectly?
The question was Write a program to copy elements of one array into another array.
A:
Your first code is wrong. It assigns b[0] = a[0], then b[0] = a[1] etc. Your break prevents the loop from going to j = 1.
|
emainder when r is divided by 30.
8
Let u(a) = -2*a - 4 + 3*a + a - 5. Let l be u(10). Let d = -5 + l. What is the remainder when 9 is divided by d?
3
Let m be (-2)/(-9) - 3002/(-18). Suppose 3*q - 482 = -4*h, 0 = -4*h + q + 307 + m. Calculate the remainder when h is divided by 40.
39
Suppose -4*l - 12 = 0, -4*y + 3*l = -24 + 71. What is the remainder when (-1002)/y + (-3)/(-7) is divided by 25?
22
Suppose -x = x - 28. Let k = 1301 - 1265. Calculate the remainder when k is divided by x.
8
Let t be 8/(-1 - (4 + -6)). Suppose -3*r + 27 = q, -4*q + 46 = -2*r + t. Calculate the remainder when 23 is divided by q.
11
Suppose -2*t + 5*c = -4*t + 65, t - 40 = -5*c. What is the remainder when 221 is divided by t?
21
Suppose 38*a - 2501 - 349 = 0. Suppose 5*n = 2*h - 93, 4*h - 4*n + 7*n - 147 = 0. What is the remainder when a is divided by h?
36
Let s(z) = -2 - 30*z + 33*z - 3*z**2 - 3*z**2 - 6*z**3 + 4*z**2. What is the remainder when s(-3) is divided by 27?
25
Suppose 0 = -p + 2*p - 15. Suppose 0 = -21*n + 24*n - 174. Calculate the remainder when n is divided by p.
13
Suppose 4*g = 2*g + 8. Suppose -3*q = g*c + 26, -q + 23 = -0*q - 5*c. Calculate the remainder when (6/q)/(6/(-26)) is divided by 4.
1
Suppose 78 + 90 = 4*i. Suppose -30 = 2*s - i. Calculate the remainder when 8 is divided by s.
2
Let v(t) = t**3 - 5*t**2 - 7*t - 24. Calculate the remainder when v(10) is divided by 12.
10
Let x = 111 + -108. Suppose -16*j = -x*j - 702. What is the remainder when j is divided by 19 - 0*(-2)/4?
16
Let o(i) = 2*i**2 + 4*i - 4. Let g be o(4). Suppose 3*q - 5*c = -0*q + g, q = c + 14. Calculate the remainder when (-3 + (-51)/(-9))*9 is divided by q.
11
Suppose -4*k = -4*t - 192, -17*k + 189 = -13*k - 5*t. Calculate the remainder when k is divided by 6/(-9)*87/(-2).
22
Let t(r) = -2*r**2 + 35*r - 106. Calculate the remainder when 2177 is divided by t(13).
10
Let z = -14 + 27. Suppose 0 = -k + 155 + 102. Suppose k = 4*b - 6*y + y, -184 = -3*b - 5*y. What is the remainder when b is divided by z?
11
Let p = -4115 - -4159. Suppose -36 - 12 = -2*c. What is the remainder when p is divided by c?
20
Let g be 0 - 7 - 0/(-1). Let c = g - -11. Suppose -c*k + 50 = -2*k. What is the remainder when k is divided by 7?
4
Let a be (-10)/(4*(-1)/2). What is the remainder when ((-54)/(-5))/(1/a) is divided by 247/(-78)*3*-2?
16
Suppose 2*s - 23 = 5*d, 0*d - 2*d - 68 = -5*s. What is the remainder when 86 is divided by s?
2
Suppose 40 = 3*b - 14. Suppose 2*f = 8 + b. What is the remainder when f is divided by 5?
3
Suppose -7*a + 136 = -690. Suppose 5*b + 1 = 6*b. Calculate the remainder when a is divided by b + -1 + 0 + 30.
28
Suppose -24626 + 283634 = 96*r. What is the remainder when r is divided by 12?
10
Let h = -73 + 81. Let o(w) = 15*w - 4. Let k be o(4). Let s = k + -33. What is the remainder when s is divided by h?
7
Suppose 5*q - 7 - 3 = 0. What is the remainder when 22 is divided by (q/(-12)*22)/(1/(-3))?
0
Let f(d) = -4*d**2 + d**2 + 4*d**2 + 9*d - 15 + 0*d**2. Let u be f(-11). Let v(m) = 2*m - 6. What is the remainder when v(u) is divided by 5?
3
What is the remainder when ((-1017)/(-18))/(2/4) is divided by 38?
37
Let i(p) = -p - 35. Let y be i(0). Let v = y + 58. Let w = v + -18. What is the remainder when w is divided by 3?
2
Let r be (-10)/15 - 2/(-3). Let o = 11 - r. Suppose 4*c - 231 = 5*j, -153 = -3*c - 2*j - j. Calculate the remainder when c is divided by o.
10
Calculate the remainder when -16*(279/(-6))/(2 + 1) is divided by 14.
10
Suppose 4*c = -31*a + 29*a + 36, -16 = 4*a. Let v = 80 - 39. What is the remainder when v is divided by c?
8
Let z = 8 + -9. Let g be 126/(-12) - z/2. Let w(x) = -x**3 - 11*x**2 - 11*x + 13. Calculate the remainder when w(g) is divided by 6.
5
Suppose -p - p - 5*u + 469 = 0, 3*p = 5*u + 641. Suppose -5*m + p = m. Calculate the remainder when m is divided by 10.
7
Let t(p) = -3*p**3 + 5*p + 2. What is the remainder when 376 is divided by t(-2)?
8
Let l(v) = 4*v + 10. Let s be l(16). Let n = s - 69. Calculate the remainder when 17 is divided by n.
2
Let w(v) = -v**2 + 19*v + 18. What is the remainder when 225 is divided by w(16)?
27
Let b be 0/2 + 1 - 51. Let r(c) = 2*c**2 - 11*c - 82. Let s be r(12). Let h = b + s. What is the remainder when 93 is divided by h?
21
Let c(f) = 3*f**2 + 17*f + 4. Let j be (28/(-8))/((-2)/(-4)). Calculate the remainder when c(j) is divided by 9.
5
Let c(z) = 2*z**2 + 7*z + 3. Let r be c(-2). Calculate the remainder when (7/4 - r)/((-1)/(-16)) is divided by 11.
10
Let r(d) = 2*d**2 - 2*d + 5. Let p = 66 - 42. Calculate the remainder when r(5) is divided by p.
21
Let w(n) = -6*n**3 - 4*n**2 + 1. What is the remainder when w(-2) is divided by 12?
9
Suppose 4*t - 4 - 156 = 0. Suppose -42 = -8*c + 70. What is the remainder when t is divided by c?
12
Let o = 759 - 626. What is the remainder when 415 is divided by o?
16
Let x(d) = -8*d**3 + 8*d**2 - 8*d + 11. Let k(w) = -3*w**3 + 3*w**2 - 3*w + 4. Let s(p) = 11*k(p) - 4*x(p). Calculate the remainder when s(-3) is divided by 14.
11
Let c = -561 + 568. Calculate the remainder when 103 is divided by c.
5
Let j(k) = -21*k**3 - 4*k + 5. Let g(u) = -4*u**3 - u + 1. Let c(t) = -11*g(t) + 2*j(t). Calculate the remainder when 62 is divided by c(2).
20
Let t = -277 - -282. Suppose 85 = 5*u - 5*k, -3*u + 5*k - 83 = -6*u. What is the remainder when u is divided by t?
1
Let f = -103 - -128. What is the remainder when f is divided by 9?
7
Let v = 15 - -89. Let a = 9 + 6. Calculate the remainder when v is divided by a.
14
Calculate the remainder when 735 is divided by -10*(-20)/(-50) - (0 + -36).
31
Suppose 134 = -5*u + 674. Suppose -p = -5*a + u, -2*a + 36 = -0*p - 4*p. What is the remainder when a is divided by 15?
7
Suppose -7*r + 4*r + 240 = 0. Suppose -4*u - 5*f = -5*u + 4, 0 = -5*u - 5*f + r. Calculate the remainder when u is divided by 6.
2
Suppose -3*c - 463*n + 466*n + 78 = 0, n = -4*c + 89. What is the remainder when 308 is divided by c?
9
Let w(o) = -12*o + 230. Suppose z - 16 = -3*z. Calculate the remainder when w(17) is divided by z.
2
Suppose 5*l = -3*v + 2*v + 146, -v = -1. Suppose -6*k - 2*k + 920 = 0. What is the remainder when k is divided by l?
28
Let t(l) = 6*l**2 + 14*l + 45. Calculate the remainder when t(-4) is divided by 6.
1
Let f(z) = -z**2 - z - 1. Let b be f(5). Suppose -69*y - 12 = -68*y. Let o = y - b. What is the remainder when o is divided by 7?
5
Let r be 3 - -3*(-2)/(-3). Suppose 0 = 3*v - 3*u - 15, 0*u + 24 = 2*v + r*u. Calculate the remainder when v is divided by 3.
1
Let r(s) = -14*s - 4. Calculate the remainder when r(-7) is divided by 26.
16
Let p(a) = a**3 - 5*a**2 + 2*a - 6. Let y be p(5). Suppose -4*o = -5*j - 145, -4*o + 118 + 26 = -y*j. What is the remainder when 104 is divided by o?
34
Let o = 17 + -17. Suppose o = 5*y - 3*u - 72, -4*y + 57 = -0*y - 3*u. What is the remainder when 27 is divided by y?
12
Let m = -75 - -110. Calculate the remainder when m is divided by 14.
7
Suppose -3*p = -p - 12. Let j = -27 - 17. Let k = j + 65. Calculate the remainder when k is divided by p.
3
Let u = 585 - 495. Calculate the remainder when 110 is divided by u.
20
Let r(k) be the first derivative of -k**2 + 12*k + 6. What is the remainder when 64 is divided by r(-5)?
20
Let w(i) = 4*i**2 + 11*i + 3. Suppose -4*y + y = 9. What is the remainder when 8 is divided by w(y)?
2
Let d(p) = -p**3 + 5*p**2 + 26*p - 24. Calculate the remainder when 180 is divided by d(-5).
84
Let h(j) = -2*j**3 - j**2 + 4*j. Let d be h(-2). Suppose -d*m - 84 = -4*k - 0*m, 2*k - 36 = 5*m. What is the remainder when k is divided by 9?
5
Let f = -26 - -39. Let p = 13 + f. Let d(l) = 6*l**3 + 2*l**2 - 1. Calculate the remainder when p is divided by d(1).
5
Let j(y) = y - 3. Suppose -4 = -4*o - 0*o, -4*x + 18 = 2*o. Calculate the remainder when 1*((-10)/x)/(2/(-4)) is divided by j(7).
1
Let s = 550 + -233. Let k = s - 137. Suppose -h + 4*d = 3*h - k, 1 = d. Calculate the remainder when h is divided by 16.
14
Let s = 9 - 6. Suppose -35 - 13 = -s*f. Calculate the remainder when 141 is divided by f.
13
Suppose 108*w - 106*w = 190. Calculate the remainder when w is divided by 49.
46
Let j be 0 - (5 + -2 - (-2 + -11)). Let n(d) = -2*d**3 - 33*d**2 - 25*d - 17. What is the remainde |
Telomeres are tandem repeat nucleotides sequence (TTAGGG)~n~at the end of linear chromosomes which form a protective cap and maintain the chromosomal stability \[[@b1-ad-11-3-494]\]. Telomere length is genetically determined at birth and shortened gradually with aging \[[@b2-ad-11-3-494],[@b3-ad-11-3-494]\]. Attrition rate of telomere length reflects the cumulative lifetime burden of genetic factors and environmental stressors of a person more precisely than chronological age, and hence, it has been an appealing research target \[[@b4-ad-11-3-494]\]. Emerging evidence has demonstrated that age-dependent telomere length shortening in circulating leukocytes is correlated with higher risk of atherosclerosis as well as cardiovascular diseases \[[@b5-ad-11-3-494]-[@b8-ad-11-3-494]\], and leukocytes telomere dynamics contribute to the age-related process of vascular damage and cardiovascular mortality \[[@b9-ad-11-3-494]-[@b11-ad-11-3-494]\]. To date, studies have not drawn convincing conclusions with respect to the relationship between telomere length and hypertension.
Aging is a major risk factor for hypertension. Telomere length has been reported to inversely associate with increased systolic blood pressure (SBP) and pulse pressure (PP), which is familial \[[@b12-ad-11-3-494], [@b13-ad-11-3-494]\]. Several epidemiology studies showed that mean leukocyte telomere length is shorter in hypertensive than in normotensive subjects and contributes to the risk of developing hypertension and future cardiovascular diseases \[[@b14-ad-11-3-494]-[@b16-ad-11-3-494]\], whereas not found in other studies \[[@b17-ad-11-3-494]\]. The Framingham heart study has demonstrated that association between hypertension and leukocyte telomere length is attributable to insulin resistance \[[@b18-ad-11-3-494]\]. The inconsistency may be partly explained by the limitation of a single measurement of baseline telomere length in these studies, as well as the difference in geography and ethnicity. Whether the rate of telomere attrition could serve as a useful predicting tool in hypertensive patients requires further data on longitudinal change of telomere length during the follow-up.
In addition, antihypertensive drugs may affect cell senescence and telomere length. Data from the Framingham heart study showed that shortened leukocyte telomere length is more frequently present in hypertensive patients with a higher plasma renin-angiotensin ratio \[[@b19-ad-11-3-494]\], and treatment with an angiotensin II receptor antagonist can prevent telomere length shortening in spontaneously hypertensive rats through attenuating the process of aging \[[@b20-ad-11-3-494]\], which indicates a close link between telomere length and the renin-angiotensin-aldosterone system (RAAS). It has been reported that the individual-level difference in blood pressure response to antihypertensive drugs can be induced in large part by differences in plasma renin activity \[[@b21-ad-11-3-494]\]. Moreover, the calcium channel blocker (CCB) is also shown to affect telomere length through an endothelial nitric oxide synthase (eNOS)-dependent anti-senescence effect in human endothelial cells \[[@b22-ad-11-3-494]\]. However, there is lack of data whether change of telomere length in patients with hypertension is related to the heterogeneity of blood pressure response to antihypertensive therapy.
Therefore, in this study, we aimed to investigate longitudinal change of leukocytes telomere length in a prospective population-based study of 1,108 individuals with hypertension who received antihypertensive therapy, and further assess the relationship between BP lowering and telomere attrition rate, which may provide new sight on telomere biology in hypertension and antihypertensive intervention.
MATERIALS AND METHODS
=====================
Study Design and Participants
-----------------------------
This prospective community-based study was conducted in the BenXi County, Liaoning Province, in the northern region in China. A multistage cluster sampling method was used to select a representative sample of urban community residents aged 35 to 75 years. First, three communities were randomly selected from a total of six residential communities in the BenXi County. Secondly, 12 districts were randomly selected from a total of 24 districts in this three residential communities. A total of 13,000 subjects (7,540 men and 5,460 women) completed the survey with a response rate of 85.1%. Among them, 3,671 participants with primary hypertension were identified and recruited in this cohort. Subjects were excluded from the study when they had any known diseases including heart failure, renal failure, valvular heart disease, or severe debilitating chronic illness (cancer or hepatic diseases). History of possible secondary hypertension was evaluated using a standardized questionnaire assessment when the patients were surveyed, including history of renal diseases, sleep apnoea, symptoms suggestive of thyroid disease or hyperparathyroidism, signs of Cushing's disease or acromegaly, young onset of stage 2 or 3 hypertension (\<40 years), or sudden development of hypertension or rapidly worsening BP in older patients. Those with known secondary hypertension (e.g. renal artery stenosis, chronic renal insufficiency, or endocrine origin) diagnosed by imaging techniques and humoral measurements, were excluded. In addition, the apparent treatment-resistant hypertensions were also excluded which used the following definitions: uncontrolled BP (≥140/90 mm Hg) despite antihypertensive regimen of at least 3 different antihypertensive drugs including diuretics, or controlled BP (\<140/90 mm Hg) while being received with ≥4 antihypertensive drugs \[[@b23-ad-11-3-494]\].
Among the 3,671 hypertensive patients recruited in this cohort, 1,382 subjects provided blood samples at baseline. No significant differences in characteristics were observed between total recruited patients and those having blood samples, except that those providing blood samples had a little higher level of SBP and medical history of cardiovascular diseases and diabetes mellitus ([Supplemental Table S1](#SD1-ad-11-3-494){ref-type="supplementary-material"}). This cohort was prospectively followed up at a 2.5-year period, blood samples were collected again in 2016, and 1,197 patients provided for the second time. A total of 185 patients were not reached due to immigration, in addition, 89 blood samples were excluded due to insufficient quality. Finally, 1,108 patients available with blood samples both at baseline and at follow-up, were included in the analysis for telomeres change, as shown in the flowchart (Supplementary [Fig. 1](#F1-ad-11-3-494){ref-type="fig"}). There were no significant differences between patients with and without the follow-up blood samples ([Supplemental Table S2](#SD1-ad-11-3-494){ref-type="supplementary-material"}).
This study protocol was reviewed and approved by the Ethics Committee of FuWai hospital and local hospitals. All participants gave their written informed consent.
Collection of Data at Baseline
------------------------------
Each enrolled participant was interviewed and completed a standardized questionnaire assessment at baseline survey that included demographic characteristics (e.g., age, gender, education levels), medical history, drugs used for hypertension, and lifestyle behaviors (e.g., smoking, drinking, and exercise). Body weight and height were measured by trained nurses, and body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Waist circumference was measured on standing subjects with a soft tape midway between the lowest rib and the iliac crest, and hip circumference was measured over the widest part of the gluteal region.
BP was measured by trained nurses with a validated oscillometric BP monitor with appropriately sized arm cuffs (regular adult, large, or small). All participants were advised to avoid alcohol, cigarette smoking, coffee/tea, and exercise for at least 30 minutes before their BP measurement. The average of three readings in a sitting position after at least 5 minutes of rest, recorded at least 5 minutes apart, was obtained for analysis. Hypertension was defined as systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg, and/or receiving antihypertensive drugs, and/or history of hypertension, according to the 2010 Chinese Guidelines for the Management of Hypertension \[[@b24-ad-11-3-494]\]. The stages of hypertension at baseline were classified into 4 groups: the controlled BP, stage 1, 2, and 3 hypertension, in which the controlled BP was defined as BP\<140/90 mm Hg, stage 1 as SBP 140-159 mm Hg and/or DBP 90-99 mm Hg, stage 2 as SBP 160-179 mm Hg and/or DBP 100-109 mm Hg, and stage 3 as SBP ≥180 mm Hg, and/or DBP≥110 mm Hg.
Blood samples and measurement of biochemical parameters
-------------------------------------------------------
Blood samples were collected from the antecubital vein after an overnight fast at baseline. This study included the hypertensive patients who either never received antihypertensive therapy at the first interview, or already received antihypertensive drug treatment. For the former participants, we collected their blood samples before hypertensive drug intervention. For the patients on previous antihypertensive drug therapy, they were required to receive the antihypertensive agents provided by the study at no cost, including calcium channel blocker (CCB), angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), or thiazide-type diuretics, unless intolerance was reported or there was a compelling indication for other drugs. In this case, the blood samples were collected at two weeks after the enrollment. We compared the baseline characteristics between included patients with and without receiving antihypertensive treatment at recruitment, and the results showed no significant differences between the two groups, except that those never receiving antihypertensive drugs had a lower rate of history of cardiovascular diseases. Moreover, there were no remarkable differences in the baseline telomere length of leukocytes and annual telomere attrition rate during the follow-up between the two groups ([Supplemental Table S3](#SD1-ad-11-3-494){ref-type="supplementary-material"}).
Blood serum was separated on-site, then transported on dry ice to Beijing center laboratory, and stored at -80°C until measurement. Concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and fasting glucose were measured by an automatic analyzer (Hitachi 7060, Hitachi, Tokyo, Japan). All measurements were taken at Beijing FuWai Clinical Laboratory qualified by the Centers for Disease Control and Prevention.
Follow-up and Outcome Assessment
--------------------------------
Patients were followed up by face-to-face interviews by trained physicians from May to November in 2016. Information on anthropometric measurements, physical examination, lifestyle behaviors, and drugs used for hypertension were updated via structured questionnaires during the follow-up survey. Participants underwent routine assessment of their blood pressure using the same standardized protocol as the baseline. Blood samples after a 12-hour overnight fast were collected again for measuring biochemical parameters and leukocytes telomere length. The main outcome was defined as a composite of myocardial infarction (MI), stroke (ischemic or hemorrhagic, fatal or nonfatal), hospitalization for unstable angina or acute decompensated heart failure, coronary revascularization, and deaths from cardio-vascular causes. The endpoints were ascertained by local physicians primarily through self-reports and review of medical records, and clinical medical records and imaging evidence were required to support all diagnosis. Deaths were reported by family members, work associates and/or obtained from death certificates and medical records. Definition of the endpoints were presented in the Supplementary materials.
Measurement of Leukocytes Telomere Length
-----------------------------------------
Genomic DNA was isolated from peripheral blood leukocytes according to standard procedures using MiniBEST Universal Genomic DNA Extraction Kit (Takara Biomedical Technology Co., Ltd., Dalian, China). Relative mean telomere length of leukocytes was determined by a quantitative real-time PCR method which compares telomere repeat copy number (T) to single-copy gene copy number β-globin (S) (T/S ratio) as described previously \[[@b25-ad-11-3-494], [@b26-ad-11-3-494]\]. In brief, each sample was measured in triplicates on an ABI 7500 Real-Time PCR System (Applied Biosystems) and the mean relative T/S ratio was calculated. A reference calibrator sample was included with each measurement to control inter-assay variability, and the average inter-plate coefficients of variability for the telomere and β-globin assays were \<5.0%. A standard curve was also examined by using serially diluted reference DNA (1.56-100 ng; 2-fold dilution; seven points) with good linearity (R^2^\> 0.97) for both the telomere and the β-globin measurement. The primers were as the following: for telomeres, forward 5'-CGGTTTGTTTGGGTTTGGGTTTGGGTTTGGGTTT-GGGTT-3' and reverse 5'-GGCTTGCCTTACCCTTA- CCCTTACCCTTACCCTTACCCT-3'; for β-globin measurement, forward 5'-GCTTCTGACACAACTG- TGTTCACTAGC-3' and reverse 5'-CACCAACTTC- ATCCACGTTCACC-3'. In this study, 20% of samples were randomly chosen to test the reproducibility of measurements.
Statistical Analysis
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Clinical characteristics of participants were compared between groups by the chi-square test for categorical variables (expressed as numbers \[percentages\]) and the*t* test for quantitative variables (expressed as mean ± standard difference \[SD\]). For triglycerides and relative mean telomere length of leukocytes, the non-parametric Mann-Whitney *U* test was used due to their sewed distribution. In this study, values of telomere length were logarithm (Lg) transformed so as to reach a normal distribution for analyzing the relation between telomere attrition and blood pressure lowering. Annual telomere attrition rate was calculated using the formula: (follow-up telomere length-baseline telomere length)/follow-up years. All participants were categorized into two groups, of those who experienced telomere length shortening (annual rate of telomere attrition \<0) were categorized as "shorten group", and those who experienced an increase of telomere length (annual rate of telomere attrition \>0) as "lengthen group". Here, according to difference in means of telomere length (Lg-transformed) between the shorten (mean, 0.24; SD 0.19) and the lengthen group (mean, 0.07; SD, 0.21), the power would achieve \>98% to detect a difference in blood pressure lowering with a two-sided α level of 0.05 in 1,108 participants by using the PASS software program ([www.ncss.com](http://www.ncss.com)).
Linear regression analysis was used to examine the relation between annual telomere attrition rate and baseline telomere length and age. The correlations of annual telomere attrition rate with SBP change (ΔSBP), DBP change (ΔDBP) and pulse pressure change (ΔPP) (ΔPP=ΔSBP-ΔDBP) were examined by multivariate linear regression models which first adjusted for age, gender, medical history, baseline features of smoking status (current, former, or never), alcohol intake (current, former, or never), BMI, waist-to-hip, the stage of baseline blood pressures, fasting glucose, TC, triglycerides, HDL-C, LDL-C, and telomere length (model I), and then further adjusted for changes in BMI, waist-to-hip, fasting glucose, total cholesterol, triglycerides, HDL-C, and LDL-C from 2014 to 2016 during the follow-up. Generalized linear regression model was used to compare the differences in blood pressure change between the shorten and the lengthen group which adjusted for age, gender and covariates mentioned above. The effects of antihypertensive drug treatment on the correlation of annual telomere attrition rate with blood pressure lowering were examined in further stratified analysis by age and gender.
The Cox proportional hazards regression model was used to examine the association between annual telomere attrition rate and cardiovascular outcome events. Person-years of follow-up started from the date of recruitment until the occurring date of cardiovascular outcomes, death, or the end of follow-up (November 30, 2016), whichever came first. A two-tailed probability value of ≤0.05 was considered significant. Analyses were performed with SPSS Statistics 20.0 (SPSS Inc, Chicago, USA).
RESULTS
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Clinical Characteristics of Hypertensive Patients
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A total of 1,108 hypertensive patients (age 31 to 89 years) with blood samples both at baseline and at follow-up were included in this study for assessing the telomeres change, as shown in the flowchart (Supplementary [Fig. 1](#F1-ad-11-3-494){ref-type="fig"}). The average age of patients was 61.7 (SD=9.7) years and men accounted for 38.8%. In this study, the values of baseline telomere length and follow-up telomere length of leukocytes showed a skewed distribution, and after further logarithmic transformation, they showed a normal distribution for analysis (Supplementary [Fig. 2](#F2-ad-11-3-494){ref-type="fig"}). Age as an independent predictor was inversely associated with both baseline telomere length (*β*= -0.14;*P*\<0.001) and follow-up telomere length (*β*= -0.16; *P*\<0.001) (Supplementary [Fig. 3](#F3-ad-11-3-494){ref-type="fig"}).
All studied participants were divided into two groups depending on annual rate of telomere attrition, one is the shorten group (n=386) who had a decrease of telomere length, and the other is the lengthen group (n=722) who had an increase of telomere length ([Supplemental Figure S4](#SD1-ad-11-3-494){ref-type="supplementary-material"}). The clinical characteristics at baseline were shown in [Table 1](#T1-ad-11-3-494){ref-type="table"}, and there were no significant differences in BMI, blood pressure, lipid profiles, fasting glucose, smoking status, alcohol intake, and medical history of cardiovascular diseases. Of note, patients who experienced telomere shortening at follow-up were more likely to have a longer baseline telomere length (median, 1.8; interquartile range, 1.4-2.3), and in contrast, those who experienced telomere lengthening at follow-up had a shorter baseline telomere length (median, 1.2; interquartile range, 0.9-1.6). There was a significantly inverse correlation between annual telomere attrition rate and baseline telomere length (*β*=-0.52; *P*\<0.001) ([Fig. 1](#F1-ad-11-3-494){ref-type="fig"}). Aging was an independent predictor for telomere length attrition rate after adjustment for baseline telomere length ([Supplementary Table 4](#SD1-ad-11-3-494){ref-type="supplementary-material"}).
Considering that the stage of baseline blood pressures might affect the relation between telomere attrition rate and blood pressure lowering, we also compared the characteristics and annual telomere attrition rate for hypertensive patients of different stages ([Supplemental Table S5](#SD1-ad-11-3-494){ref-type="supplementary-material"}). Patients at stage 3 hypertension were more likely to be older, and had a higher level of serum glucose compared with those having the controlled BP (\<140/90 mmHg). Moreover, the baseline leukocytes telomere length of patients at stage 1, 2 and 3 hypertension were significantly shorter than that of those having the controlled BP (All *P*\<0.05). There were no remarkable differences among the stages of hypertension for other traditional vascular risk factors including BMI, lipid profiles, smoking status, alcohol intake, and medical history of cardiovascular diseases as well as diabetes mellitus. In the further analysis of association between telomere attrition rate and blood pressure lowering, we further adjusted for the stage of baseline blood pressure as a covariate in the multiple linear regression models.
Figure 1.Inverse correlation between annual telomere attrition rate and baseline telomere length of leukocytes. The leukocyte telomere length of all participants was plotted as Lg-transformed T/S ratio. Annual telomere attrition rate was calculated by the equation: (follow-up telomere length- baseline telomere length)/follow-up years. The correlation coefficient *β*was -0.52 and *R^2^* was 0.27 (*P*\<0.001).
######
Baseline characteristics of patients between the shorten and lengthen groups categorized by annual telomere attrition rate during 2014-2016.
Annual telomere attrition rate
--------------------------------------- -------------------------------- ----------------------- ------------------------ -------------
Characteristics Total (n=1,108) Shorten group (n=386) Lengthen group (n=722) *P*value^†^
Age, years 61.7 ± 9.7 62.3 ± 9.6 61.4 ± 9.8 0.13
Men, No. (%) 430 (38.8%) 155 (40.2%) 275 (38.1%) 0.52
BMI, kg/m^2^ 26.2 ± 3.1 26.3 ± 3.2 26.2 ± 3.1 0.85
Waist-to-hip ratio 0.90 ± 0.05 0.90 ± 0.05 0.90 ± 0.05 0.09
Systolic BP, mm Hg 160 ± 21 159 ± 21 160 ± 21 0.27
Diastolic BP, mm Hg 89 ± 12 89 ± 11 89 ± 12 0.92
Fasting serum glucose, mmol/L 6.2 ± 1.7 6.1 ± 1.5 6.3 ± 1.8 0.10
Lipids, mmol/L
Total cholesterol 5.7 ± 1.1 5.6 ± 1.1 5.7 ± 1.1 0.41
Triglycerides 1.6 (1.1-2.3) 1.6 (1.1-2.2) 1.6 (1.1-2.4) 0.23
HDL-C 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.3 0.40
LDL-C 3.6 ± 0.9 3.6 ± 0.9 3.6 ± 0.9 0.48
Smoking status, %
Never 73.8 73.1 74.1 0.41
Former 7.4 8.8 6.6
Current 18.8 18.1 19.1
Alcohol intake, %
Never 77.0 77.7 76.6 0.58
Former 5.1 5.7 4.7
Current 18.0 16.6 18.7
Medical history, %
Diabetes mellitus 23.8 21.8 24.9 0.27
Stroke 21.1 23.1 20.1 0.25
Coronary heart disease 29.7 30.6 29.2 0.68
Antihypertensive drugs, No. (%)
Calcium channel blocker 744 (67.1) 251 (65.0) 493 (68.3) 0.28
Angiotensin receptor blocker 590 (53.2) 192 (49.7) 398 (55.1) 0.09
ACE inhibitor 87 (7.9) 35 (9.1) 52 (7.2) 0.29
Beta-blocker 24 (2.2) 11 (2.8) 13 (1.8) 0.28
Diuretics 300 (27.1) 104 (26.9) 196 (27.1) 0.99
Leukocytes telomere length, T/S ratio
At baseline 1.4 (1.0-1.8) 1.8 (1.4-2.3) 1.2 (0.9-1.6) \<0.001
At follow-up 1.9 (1.3-2.5) 1.1 (0.8-1.5) 2.2 (1.7-3.0) \<0.001
Telomere length, base pairs (Kb)^\*^
At baseline 6.6 (5.7-7.7) 7.5 (6.5-8.9) 6.3 (5.5-7.2) \<0.001
At follow-up 7.8 (6.3-9.4) 6.0 (5.2-6.9) 8.6 (7.4-10.4) \<0.001
Abbreviations: BMI, Body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ACE, angiotensin converting enzyme; T, telomere repeat copy; S, single-copy gene globin copy; Kb, kilo base pairs. Data were given as mean ± SD, number (%), or median (interquartile range). The leukocytes telomere length was expressed as T/S ratio. ^\*^Base pairs of telomere length were calculated based on the equation= 3274 + 2413 × (T/S ratio)^\[[@b55-ad-11-3-494]\]^. ^†^*P* value was calculated by the chi-square test for categorical variables, the*t* test for continuous variables, or the Mann-Whitney *U* test for triglycerides and telomere length.
######
Association of annual telomere attrition rate with BP change during 2014-2016.
Annual telomere Mode I^\*^ Model II^†^
-------------------- ------------------ ------------ ------ ------------- ------- ------ ----------
Change in BP attrition rate *β* SE *P*value *β* SE *P*value
Total (n=1,108)
ΔSBP Shorten (n=386) Ref. Ref.
Lengthen (n=722) -3.20 1.35 0.02 -3.28 1.37 0.02
ΔDBP Shorten (n=386) Ref. Ref.
Lengthen (n=722) -0.58 0.73 0.43 -0.78 0.74 0.29
ΔPP Shorten (n=386) Ref. Ref.
Lengthen (n=722) -2.74 1.10 0.01 -2.53 1.11 0.02
Men (n=430)
ΔSBP Shorten (n=155) Ref. Ref.
Lengthen (n=275) -2.19 2.14 0.31 -2.68 2.16 0.15
ΔDBP Shorten (n=155) Ref. Ref.
Lengthen (n=275) -0.78 1.20 0.52 -1.05 1.19 0.38
ΔPP Shorten (n=155) Ref. Ref.
Lengthen (n=275) -1.48 1.73 0.39 -1.34 1.72 0.44
Women (n=678)
ΔSBP Shorten (n=231) Ref. Ref.
Lengthen (n=447) -3.91 1.73 0.02 -3.56 1.76 0.04
ΔDBP Shorten (n=231) Ref. Ref.
Lengthen (n=447) -0.71 0.92 0.45 -0.81 0.94 0.39
ΔPP Shorten (n=231) Ref. Ref.
Lengthen (n=447) -3.42 1.42 0.02 -3.25 1.44 0.03
≤60 years (n=506)
ΔSBP Shorten (n=169) Ref. Ref.
Lengthen (n=337) -6.41 1.90 0.001 -6.82 1.91 \<0.001
ΔDBP Shorten (n=169) Ref. Ref.
Lengthen (n=337) -2.37 1.10 0.03 -2.49 1.11 0.03
ΔPP Shorten (n=169) Ref. Ref.
Lengthen (n=337) -3.97 1.46 0.007 -4.23 1.47 0.004
\>60 years (n=602)
ΔSBP Shorten (n=217) Ref. Ref.
Lengthen (n=385) -1.53 2.08 0.46 -1.42 2.13 0.51
ΔDBP Shorten (n=217) Ref. Ref.
Lengthen (n=385) 0.76 0.97 0.43 0.41 1.0 0.68
ΔPP Shorten (n=217) Ref. Ref.
Lengthen (n=385) -1.46 1.58 0.35 -1.74 1.77 0.33
Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; *β*, regression *β* coefficients; SE, standard error; Ref., reference. ^\*^Model I and ^†^Model II were multiple linear regression models for analyzing the correlation between annual telomere attrition rate and BP change during 2014-2016. ^\*^Model I adjusted for baseline characteristics including age, gender (except in gender-stratified analysis), BMI, waist-to-hip, smoking status, alcohol intake, medical history, the stage of baseline blood pressures, leukocytes telomere length, serum fasting glucose, total cholesterol, triglycerides, HDL-C, and LDL-C. ^†^Model II further adjusted for changes in BMI, waist-to-hip, fasting glucose, total cholesterol, triglycerides, HDL-C, and LDL-C from 2014 to 2016, besides the covariates in Model I.
Fig 2.Differences of blood pressure lowering between the lengthen and the shorten groups during 2014-2016. Abbreviations: SBP, systolic blood pressure; PP, pulse pressure. ^\*^*P*\<0.05, ^\*\*^*P*\<0.01. *P* values and adjusted mean were calculated by generalized linear model adjustment for covariates including age, gender (except in gender-stratified analysis), smoking status, alcohol intake, medical history, the stage of baseline blood pressures, baseline telomere length, and changes in BMI, waist-to-hip, fasting glucose, TC, triglycerides, HDL-C, and LDL-C from 2014 to 2016. Error bars indicate 95%CI.
Correlation of telomere attrition with blood pressure lowering
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Compared with hypertensive patients in the shorten group who experienced telomere length shortening, those in the lengthen group showed significantly lower levels of SBP and PP during follow-up from 2014 to 2016. With the use of generalized linear regression analysis adjusting for covariates including age, gender, smoking and alcohol status, medical history, the stage of baseline blood pressures, baseline telomere length, and changes in BMI, waist-to-hip, fasting serum glucose, TC, triglycerides, HDL-C, and LDL-C during 2014-2016, the results showed that ∆SBP was -10.2 mm Hg (95%CI, -12.8 to -7.6) for the lengthen group and -6.9 mm Hg (95%CI, -10.1 to -2.9) for the shorten group (*P*=0.03) ([Fig. 2A](#F2-ad-11-3-494){ref-type="fig"}); the ∆PP was -7.9 mm Hg (95%CI, -10.0 to -5.8) for the lengthen and -5.5 mm Hg (95%CI, -8.1 to -2.9) for the shorten group (*P*=0.04) ([Fig. 2B](#F2-ad-11-3-494){ref-type="fig"}). Next, when stratified by age and gender, the differences in ∆SBP and ∆PP were more significant in women (*P~interaction~*=0.05 by gender) and patients aged≤60 years (*P~interaction~*\<0.05 by age) ([Supplementary Table 6](#SD1-ad-11-3-494){ref-type="supplementary-material"}). There was no significant difference in change of DBP between the lengthen and shorten group.
The correlation coefficients between annual telomere attrition rate and blood pressure lowering were further assessed by multiple linear regression analysis, and the coefficient *β* was -3.28 (*P*=0.02) for ∆SBP and -2.53 (*P*=0.02) for ∆PP, respectively ([Table 2](#T2-ad-11-3-494){ref-type="table"}). The correlations still remained after adjustment for changes in BMI, waist-to-hip, fasting glucose, TC, triglycerides, HDL-C, and LDL-C at follow-up. Similarly, when stratified by age and gender, the correlations between annual telomere attrition rate and ∆SBP or ∆PP were observed in women and patients aged≤60 years. We also examined whether baseline telomere length could affect blood pressure lowering and found no significant correlation between baseline telomere length and change in SBP or PP ([Supplemental Fig. 5](#SD1-ad-11-3-494){ref-type="supplementary-material"}).
Association Between Telomere Attrition and the Effects of Antihypertensive Treatment
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The association between annual telomere attrition rate and blood pressure lowering differed in antihypertensive treatment ([Supplemental Table S7](#SD1-ad-11-3-494){ref-type="supplementary-material"}). Among patients using the CCB or ARB treatment, those in the lengthen group showed a significantly lower level in ∆SBP and ∆PP than those in the shorten group during 2014-2016. For CCB users, the difference between the lengthen and shorten group was 5.4 mm Hg (95% CI, 1.1-9.7; *P*=0.01) for ∆SBP and 3.6 mm Hg (95% CI, 0.3-6.9; *P*=0.03) for ∆PP; for ARB users, the difference was 4.7 mm Hg (95% CI, 0.6-8.7; P=0.02) for ∆SBP and 3.5 mm Hg (95% CI, 0.3-6.7; P=0.03) for ∆PP ([Fig. 3](#F3-ad-11-3-494){ref-type="fig"}). Consistently, the correlation between telomere attrition and ∆SBP or ∆PP during follow-up was observed in patients treated with CCB and ARB, but not in those with diuretics ([Table 3](#T3-ad-11-3-494){ref-type="table"}).
######
Association of telomere attrition with effects of antihypertensive treatment.
Change in blood Annual telomere Model I^\*^ Model II^†^
-------------------------- ------------------ ------------- ------ ------------- ------- ------ ----------
pressure attrition rate *β* SE *P*value *β* SE *P*value
CCB therapy (n=744)
ΔSBP Shorten (n=251) Ref. Ref.
Lengthen (n=493) -4.72 1.95 0.02 -4.73 1.98 0.02
ΔDBP Shorten (n=251) Ref. Ref.
Lengthen (n=493) -1.56 0.98 0.11 -1.62 0.99 0.10
ΔPP Shorten (n=251) Ref. Ref.
Lengthen (n=493) -3.59 1.51 0.02 -3.53 1.53 0.02
ARB therapy (n=590)
ΔSBP Shorten (n=192) Ref. Ref.
Lengthen (n=398) -5.08 2.13 0.02 -4.75 2.16 0.03
ΔDBP Shorten (n=192) Ref. Ref.
Lengthen (n=398) -1.19 1.08 0.27 -1.31 1.09 0.23
ΔPP Shorten (n=192) Ref. Ref.
Lengthen (n=398) -4.20 1.68 0.01 -3.56 1.70 0.04
Diuretic therapy (n=300)
ΔSBP Shorten (n=104) Ref. Ref.
Lengthen (n=196) -4.19 2.99 0.16 -2.86 3.06 0.35
ΔDBP Shorten (n=104) Ref. Ref.
Lengthen (n=196) -1.39 1.53 0.36 -1.37 1.53 0.37
ΔPP Shorten (n=104) Ref. Ref.
Lengthen (n=196) -2.10 2.61 0.42 -0.84 2.65 0.75
Abbreviations: CCB, calcium channel blocker; ARB, angiotensin receptor blocker; and the others same as in [Table 2](#T2-ad-11-3-494){ref-type="table"}. ^\*^Model I and ^†^Model II were multiple linear regression analysis for association between annual telomere attrition rate and effect of antihypertensive therapy during 2014-2016, which adjusted for the same covariates described in the footnote of [Table 2](#T2-ad-11-3-494){ref-type="table"}.
Association of Telomere Attrition Rate with Cardiovascular Outcomes
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During a median follow-up of 2.2 (range 1.5-2.4) years, there were 70 cardiovascular events and 40 stroke events. The results showed that there was no significant correlation between annual telomere attrition rate and cardiovascular events, and the antihypertensive drugs also did not affect this correlation (all *P*\>0.05, [Supplemental Table S8](#SD1-ad-11-3-494){ref-type="supplementary-material"}). In addition, the baseline telomere length as a continuous variable was also not observed to associate with total cardiovascular disease events, and the hazard ratio is 0.76 (95%CI, 0.26-2.24; *P*=0.62).
Fig 3.Effects of antihypertensive drugs on blood pressure lowering in the lengthen and shorten groups during 2014-2016. Abbreviations: SBP, systolic blood pressure; PP, pulse pressure; CCB, calcium channel blocker; ARB, angiotensin receptor blocker. ^\*^*P*\<0.05, ^\*\*^*P*\<0.01. *P* value and adjusted mean were calculated by generalized linear model adjustment for covariates mentioned in the [Figure 2](#F2-ad-11-3-494){ref-type="fig"}. Error bars indicate 95%CI.
DISCUSSION
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In this study, we for the first time investigated the relation between annual telomere attrition rate and blood pressure lowering in a longitudinal cohort of 1,108 primary hypertensive patients in China. The key findings showed that telomere lengthening was independently associated with decrease in SBP and pulse pressure during the follow-up period. Compared with hypertensive patients who experienced telomere length shortening, those patients in the lengthen group who experienced an increase of telomere length showed significantly lower levels of SBP and pulse pressure during 2014-2016, and this association was independent of conventional vascular risk factors. Of note, the differences in ∆SBP and ∆PP were more significant in women and patients aged≤60 years. Moreover, the association between annual telomere attrition rate and BP lowering differed in antihypertensive treatment. Among patients using the CCB and ARB therapy, those in the lengthen group showed a significantly lower level in ∆SBP and ∆PP. However, there was no significant correlation between annual telomere attrition rate and incidence of cardiovascular events.
The major strengths of this study are the repeated measurements of blood pressure and telomere attrition via a prospective, longitudinal design with a large sample size as well as the detailed antihypertensive drug records. Several studies have reported cross-sectional associations between shorter leukocyte telomere length with higher levels of blood pressure and pulse pressure \[[@b12-ad-11-3-494],[@b15-ad-11-3-494],[@b16-ad-11-3-494],[@b18-ad-11-3-494],[@b27-ad-11-3-494]\], although there is inconsistence in other study \[[@b17-ad-11-3-494]\]. Here, our data regarding the longitudinal change of telomere length in patients with hypertension provided the evidence that the annual telomere attrition rate was negatively correlated with blood pressure lowering of SBP and pulse pressure during the follow-up, and the association was independent of the stage of baseline blood pressures.
The leukocytes telomere length is highly heterogeneous at birth and changes throughout the lifetime, which is affected by genetic and environmental factors \[[@b2-ad-11-3-494],[@b3-ad-11-3-494]\]. Aging is a major determinant of telomere attrition \[[@b4-ad-11-3-494]\], and as expected, we found that increasing age, as an independent predictor, was inversely associated with both baseline telomere length and follow-up telomere length. In addition, baseline telomere length was observed to independently associate with accelerated telomere attrition, supporting the concept that telomere length shortens much faster at longer baseline telomeres \[[@b28-ad-11-3-494]\].
Several studies have observed that telomere lengthening occurs in approximately 12%-24% of healthy individuals \[[@b10-ad-11-3-494],[@b29-ad-11-3-494]\], but the change of telomere length has not previously been evaluated in patients with hypertension. Given the accumulating pathophysiological burden in chronic illness, it might be expected that telomere shortening would occur in a greater proportion of hypertensive patients. However, almost a third of patients in this study experienced telomere shortening, and more than a half actually lengthened their telomeres during the 2-year follow-up. We did not find that traditional vascular risk factors such as BMI, waist-to-hip ratio, lipid profiles, and serum fasting glucose, were associated with temporal change of leukocytes telomere at follow-up. The regression analysis showed a strong correlation between telomere attrition and baseline telomere length, in which patients who experienced the greater amount of telomere attrition at follow-up were more likely to have a longer baseline telomere length, and in contrast, those who experienced telomere lengthening at follow-up had the shorter baseline telomeres. Supported by the mathematical model of telomere shortening \[[@b30-ad-11-3-494]\], these findings further suggest that there may be a negative feedback regulation of leukocytes telomere length in humans.
Telomere biology is emerging as an important factor in the pathogenesis of hypertension. Low telomerase activity was detected in endothelial progenitor cells (EPC) from hypertensive rats and patients with essential hypertension, which may contribute to premature cell senescence \[[@b31-ad-11-3-494]\]. Moreover, the long-term exposure to risk factors such as oxidative stress and insulin resistance, which are frequently associated with high blood pressure and are known to inhibit telomerase activity and accelerate telomere shortening, may ultimately provoke vascular senescence and promote disease progression by increasing arterial stiffness \[[@b32-ad-11-3-494]-[@b34-ad-11-3-494]\]. Okuda et al identified a higher rate of telomere attrition in abdominal aorta, suggesting that telomere shortening may occur in vascular segments susceptible to hemodynamic stress \[[@b35-ad-11-3-494]\]. More basic research is needed to clarify the temporal change of telomerase activity and telomere length in arterial cells from hypertensive patients.
In this study, younger patients (≤60 years) with lengthened telomeres at follow-up had significant blood pressure lowering in ΔSBP, ΔDBP and ΔPP. Elevated blood pressures, considered as clinical markers of large artery stiffness, usually aggravate with aging \[[@b36-ad-11-3-494],[@b37-ad-11-3-494]\]. The increased arterial stiffness can reduce the buffering function of conduit arteries near the heart and increase pulse wave velocity, both of which can increase SBP and pulse pressure \[[@b38-ad-11-3-494]\]. Stiffer arteries make the pressure wave travel faster in the arterial tree, which usually induces systolic rather than diastolic augmentation \[[@b39-ad-11-3-494]\]. Thus, it is possible that the correlation of telomere lengthening with blood pressure lowering among older patients could be attenuated by age-associated arterial stiffness. To date, studies regarding telomeres and cardiovascular diseases among older people also remain inconsistent \[[@b40-ad-11-3-494]\].
A number of studies have found leukocytes telomere length to be longer in women than in men, and the rate of telomere length shortening was slower in women \[[@b41-ad-11-3-494]-[@b45-ad-11-3-494]\]. Men tend to have unhealthy life-style behaviors than women \[[@b46-ad-11-3-494]\], and these unhealthy behaviors are associated with reduced telomere length \[[@b47-ad-11-3-494],[@b48-ad-11-3-494]\]. As expected, men in our cohort had greater frequencies of smoking and drinking, a higher level of waist-to-hip ratio, and shorter telomere length at baseline. In addition, estrogen can stimulate telomerase activation by reducing the oxidative stress and thus may be protective against reactive oxygen species damage \[[@b49-ad-11-3-494]\]. These might explain the significant correlation of blood pressure lowering with the lengthened telomere in women, but not in men. For subgroup analysis, this study also had a sufficient power (\>90%) to detect blood pressure difference with a two-sided α level of 0.05, based on the difference in means of leukocytes telomere length between the shorten (mean, 0.23; SD, 0.21) and the lengthen group (mean, 0.05; SD, 0.21). Further studies are useful for assessing the effects of gender on telomere maintenance and telomerase in hypertension.
Interestingly, we found that annual telomere attrition rate was associated with the heterogeneity in blood pressure lowering in response to antihypertensive drugs, and telomere lengthening had significantly beneficial effects in ΔSBP and ΔPP among patients treated with CCB or ARB. Antihypertensive drugs may affect cell senescence and telomere length shortening. The CCB has been shown to possess antioxidant properties and reduce the oxidative stress in cardiovascular structures, in which suggested mechanisms are to prevent the inactivation of telomerase and increase eNOS activity during the process of vascular endothelial cell senescence \[[@b50-ad-11-3-494]\]. Data from the Framingham heart study showed that shortened leukocytes telomere length is more frequently presented in hypertensive patients with a higher plasma renin-angiotensin ratio \[[@b19-ad-11-3-494]\]. In addition, animal experiments showed that treatment with an angiotensin II receptor antagonist was associated with reduced oxidative stress and increased telomere length in the spontaneously hypertensive rats \[[@b20-ad-11-3-494]\]. The blood pressure lowering response to antihypertensive drugs in relation to telomere attrition may be in part explained by the link between telomeres and renin-angiotensin system. More examination on serum renin and angiotensin level is helpful to clarify the mechanisms.
Emerging evidence has demonstrated that leukocytes telomere length shortening is associated with higher risk of cardiovascular diseases; however, to date, the results of systematic review and meta-analysis are inconsistent in the literatures on the relation between telomeres and cerebrovascular diseases such as stroke, due to the between-studies heterogeneity. Moreover, these meta-analyses are based on observational studies reflecting the measurement of telomere length at a single time point at baseline. For example, Haycock et al reviewed 24 studies involving 43,725 participants and 8,400 patients with cardiovascular disease (5,566 with coronary heart disease and 2,834 with cerebrovascular disease) and showed that shorter leukocyte telomeres are associated with coronary heart disease, but the association with cerebrovascular disease is less certain \[[@b8-ad-11-3-494]\]. The meta-analysis by D\'Mello et al showed that shortened leukocytes telomere length has a significant association with stroke and myocardial infarction, but with a high level of heterogeneity among these studies, indicating that larger, well-designed studies are needed to confirm these findings and explore sources of heterogeneity \[[@b51-ad-11-3-494]\]. A recent meta-analysis demonstrated that increased risk of ischemic stroke is associated with shorter telomere length, but this association is stronger in the retrospective studies and in the Asian population \[[@b52-ad-11-3-494]\].
Longitudinal studies demonstrate that accelerated telomere attrition rate might show stronger association with increased risk of mortality from cardiovascular disease in high-risk population, such as older people aged ≥70 years \[[@b10-ad-11-3-494]\] or patients with stable coronary artery disease \[[@b53-ad-11-3-494]\]. In addition, longitudinal change of leukocytes telomere dynamics contributes to the risk of cardiovascular-related phenotypes, including subclinical atherosclerosis, metabolic syndrome components, and left ventricular mass \[[@b11-ad-11-3-494], [@b54-ad-11-3-494]-[@b56-ad-11-3-494]\]. Notably, the relation between telomere attrition rate and cardiovascular outcomes in hypertensive patients is uncertain.
In the present study, our data showed that there was no significant relationship between telomere attrition rate and incidence of cardiovascular events in hypertensive patients during the follow-up. This might be explained that all hypertensive participants in our cohort had received the antihypertensive treatment, which would reduce the occurrence of cardiovascular events, and thus, the potential effects of accelerated telomere attrition may be attenuated. However, in our study, the limited follow-up period, a relatively smaller person-years, and a short-term exposure duration of telomere attrition, may affect the association between annual telomere attrition rate and cardiovascular events. Further studies with a larger sample size and long-term follow-up will support to identify the relation of telomere attrition with future cardiovascular risk among the hypertensive patients.
Some potential limitations in this study should be mentioned. First, the measurements were restricted to telomere length in circulating leukocytes which do not necessarily reflect telomere attrition in other cell types such as myocardium, endothelium, or atherosclerotic plaque. However, studies by Wilson et al \[[@b9-ad-11-3-494]\] and Zhang et al \[[@b26-ad-11-3-494]\] showed that leukocytes telomere can serve as an appropriate indicator of telomeres in vessel wall and in human atherosclerotic plaques. Second, the quantitative PCR technique employed in this study measures the mean telomere length across all chromosomes present in the patient's leukocytes. Evidence from animal models suggests that the shortest telomere, rather than the mean telomere length, may be the more important determinant of cell viability and chromosomal stability \[[@b57-ad-11-3-494]\]. Thus, use of mean telomere length could have resulted in a loss of precision with regard to the shortest telomere length in each cell. Third, telomerase activity assays were not performed, which might further clarify the mechanisms of telomere lengthening in hypertensive patients. In addition, it has been reported that statins can attenuate the risk of cardiovascular events conferred by shorter telomeres, whereas this effect is not associated with telomeres lengthening \[[@b58-ad-11-3-494]\]. Given that statin use in this cohort only accounted for 19 (4.9%) in the shorten group and 38 (5.3%) in the lengthen group (*P*=0.89), respectively, their use may not affect the correlation of telomere attrition rate with antihypertensive drugs.
Conclusion
----------
In summary, this study for the first time showed an association between annual telomere attrition rate and blood pressure lowering in a prospective, longitudinal cohort of primary hypertensive patients. Telomere lengthening was independently associated with decrease in SBP and pulse pressure during the follow-up period of 2 years, and the differences in ∆SBP and ∆PP were more significant in women and younger patients aged≤60 years. Moreover, in patients using CCB or ARB therapy, those having lengthen telomeres showed a significantly lower level of ∆SBP and ∆PP. Our data supported that telomere attrition may provide new sight on telomere biology in clinical intervention for hypertension. Future randomized controlled studies will be helpful to clarify the role of antihypertensive interventions in telomeres lengthening.
Supplementary Materials
=======================
######
The Supplemenantry data can be found online at: [www.aginganddisease.org/EN/10.14336/AD.2019.0721](http://www.aginganddisease.org/EN/10.14336/AD.2019.0721).
**Disclosures**
The authors declared no potential conflicts of interest.
We would like to acknowledge the technicians and staffs at the State Key Laboratory of Cardiovascular Disease, FuWai Hospital, and the staffs at Benxi Railway Hospital for data collection and management. We would also like to thank for generous supports from Qingdao Huang Hai Pharmaceutical Co., LTD., Shandong province, China.
The study is supported by the grants from the National Science and Technology Pillar Program during the Twelfth Five-year Plan Period \[No. 2011BAI11B04\], Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences \[No. 2016-I2M-1-006\], and the National Natural Science Foundation of China \[No. 81670038 and 91339101\].
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Tuesday, June 26, 2012
Allowing Yourself to be Feminine
I have always had an eye for beautiful things. I love a
beautiful nature scene, pretty pictures, flowers, delicate antiques, baroque
frames, etc. When I think of how God made women, I think that he made us to be things
of beauty, too. We are different from men, as much as modern society tells us
we are not. We are softer, rounder, curvier, more delicate. Our bodies are made
with graceful lines and curves meant to nurture children. We are just as much
works of beauty and art as a beautiful sunset, or a rose garden. (I’m becoming
quite poetic, don’t you think?).
What we need to be careful of is taking our
beauty to an extreme which is vain, vulgar, overtly sexual, or distracting from
our personalities. I struggled much in the past with being vain and dressing
too sexually. I cringe when I think about some of the clothing items I used to
wear on a regular basis. My goal then was to be sexually appealing to men.
Now, however, my goal is to be feminine. To embrace that God
made me differently from men and that is a wonderful thing. It is ok to spend
some time on my appearance, so long as I spend more time on my inward appearance
(spending time in prayer, worship, Bible reading, memorizing verses, or serving
others).
One thing I have encountered even with Christian women is a
reluctance to be feminine. Society glorifies femininity in the sexual form, but
makes femininity in the pretty form to be something childlike and naïve.
I was at a conference recently for my work and a coworker
from our New York office made
some jibes at my clothing. She said I look “so Midwestern”, and that I look so “country”.
I dress modestly and always wear skirts, but I do enjoy fashion and try to be
fashionable in my modest choices. But the mere fact that I was wearing a skirt
that went below my knees and that my clothes weren’t tight or revealing made me
seem childlike to her.
I heard through the grapevine that another coworker from our
Los Angeles office called me “naïve”.
Really? Me? Naïve? My immediate response was indignity. I thought “I’ve
traveled the world, speak 5 languages, have been through more difficulty than
you could imagine, and I’ve sinned like you couldn’t believe.” But isn’t that
just such a worldly point of view? I should be proud that others perceive me as
naïve. In a world were sin and
corruption are celebrated, I should be proud that I give off a spirit of purity
and naivety. I should be proud that God has not only forgiven me of all my
past sins, but has made me appear to be pure before others. I should be
celebrating that others perceive my innocence, not indignant that they can’t
see how sinful I am.
The world sees naivety as a sign of being simple or unwise.
But we see in the book of Proverbs over and over that being wise is very
important. (See Proverbs 14:15, Proverbs 27:12, Proverbs 7:7). But the Bible
sees being wise (not naïve) as making sound decisions and avoiding the dangers
of sin. The world sees this the opposite way. They see being naïve as being
ignorant of sin, rather than avoiding it.
This world thinks that to be feminine without being sexual
is to be naïve and therefore undesirable. But you know what? That is exactly
the kind of women God calls us to be! God made men and women to reflect
different aspects of His character to the world. We are to reflect differently
than men are, and we need to give ourselves permission to do so.
There was a time when I never even owned a skirt because I
perceived them as reflecting a weak spirit. I saw them as too “soft”. I still
know women in my church who perceive skirts and femininity as too “soft”. Some
women feel that they will look stupid if they wear feminine clothing, simply
because they have always perceived themselves as tomboys or “capable” women. I
spoke recently with a young woman at my church who felt that way. She has
always enjoyed carpentry and is very handy. She never enjoyed playing with
dolls as a child. To this day she said she feels “stupid” when she dresses
femininely because she doesn’t feel it is “her”.
Her feeling that being feminine is not “her” is a reflection
of the worldly idea that dressing femininely makes her appear naïve, weak,
incapable, and childlike. Not all women are the same. Some of us are better
with a hammer and nails than with babies. Some of us are amazing in the kitchen
and others cannot scramble an egg without burning it. Whatever your personality, however, you are still a woman, and you are
still supposed to display a feminine spirit to the world. God created women
to be beautiful, nurturing, and feminine. It is ok for you to buck how society
expects you to dress and act, and instead do what God MADE you to do. It’s ok
for you to appear to be feminine, naïve, and innocent, because those are qualities Christ instructed us to have. Christ called all of us to have child-like faith, and
that faith should be reflected in our lives. It is only the world that labels those
things as bad.
I had to make a conscious decision in the last year to allow
myself to be feminine without appearing sexual. It is sad that we have to
fight society’s hold on us and give ourselves permission to be who God created
us to be, but we do! I urge you to give yourself permission to be feminine. To
take pride in your femininity, but not to use it as a sexual weapon. To enjoy
the feminine feel of a skirt swirling around your ankles. To endeavor to be
graceful in body and spirit. To ignore the cruel comments and instead
acknowledge the fact that men look at you as a thing of beauty, like a rose or
a sunset, and not as a thing of sex. To
take joy in the fact that God made you to be a woman.
I encourage all of you to read a wonderful 8-week biblestudy I just finished on the topic of femininity in the Bible.
The study talks in
a very overarching way about the Biblical concept of femininity. It also talks
about the history and ideology behind the feminist movement and how we as Christian
women should respond. I promise you won’t be disappointed with this study.
6 comments:
I'm going to link to this post on my blog. I loved it! You write so beautifully. You are a blessing.I hope to read that bible study one day soon but have a few other things to work through first. Can I also recommend Victoria Botkin's 9 CD webinar on Biblical femininity? It changed my life a whole lot too. I listen to it over frequently for reminders. It is called 'She Shall be Called Woman'.
I'm glad you wrote this article, I really agree. I've found that when you like feminine things people just look at you like you're immature, and when you dress modestly they think you're naive and sheltered. Before I became a Christian I lived a terrible life, the way I dressed, the things I did, but it definitely wasn't a sheltered life and I don't think anyone would believe me now if I told them about it, so I guess if the worst thing they think about me is I'm immature and sheltered then that's pretty good, it's better than what they would have thought of the old me!
I also find there's this attitude, and I wonder if you agree, in reference to the naivety and sheltered side of things, that because you're a Christian people think 'Oh well she can believe in God, nothing terrible or tragic has happened in her life so it would be easy for her to believe that.' I tend to experience that a lot, It's like people think if I had suffered like other people in the world have suffered maybe I'd be less likely to believe?
Great post! I am beyond sick and disgusting with this pro-tomboy, anti-girl movement. it is now a social crime to be a lady, modest, girly, etc. to be girly is to be stupid; modest, insecure and ashamed; gentle, weak and bland. how very sexist and misogynistic is it to imply women are only intelligent, beautiful, capable, and worthy of respect when they ACT LIKE MEN!
I have to say though, on one thing- women are NOT round/fat and are not meant to be, plus many women are not curvy, and it's much healthier to be toned than soft (a politically corret term for flabby). where did you get that idea? I can't stand when people imply being thin, uncurvy or toned is unfeminine- quite the opposite.
Thank you for your comment! I appreciate your insight. While it is perfectly fine for a woman to be toned or even muscular, it is a fact that women had a higher fat body percentage than men do. Most women (although I know some women who do not) have hips and breasts, and those are soft. If you take a typical man and a typical woman and put them next to each other, you will usually find the man is harder (more muscular) naturally than the woman. I am not fat at all, but I still consider my body to be much softer than my husband's.Thanks again!
About Me
I am a 29 year old child of God. I'm completely imperfect and yet saved by God's grace. I consider this my little online coffee shop (probably more of a tea shop if it was my taste), where I get to talk with other Christian women and share some of my interests: living debt-free, crafts, cooking, fashion, family, pregnancy, babies, etc. I live in Ohio with my husband and baby. Feel free to contact me anytime at cornerjoyk@gmail.com |
You are responsible for the sportsmanship of your players. If one of your players is disrespectful, irresponsible, or overly aggressive, take the player out of the game, for as long as you deem necessary.
In addition ALL individuals representing POBSC as a Coach MUST be represented in proper POBSC attire (POBSC Coaches shirt) when they are acting as a coach during home and away games (weather permitting). No exception to this rule.
Respect the Referee and Observe Zero ToleranceYou are responsible for the conduct of the parents and spectators of your players. Enlist a parent to take charge on the opposite sideline if you need to.
You must explain acceptable player and spectator conduct before the season begins. Be sure to emphasize the Zero Tolerance Rule, which prohibits coaches, players, and spectators from saying ANYTHING to the referee.
The Plainview Old Bethpage Soccer Club Coach Code of Conduct reflects the Club’s desire that coaches act first and foremost in the best interests of the character development and safety of the players in their care. Persistent or flagrant disregard for these priorities may result in a coach being suspended for a certain number of games, required to take certain coach training courses, or, in extreme cases, relieved of coaching responsibilities permanently.
Parents Code of Conduct
Cheer for Your Child’s Team – Don’t Coach It. “Well done”, “Great try” are welcome cheers. Instructions – “shoot”, “get rid of it”, “pass it” – are not received as the helpful advice you intend it to be, and it may contradict what the coach is trying to teach the players. You can’t see what the players see, and they need to make their own decisions. Let them play.
Respect the Referee and Observe Zero Tolerance. The rules forbid parents from addressing the referee. Good sportsmanship does too. Referees do their best, whatever mistakes they make are as much a part of the game as the mistakes our children make, they have a better view than spectators.
Make the Coach’s Job Easier. Help your player understand the importance of attending and behaving well at practice. Be on time, dropping off and picking up. And communicate with the coach if/when you can’t make a practice or game. Coaches plan better practices when they know who’s coming. We know you’re busy, but so are the coaches – they’re taking the time to coach our children!
The Plainview Old Bethpage Soccer Club Parent Code of Conduct recognizes the significant benefits of parental support in youth sports while reminding all involved that the games are for the fun and development of the players and should be kept in perspective for the benefit of the players. Persistent or flagrant disregard of the Parent Code of Conduct may result in a parent being asked to leave a game, refrain from attending games, or, in extreme cases, in the suspension of the parent’s child from the Soccer Club.
Players Code of Conduct
Honor your commitment to the team by coming to all practices and games unless you have a conflict that you have already told your coach about.
Appreciate your volunteer coach by behaving well, and by always being ready to listen, learn and have fun.
Respect your opponents and yourself with clean play and clean language. Always.
Respect the referee – don’t complain. Enjoy playing the game and let the referee call it.
Respect and abide by the Laws of the Game – and make sure you KNOW them. Read the Laws of the Game on www.fifa.com.
Support your teammates – encourage them, don’t criticize them.
The Plainview Old Bethpage Soccer Club Player Code of Conduct is simple and fair. The Club expects its players to respect and abide by the Code. Persistent or flagrant disregard for the Code may result in a player incurring reduced playing time, being suspended for a specific number of games, or, in extreme cases, being expelled from the Soccer Club.
Violation of Code of Conduct
The Club believes that the most effective method for addressing grievances and concerns, and for preventing small grievances from becoming larger grievances, is always constructive communication between the parties involved. We encourage coaches and parents to discuss issues of concern regarding adherence to the Code of Conduct; the Club’s Age Division Head may be a helpful third party to such discussions.
The Club also recognizes that certain behaviors require more serious and formal discussion. Where violations of the Code of Conduct persist beyond discussion or are sufficiently serious, the Club encourages coaches and parents to contact the Division Head of Coach. The Division Head will draw upon the resources of the Club as necessary (by speaking to assistant coaches, and relevant parents) to ascertain the facts and present the matter to the Board for resolution in a timely manner.
External links are provided for reference purposes. Plainview-Old Bethpage Soccer Club is not responsible for the content of external Internet sites.
Copyright Plainview-Old Bethpage Soccer Club All rights Reserved. |
A peptide (A) accumulation is an important cause of AD, but may not be sufficient to cause cognitive deterioration. At diagnosis, neurotoxic pathways arguably downstream of A may prove better or additional therapeutic targets. Recent data from our lab and others implicate soluble tau oligomers. Our data show that curcumin selectively reduces soluble tau dimers, and transgene dependent defects in heat shock proteins (HSPs), behavior, synapses and Fyn, a tau kinase implicated in Abeta toxicity. In contrast to curcumin, our data show that another polyphenol, fisetin, can reduce total tau and pS422 monomers. We propose to study the impact of fisetin, a CDK5 inhibitor and SIRT1 activator (fisetin) found in fruits (strawberries) an its synergism with curcumin on pTau species and synaptic and cognitive deficits in a tauopathy model, comparing efficacy to a novel tau aggregation inhibitor D-TKJ1VW. General Design: We will explore the relative impact of fisetin using a human wildtype tau huTauTg model relevant to sporadic AD (with or without A infusion) on HSPs, autophagy, inflammation, synaptic proteins, fyn, cdk5,microtubule/ transport and mitochondria defects, behavior, tau oligomers and tau species. Objectives: Aim 1, To determine relative efficacy of fisetin versus a specific tau aggregation inhibitor in huTauTg mice with or without icv infusion of A. Aim 2: To determine synergism between fisetin and curcumin in huTau Tg mice (with or without icv infusion of A). Hypotheses: Interventions are used to clarify target engagement and significance of candidates (tau species, cdk5 or fyn activation, enhancing HSPs responses or autophagy) in correcting tauopathy, including identification of certain tau species that may be beneficial. 1. Fisetin will reduce tau transgene-associated hyperactivation of cdk5 but not fyn. 2. Fisetin reduces monomeric and insoluble ptau and increases unphosphorylated tau and stabilizes microtubules; however it does not result in reduction of oligomers, and only causes modest improvements in synaptic indices insufficient to improve cognition. 3. Unlike curcumin, fisetin wil not correct transgene-dependent heat shock responses. 4. Curcumin, but not fisetin will reduce total fyn, tau oligomers, the redistribution of CP13 ptau to dendrites as well as synaptic and cognitive deficits, but not NFT and insoluble tau. 5. Curcumin but not fisetin will stimulate Akt and downstream, p214 tau or MARK/ p262 tau. 6. Fisetin activates macroautophagic pathways via SIRT1 activation, while curcumin increases chaperone mediated microautophagy. 7. Bioavailable fisetin and curcumin will reduce different pathogenic species of ptau but act synergistically to reduce cognitive deficits, NFT, tau oligomers and insoluble tau and correct NR2B or PSD-95 receptor complex dysregulation in aged htau mice. 8. Anti-aggregation tau inhibitors but not the control peptide reduce pTau including oligomers but not pre-formed insoluble deposits or A induced deficits and correct synaptic and cognitive but not HSPs defects. 9. A +Tau models with tau-specific aggregate inhibition will help delineate A vs. tau mechanisms and relative efficacies of the interventions. Potential Outcomes: Because fisetin directly inhibits CDK5, stabilizes microtubules and stimulates autophagic pathways, but has no effect on fyn, while curcumin reduces pathogenic fyn and selectively reduces tau oligomers, fisetin should differentially impact tau kinase/phosphatase balance, pTau and aggregates. Some but not all pTau species will correlate with NR2B/ PSD-95 receptor complex dysregulation and impact cognitive, synaptic and inflammatory endpoints. In summary, these studies are both mechanistic and translational, advancing knowledge in identification of the soluble toxic tau species and exclusion of non-toxic species, and protective tau clearance pathways. Completion of aims will move the field forward in demonstrating interrelationship between tau aggregation, synapto/neuro-protection, inflammation, autophagy and the HSPs. |
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HAPPY VALENTINE
Whether you're male or female, straight or gay... VALENTINES could be a special day.
Some say VALENTINES DAY is the day we're encouraged to make romantic gestures.
Whichever path you've chosen, you may consider saying:
You are the sauce to my dumplings, the apple in my eye, the sunshine of my life, the fresh air that I breathe, my heart and my love, my soul, and my inspiration, everything to me, my chief executive, the one I adore, the one I want to grow old with, my better half, the horizon to my sky, the cheese to my macaroni, the peanut butter to my jelly, the petals of my rose, the flash to my camera, the bacon in my eggs, the laces in my shoes, the bubbles in my bath, the ink in my pen, the ketchup on my french fries, the water in my ocean, the icing on my cake, the modem in my computer, the cartridge in my printer, the fish in my chips, the smile on my face, or the yin to my yang... etc. Keep in mind, every day is valentines day!
But back this up with this positive gestures following a 1-2-3 basic communication formula.
Positive comments are essential for the maintenance of a healthy relationship. The development of this good habit takes a great deal of work, but it is well worth the effort.
No matter which language you speak, your communication should be respectful, cheerful, relaxed, mature and confident.
1/ Respect... Never control
The tendency to dominate and control is a common human weakness that must be mastered in order to maintain a healthy relation. This conflict often arises from severe childhood pains, from divorce trauma, from selfishness and from a lack of confidence.
Excessive anxiety, like excessive anger, is a source of significant stress. Today, both individuals often worry too much about their work or providing for the family. This anxiety regularly can give rise to irritability that can be misdirected. In this challenging society, both can benefit from growing in the virtue of faith and of trusting to be effective in diminishing anxiety.
Finally, lack of balance in family life and too many responsibilities can be problematic and a major source of a lack of balance.
3/ Cheerful Giving
Cheerfulness is an essential virtue in couples. A warm, smiling face often helps your significant other to cope with many pressures, burdens, and responsibilities. |
This approximately two-hour clinic is designed to help coaches in all of your girls high school sports. Learn about what constitutes success, the importance of building a program, identifying the type of program you want, discipline, dealing with parents, respect and pride. Learn how to discuss goals and how the girls can "own" their team. Find out how to build better people which translates into building better teams and programs. See how injecting fun away from the game into your program reaps huge benefits.
All of the above is just a taste of the information you will receive on Team and Program Building. An 18-page booklet with ideas and tips on how to better build a program is included with the clinic. This clinic is perfect to run for all of your girls sports together . . . or all of the fall sports together, all of the winter sports, etc. The information is not sport specific so is helpful to all coaches in all girls sports.
This is the same information given in the first part of the High School Softball Coaches Clinic and you could combine the two groups for one clinic. The coaches of other sports could then leave at break time or stay for the fundamentals and practice organization portion of the softball clinic. Most coaches in any sport will get a lot out of the section, as it gives basic organization and time management ideas that are pertinent to any program.
The most cost effective way is to combine all of your girls sports coaches together at hhe beginning of the year or to combine another school from your area . . . or better yet your whole league as the clinic price is capped once you reach four teams.
If you would like the clinic outline e-mailed to you please send your request to Terry at: |
Q:
Subset data using non-sequential row numbers
I have a data frame with 30 rows and 100 columns (X).
I would like to create a new data frame (Y) with specific rows from the larger data frame.
For example, I would like data frame (Y) to contain rows 1 through 5, 10 through 14, and 20.
I know that I can use the code:
Y<-X[1:5,]
and obtain the first five rows, but I cannot work out a similar code to obtain rows 1:5, 10:14, and 20.
A:
Generally, when selecting rows in a data frame or matrix, one uses the familiar X[rows, cols] format. It's helpful to remember that both of the parameters can be generated not simply as simple numbers or sequences, but also through the concatenation of numbers and sequences. Therefore, for your problem you can use something like the following:
Y <- X[c(1:5, 10:14, 20), ]
This will select rows 1 through 5, rows 10 through 14, and row 20, together with all of the columns in X, and assign the result to Y.
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Bamboo Encased Mouse
Business partners and friends will definitely have something to say about this handmade 3D USB optical computer mouse—it's casing is made entirely of bamboo. Despite its exotic exterior, the mouse works as an ordinary one would and features a scroll wheel along with right- and left-click buttons. To boot, no mouse pad is required as this model promises a smooth roll every time. About $17; SourcingMap |
November 15, 2016 13:38 IST
For the first time, the Central Reserve Police Force has deployed a team of women commandos in anti-Naxal operations in Jharkhand.
The 135 women, belonging to the 232 battalion’s Delta company, are currently undertaking operations under the close supervision of CRPF’s 133 battalion in Naxal-infested forests on the outskirts of Ranchi near Khoonti area.
Sanjay A Lathkar, CRPF IG of Jharkhand, said, “On October 17, a company of woman commandos was for the first time inducted in CRPF to counter Naxal insurgency in Jharkhand. They have started carrying out anti-Naxal operations.”
Neeraj Pandey, CRPF Commandment of 133 battalion, said, “The women are brave and currently undertaking first hand experience of anti-Naxal operation in forests outside Ranchi. They have been provided extensive training in CRPF academies specially for countering the Naxals.”
“Since the induction of women commandos, the strength of our operation in Naxal-infested areas has increased two-fold,” Pandey said.
The women commandos are second to none and have been given training on a par with men. They are equally able to tackle the Naxal issue, he said.
“We wanted to serve our country and that is why we are here. We have resolved to eradicate the Naxal menace completely as it is not only harmful and fatal for people but also affecting the progress of the country,” said Shakti Tirkey, Delta company commander who is heading the 135 woman commandos.
G V H Giri Prasad, deputy inspector general, CRPF said women commandos come handy in several situations while carrying out anti-Naxal operations.
“It was felt that to tackle women Naxals, there should be women commandos who must be equally capable of neutralizing Naxals. The women commandos are well prepared and well groomed to face any situation and hardships. There is no difference between a man and a woman commando,” Prasad said.
The woman commandos are experts in carrying out all types of anti-Naxal operations.
They have been trained in several case studies and carry out their operation in a perfect manner. They are equipped with modern weapons and software to assist them in executing their plan, the CRPF officers said.
IMAGE: CRPF deploys women commandos in anti-Naxal operation for the first time in Ranchi, Jharkhand on Tuesday . Photograph: PTI Photo |
Fmr. Chisholm Man Pleads Guilty To Defrauding Customers Of $1M
MINNEAPOLIS (WCCO) — A 26-year-old Michigan man, formerly of Chisholm, pleaded guilty to defrauding customers of his custom car shop out of more than $1 million.
Edwin Scott Verdung pleaded guilty to one count of wire fraud, and one count of transaction money laundering while working at Memory Lane Classics.
Verdung admitted in his plea agreement that from April 2007 to May 2010 he took money from individuals who were in the market for classic automobiles, or who brought their own vehicles into the shop to be restored.
Verdung failed to provide the services promised, but accepted funds and sometimes required customers to make “progress” payments, where he would show fake photos as evidence of the work he allegedly was doing. |
They are accused of stealing an ATM from a Co-op store in Barry Road, Carnoustie, in the early hours of that morning.
Police said the arrests were part of an ongoing operation involving officers from the Organised Crime Unit based at the Scottish Crime Campus and Titan, the North West Regional Organised Crime Unit in England.
The five men appeared in private at Forfar Sheriff Court where they made no plea or declaration.
Sheriff Gregor Murray continued the cases for further examination and remanded the men in custody ahead of a further hearing next week. |
Physician participation in health insurance plans: evidence on Blue Shield.
Various health insurance programs, including Blue Shield, have developed arrangements whereby the physician agrees to accept the insurer's reimbursement as payment in full. Incentives facing the physician to accept an arrangement of this type are reviewed in this study. The empirical work uses data on individual physicians from a 1973 survey. The results indicate that physician willingness to accept insurer reimbursement as payment in full is sensitive to the amount the insurer pays for specific procedures and to other insurance program characteristics. Physicians located in high patient income areas and/or with relatively prestigious credentials are less likely to accept insurer payments as payment in full. The empirical findings are used to generate policy implications pertaining to the Medicare and Medicaid programs, to medical care quality-access tradeoffs, and to national health insurance. |
Lillian Anekwe for New Scientist
Hundreds of climate change activists took to the streets of London this morning for a planned two-week protest organised by the campaign group Extinction Rebellion. New Scientist spoke to several scientists who are members of the group and will be taking part in the protests to find out what prompted them to take direction action.
Charlie Gardner, a conservation scientist at the University of Kent, says he joined the organisation because he felt that his professional responsibility extended beyond “just studying and describing” the impact of climate change on biodiversity.
“We know what to do to save species, but the UK government is not giving us the funding to do it. I’ve done everything I possibly can professionally and personally, but none of that has worked, it’s all been a drop in the ocean. For me as a scientist, this is necessary – and it is going to work.”
Lillian Anekwe for New ScientistLillian Anekwe for New ScientistLillian Anekwe for New ScientistLillian Anekwe for New Scientist
Gardner is encouraging other scientists who aren’t able to join the protests to support the movement by writing in scientific publications, starting local activism groups and lobbying their institutions and employers to declare a ‘climate emergency’.
Extinction Rebellion’s latest move is a planned campaign of civil disobedience across London, taking action including blocking major streets and bridges in the city centre, occupying government department buildings and holding a mass sit in at London City Airport. The group says that there will also be simultaneous protests in 60 cities around the world.
Extinction Rebellion claims the action will be on a much larger scale than its demonstrations in central London in April, when 11 days of protests brought parts of the capital to a standstill and led to more than a thousand arrests.
Jennifer Rudd, a scientist at a UK university, says she had no choice but to join Extinction Rebellion “given everything I know about climate change”.
She has since made changes in her career to align with the movement’s values, including stopping flying to reduce her carbon footprint, which she says “has had an effect on my international collaborations and reputation”.
Lillian Anekwe for New Scientist
Lee, who didn’t want to give his full name, says he worked for a decade in climate science, but “we are now reaching the tipping point that we’ve always been fearful of”.
“It’s almost to the point when we can’t reverse it. This is our last chance. The social contract with the government has been broken and now there’s nothing left to do but rebel.”
Extinction Rebellion has three demands for the UK. It wants the government to “tell the truth” about climate change, create a citizens’ assembly to decide on action and set a target of reducing greenhouse gas emissions to net zero by 2025.
The UK has committed to a legally binding goal of slashing its greenhouse gas emissions to net zero by 2050 and laid the legislation to make this law before parliament in June. |
Pentahydroxybenzene
Pentahydroxybenzene (C6H6O5) is a chemical compound whose structure consists of a benzene ring with five hydroxy groups (–OH) as substituents. The substance forms white to pinkish crystals. It decomposes at 264–269 °C.
References
Category:Phenols |
The unkindest cut: the BoE got it wrong
Below is a link to an article I wrote about the Bank of England’s aggressive 1.5% interest rate cut that appeared in yesterday’s Guardian newspaper.
The unkindest cut, GuardianThe long and short of it is that I am very skeptical about the need for such a large cut. Many pundits felt the BoE was behind the curve and needed to send a large signal. One such figure is Willem Buiter, a former BoE Monetary Policy Committee member. However, to my mind, the move has the faint whiff of panic to it.
Moreover, while interest rate policy can be beneficial in stimulating demand, it is a blunt instrument, carrying large unintended consequences. Just ask Alan Greenspan. If the UK authorities want to stimulate demand, a smaller cut coupled with increased government spending on infrastructure is preferable to such a massive move.
The ECB demonstrated again that it is more cautious and more prudent by only moving 50 basis points on the same day.
Edward Harrison is the founder of Credit Writedowns and a former career diplomat, investment banker and technology executive with over twenty five years of business experience. He has also been a regular economic and financial commentator in print and on television for the past decade. He speaks six languages and reads another five, skills he uses to provide a more global perspective. Edward holds an MBA in Finance from Columbia University and a BA in Economics from Dartmouth College.
Negative real interest rates are just about the most distortionary and damaging thing a central bank can foist upon a capitalist economy. It erodes the incentive to save, distorts bank balance sheets, and invariably leads to inflation.
hortonheardawho says 11 years ago
I would guess that the interest rate cut was to facilitate the rollover of existing debt. The alternative is a large number of defaults and a collapse of the house of cards. |
Q:
Boolean modifier is giving intersection instead of difference
I cannot get the boolean modifier right in the following file: para3.blend
What I want is to subtract the parabolic shape ("para") from the cube.
The cube is supposed to have some kind of trough after the operation.
A:
You need to unify the normal vectors of your parabola extrusion and then the boolean will display correctly.
To unify the normal vectors:
Select the parabola extrusion in the 3D view
Hit Tab to enter edit mode
Hit A to select all of the mesh
Hit CtrlN to recalculate the normals of the outsides
This makes all of the faces point in the same direction which is necessary for Boolean operations (and a lot of other stuff) to work correctly.
Hit Tab again to exit edit mode. You'll need to hide the 'Para' object to see the effect as shown.
|
Title: 怪兽哥斯拉又来啦-Firefox(Qt port)
Date: 2011-01-08 09:22
Author: gmsh
Category: News
Slug: firefoxqt-port
算是个好消息吧。自从 Firefox 3.5 开始停滞的 Qt port，又开始开发了。
无限意淫原生的 Qt-firefox 运行在 KDE 中的神韵 ：）
之前在 Firefox 4 b6pre 时，我编译的版本是网页可以显示，UI
烂的一塌糊涂，动不动就假死。现在又有开发的消息了。
以下是截图
[](http://linuxtoy.org/img/2011/01/firefox-qt4.png)
截图中给出了编译参数， 有兴趣的可以一试。也可以去
http://ftp.mozilla.org/pub/mozilla.org/firefox/tinderbox-builds/mozilla-central-linuxqt/
下载测试
消息来源<http://blog.johnford.info/linux-qt-builds-of-firefox-now-being-generated-2/>
|
Introduction {#Sec1}
============
The bronchial epithelium plays an important role in chronic airway inflammation, bronchial hyperreactivity and airway wall remodeling in allergic asthma^[@CR1],[@CR2]^. The respiratory epithelium forms an interface with the external environment and can be damaged by oxidative stress^[@CR3],[@CR4]^. Numerous studies have reported increased levels of reactive oxygen species (ROS) and decreased levels of antioxidants in asthmatic patients^[@CR5]--[@CR7]^. The susceptibility of airway epithelial cells to oxidative stress has been shown to increases with allergic sensitization, and exposure to allergens or environmental pollutant has been shown to increase airway inflammation^[@CR8]--[@CR10]^. Bronchial epithelial cells that produce proinflammatory signals in response to ROS may worsen the airway response and have been associated to the severity of asthma^[@CR11]--[@CR13]^.
Normal bronchial epithelial cells are relatively refractory to apoptotic stimulation when exposed to ROS and death receptor ligands secreted by inflammatory cells^[@CR14]^. However, abnormal apoptotic mechanisms which disrupt the bronchial epithelial barrier have been associated with the pathogenesis of asthma. Moreover, excess oxidative stress has been reported to result in chromatin dysfunction, apoptosis and necrosis with loss of columnar epithelial cells in asthma^[@CR14]--[@CR16]^.
Autophagy is an intracellular degradation mechanism that eliminates damaged organelles and promotes survival during starvation^[@CR17],[@CR18]^. Accumulating evidence suggests that autophagy can modulate cellular death, inflammation and immune function^[@CR17]--[@CR19]^, and that impaired autophagy may lead to accelerated senescence, neurodegenerative diseases, cancer and inflammatory bowel disease^[@CR20]--[@CR23]^. The integrity of the epithelial barrier depends on homeostatic regulatory mechanisms, and autophagy may protect against oxidative stress in respiratory diseases^[@CR24]--[@CR28]^.
The complement system has been reported to be locally and systemically activated to amplify inflammatory responses in allergic asthma^[@CR29],[@CR30]^. The complement regulatory protein CD46 is widely distributed in human leukocytes, epithelial cells and fibroblasts, and it has been shown to have a protective effect against autologous complement-mediated lysis at sites of inflammation^[@CR31],[@CR32]^. Complement regulatory proteins may interfere with oxidative stress-programmed apoptosis to avoid triggering inflammation. In addition, surface CD46 has been shown to be rapidly lost from apoptotic T cells to facilitate their rapid complement-mediated removal^[@CR33]^. Crosslinking CD46 during T-cell receptor activation has been shown to lead to the development of inducible T regulatory cells^[@CR34]--[@CR36]^, which may assist in maintaining immune tolerance in autoimmune diseases^[@CR37]^ and allergic asthma^[@CR35],[@CR36]^.
A high expressions of CD46 in chronic obstructive pulmonary diseases has been reported to protect against lung inflammation by T regulatory cells and restraining complement cascade-induced apoptosis^[@CR38]^. Autophagy is important for innate cellular defense against viral and bacterial pathogens. Two CD46-binding pathogens, measles virus and group A Streptococcus, have been shown to induce autophagy pathways^[@CR39],[@CR40]^. Targeting autophagy and apoptosis manipulating factors in inflamed respiratory epithelium is important to decrease ongoing damage in respiratory epithelium and consequent airway remodeling. In this study, we assessed the functional role of CD46 in respiratory epithelium with regards to autophagy and apoptosis in asthmatic patients. Our findings may provide further evidence regarding the practical application of CD46 in clinical practice to protect respiratory epithelium in patients with asthma.
Results {#Sec2}
=======
Decreased Expression of CD46 and Increased Apoptosis in the Damaged Nasal Epithelium of the Asthmatic Patients {#Sec3}
--------------------------------------------------------------------------------------------------------------
The patient characteristics are shown in Table [1](#Tab1){ref-type="table"}. To examine the relationship between CD46 and apoptosis in the respiratory epithelium, we analyzed the expression of CD46 and apoptosis in nasal epithelium samples from the normal controls and asthmatic patients who received nasal polypectomy. The area of intact epithelium of nasal biopsy samples taken from the normal controls showed mild immunoreactivity for CD46 (Fig. [1A](#Fig1){ref-type="fig"}). However, intact epithelium from the asthmatic patients showed strong immunostaining for CD46 (red arrow), and a decreased CD46 expression in desquamated nasal epithelium (Fig. [1A](#Fig1){ref-type="fig"}). Representative confocal microscopic analysis of the nasal mucosa biopsies between intact nasal epithelium (Fig. [1B](#Fig1){ref-type="fig"}) and fragile epithelium (Fig. [1C](#Fig1){ref-type="fig"}) from the asthmatic patients were shown. Confocal microscopic analysis of the nasal mucosa biopsies from the asthmatic patients revealed increased immunoreactivity for CD46 without TUNEL staining in intact epithelium (Fig. [1B](#Fig1){ref-type="fig"}). TUNEL-positive epithelial cells (yellow arrow) were detected with decreased immunoreactivity for CD46 in fragile epithelium in the asthmatic patients (Fig. [1C](#Fig1){ref-type="fig"}). Experiments were performed with 10 paired samples, and the results showed significant statistical differences (*p* \< 0.05) (Fig. [1D,E](#Fig1){ref-type="fig"}).Table 1Patient characteristics.Asthmatic groupControl groupNumber of patients6030Mean age (years)46.6 ± 16.346.4 ± 13.0Gender (M:F)46:2419:11Der p-specific IgE (kU/l)66.5 ± 21.1NDMean FEV1 (%)89.3 ± 7.9793.5 ± 5.31ND: Not Detectable.Figure 1Increased apoptosis and decreased CD46 in the nasal mucosa of the asthmatic patients. (**A**) CD46 expression (red arrow) was increased in the asthmatic patients (n = 10) compared with the healthy controls (n = 10) as shown by immunohistochemical staining. Epithelial cell shedding and a decreased expression of CD46 (red arrow) were noted in the fragile epithelium of the asthmatic patients (n = 10). Representative confocal microscopic analysis between intact nasal epithelium (**B**) and fragile epithelium (**C**) from the asthmatic patients. Primary nasal epithelium biopsy stained with TUNEL (FITC), CD46 (PE), and 4′,6-diamidino-2-phenylindole (DAPI) (nuclear stain). The yellow arrows indicate TUNEL-positive cells. Decreased CD46 expression and increased TUNEL staining in the fragile upper airway epithelial cells are shown. Scale bar, 20 um. (**D**,**E**) Statistical data of 10 paired experiments between intact and fragile epithelium from asthmatic patients for the number of CD46 and TUNEL-positive cells (% epithelial cells stained) per high-power field. The Kruskal-Wallis test was used. \**p* \< 0.05.
Decreased CD46 and Increased *Dermatophagoides pteronyssinus* 2-mediated Cell Death of the Primary Epithelial Cells from the Asthmatic Patients {#Sec4}
-----------------------------------------------------------------------------------------------------------------------------------------------
To evaluate the role of CD46 in the pathogenesis of respiratory epithelium apoptosis, we evaluated the CD46 expression with mite allergen-induced epithelial cell death in the asthmatic patients. *Dermatophagoides pteronyssinus* 2 (Der p 2) is the major allergen in Taiwan. It contains a cysteine protease which may cause proteolysis of CD46 with a subsequent increase in the apoptosis of respiratory epithelial cells^[@CR35]^. After Der p 2 stimulation, the expressions of the apoptosis markers with cleaved CASPASE-3A and CD46 were analyzed in primary nasal epithelial cells from the asthmatic patients. A decrease in the expression of CD46 was noted in the epithelial cells (Fig. [2A](#Fig2){ref-type="fig"}), with an increase in the expression of cleaved CASPASE-3A (as shown by Western blotting; Fig. [2B](#Fig2){ref-type="fig"}) in the asthmatic patients (*p* \< 0.05). Experiments were performed with 30 paired samples, and the statistical results are shown in Fig. [2C,D](#Fig2){ref-type="fig"}.Figure 2Analysis of CD46 and cleaved CASPASE-3A activity from Der p 2-mediated apoptosis of primary upper airway epithelial cells in the asthmatic patients and control subjects. (**A**) Primary nasal epithelial cells from the asthmatic patients stimulated with Der p 2 (10 μg/ml) and CD46 expression analyzed at 12, 24 and 48 hours by flow cytometry. Representative profiles are shown. (**B**) Western blot analysis was performed to detect CD46 and cleaved CASPASE-3A activity from Der p 2-treated epithelial cells for 48 hours from the asthmatic patients and control subjects. Statistical data of 30 paired experiments between asthmatic patients and control subjects for the expressions of CD46 (**C**) and cleaved CASPASE-3A (**D**) after Der p 2 stimulation for 48 hours. The Kruskal-Wallis test (among multiple groups) and Wilcoxon signed ranked test (after Der p 2) were used. *\*p* \< 0.05 after Der p2 and ^\#^*p* \< 0.05 compared to the control group.
Autophagy Induced by CD46 Antibody Activation in Normal and Asthmatic Epithelial Cells {#Sec5}
--------------------------------------------------------------------------------------
Engagement of CD46, a ubiquitous human surface receptor able to bind several different pathogens, can induce autophagy to control infection^[@CR39]^. To further investigate the role of CD46 in the autophagy of respiratory epithelium, we examined whether antibody-driven CD46 crosslinking could induce the formation of autophagosomes. Crosslinking CD46 mAb at the surface of primary nasal airway epithelial cells induced macropinocytosis-like internalization, and led to the degradation of the cell surface of CD46 via the same molecular mechanism as the CD46 ligand (Supplement Fig. [1](#MOESM1){ref-type="media"}). CD46 mAb crosslinking increased the number of GFP-LC3 (autophagosomes) puncta per cell (Fig. [3A](#Fig3){ref-type="fig"}) in epithelial cells from the asthmatic patients and controls. Quantification of GFP-LC3 puncta per cell was assayed, and the statistical data are shown in Fig. [3B](#Fig3){ref-type="fig"}. We monitored autophagy following the conversion of LC3-I to LC3-II by Western blot of the epithelial cell lysates. The presence of CD46 resulted in an increase in LC3-II in cell lysates compared to IgG control cells (Fig. [3C](#Fig3){ref-type="fig"}). The statistical data of experiments with 30 paired samples are shown in Fig. [3D](#Fig3){ref-type="fig"} (p \< 0.05). To determine whether autophagosome detection subsequent to CD46 engagement was the result of an increase in autophagic flux or an accumulation of basal autophagosomes, we analyzed autophagy in the presence of lysosomal inhibitors with bafilomycin. We found that crosslinking CD46 mAb induced autophagy marker with LC3-II (*p* \< 0.05) during bafilomycin clamp in primary nasal epithelial cells from the asthmatic patients as shown in Fig. [3E,F](#Fig3){ref-type="fig"}.Figure 3CD46 induced autophagy in primary upper airway epithelial cells from the controls and asthmatic patients. Cells were incubated for 4 hours in complete medium in the presence of anti-CD46 mAb (5 μg/ml), isotype control antibody (IgG), or in nutrient-deprived media (starvation) and/or the autophagy inhibitor 3-methyladenine (3-MA) (10 mmol/L) (Sigma-Aldrich, St. Louis, MO). (**A**) Representative images of GFP-LC3 puncta (autophagosomes) in nasal epithelial cells are shown by confocal microscopy. (**B**) The cytosolic soluble form of LC3-I was converted into the autophagic vesicle-associated form of LC3-II and was used as a marker of autophagosome formation. The number of GFP-LC3 vesicles per cell in primary nasal epithelial cells was calculated from 200 cells for each experiment. Quantification of GFP-LC3 puncta per cell was assayed and the statistical data are shown. (**C**) Immunoblotting was used to analyze the LC3- II expression in primary upper airway epithelial cells from the controls and asthmatic patients. (**D**) Statistical data of the experiments with 30 paired samples as shown. (**E**) Primary nasal epithelial cells from the asthmatic subjects were treated with bafilomycin, and immunoblotting was used to analyze the expressions of LC3-II. (**F**) Statistical data of the experiments with six paired samples as shown. The Kruskal-Wallis test was used to determine significant differences. \**p* \< 0.05.
Crosslinking CD46 Antibody Mediated Autophagy Against Hydrogen Peroxide-induced Apoptosis in Normal and Asthmatic Epithelial Cells {#Sec6}
----------------------------------------------------------------------------------------------------------------------------------
To evaluate the protective role of CD46-induced autophagy in the prevention of respiratory epithelium apoptosis in asthma, we evaluated hydrogen peroxide-induced epithelial cell death from CD46 mAb co-cultured with the autophagy inhibitor 3-methyladenine (3-MA). In analysis of the hydrogen peroxide-mediated cells with annexin V expression, the percentage of apoptosis of CD46 mAb-pretreated primary nasal epithelium cells from the asthmatic patients was decreased compared with the IgG control group in asthmatic patients (3.3 ± 1.8% vs. 7.3 ± 2.2%, *p* \< 0.05) (Fig. [4A,B](#Fig4){ref-type="fig"}). The extent of cell death was further increased when CD46-induced autophagy was inhibited with 3-MA treatment (3.3 ± 1.8% vs. 6.4 ± 2.0%, *p* \< 0.05). Experiments were performed with 30 paired samples, and the statistical data are shown in Fig. [4B](#Fig4){ref-type="fig"}.Figure 4CD46 induced autophagy against H2O2-induced airway epithelial cell apoptosis in the controls and asthmatic patients. (**A**) To detect the role of CD46-induced autophagy in early apoptotic cells with Annexin V-positive but PI-negative primary nasal epithelium cells after exposure to hydrogen peroxide, a FITC Annexin V/propidium iodide Apoptosis Detection Kit I (BD Pharmingen, USA) was used. CD46 mAb (5 μg/ml) and/or autophagy inhibitor 3-methyladenine (3-MA) (10 mmol/L) (Sigma-Aldrich, St. Louis, MO) was co-incubated with primary nasal epithelium cells (1 × 10^5^ cells) from the asthmatic patients and then cultured with H2O2 (0.5 mM) for 1 hour followed by 8 hours recovery. Representative figures are shown. (**B**) Statistical data of the experiments with 30 paired samples. The Kruskal-Wallis test was used to determine significant differences. \**p* \< 0.05 after treatment and ^\#^*p* \< 0.05 compared to the control group.
CD46 Antibody Inhibited 8-OHdG, IL-1β and IL-6 from Hydrogen Peroxide-induced Epithelial Cells {#Sec7}
----------------------------------------------------------------------------------------------
The levels of 8-OHdG, IL-1β and IL-6 in the supernatant from CD46 mAb-pretreated primary nasal epithelium cells from the asthmatic patients after exposure to H2O2 were analyzed using ELISA. The results showed decreased levels of 8-OHdG (Fig. [5A](#Fig5){ref-type="fig"}), IL-1β (Fig. [5B](#Fig5){ref-type="fig"}) and IL-6 (Fig. [5C](#Fig5){ref-type="fig"}) compared with the IgG control group (*p* \< 0.05).Figure 5CD46 inhibited IL-1β and IL-6 from H2O2-activated airway epithelial cells from the asthmatic patients. Supernatant from anti-CD46 mAb (5 μg/ml)-pretreated primary nasal epithelium cells from the asthmatic patients after exposure to H2O2 (0.5 mM) was analyzed using 8-OHdG (**A**) and IL-1β (**B**) and IL-6 (**C**) ELISA-based systems. The Kruskal-Wallis test was used. Statistical data of the experiments with 30 paired samples are shown. *\*p* \< 0.05.
Silencing *ATG5* Decreased CD46-activated Autophagy in A549 Cells {#Sec8}
-----------------------------------------------------------------
A549 cells were transfected with siRNA targeting human *ATG5* or control siRNA and incubated with anti-CD46 mAb, isotype control antibody (IgG), or in nutrient-deprived media (starvation). Proteins were extracted from the A549 human lung epithelial cells and analyzed by Western blotting (Fig. [6](#Fig6){ref-type="fig"}). The reduced expression of the *ATG5* gene for autophagy using short siRNA prevented CD46-induced and starvation-induced autophagy with LC3-II (Fig. [6](#Fig6){ref-type="fig"}).Figure 6Silencing ATG5 decreased CD46-activated autophagy in A549 cells. A549 cells were transfected with small interfering RNAs (siRNA) targeting human ATG5 or control siRNA. The A549 cells were incubated for 4 hours in complete medium in the presence of anti-CD46 mAb (5 μg/ml), isotype control antibody (IgG), or in nutrient-deprived media (starvation). Proteins were extracted from the A549 cells and analyzed by Western blot using anti-ATG5 mAb, anti-LCB3-1 mAb, anti- anti-LCB3-2 mAb. The Kruskal-Wallis test was used to determine significant differences. Statistical data of the experiments are shown. *\*p* \< 0.05 after siRNA and ^\#^*p* \< 0.05 compared to the IgG group.
Crosslinking CD46 Antibody Enhanced GOPC and Inhibited PRO-IL-1β and NLRP3 Expressions from H2O2-activated A549 Cells {#Sec9}
---------------------------------------------------------------------------------------------------------------------
To evaluate the mechanism of CD46-induced autophagy in the respiratory epithelium, we examined whether CD46 crosslinking by mAb could induce induction of the scaffold protein GOPC. We demonstrated that crosslinking of CD46 by the specific mAb could induce the expression of GOPC in human lung epithelial A549 cells (*p* \< 0.05) (Fig. [7A](#Fig7){ref-type="fig"}). To investigate the mechanism by which CD46-induced autophagy reduced IL-1β, we evaluated the expressions of pro-IL-1β and NLRP3 inflammasome in an H2O2-induced epithelial cell model in the presence of anti-CD46 mAb and/or the autophagy inhibitor 3-MA. The expressions of PRO-IL1β and NLRP3 in the H2O2-activated A549 cells were reduced in the presence of anti-CD46 mAb, and 3-MA treatment reversed this effect (*p* \< 0.05) as shown in Fig. [7B](#Fig7){ref-type="fig"}.Figure 7CD46 enhanced the expression of GOPC and inhibited the expressions of PRO-IL-1β and NLRP3 in H2O2-activated A549 cells. (**A**) A549 cells were incubated for 4 hours in complete medium in the presence of anti-CD46 mAb (5 μg/ml), or isotype control antibody (IgG). Immunoblotting of anti-GOPC mAb was used to analyze the GOPC expression. Statistical data of experiments on six paired samples are shown. \**p* \< 0.05 (**B**) The anti-CD46 mAb (5 μg/ml)-pretreated A549 cells after exposure to H2O2 (0.2 mM) and cultured with the autophagy inhibitor 3-methyladenine (3-MA) (10 mmol/L) were analyzed by Western blot using anti-IL-1β mAb and anti-NLRP3 mAb. The Kruskal-Wallis test was used to determine significant differences. Statistical data of experiments with six paired samples are shown. *\*p* \< 0.05.
Discussion {#Sec10}
==========
The results of the present study showed a significantly increased surface expression of the complement regulatory protein CD46 in nasal epithelium from asthmatic patients compared to healthy subjects. In addition, there was an increase in apoptosis with a decrease in CD46 expression in fragile epithelium from the asthmatic patients, and a decrease in the expression of CD46 and increase in the expression of cleaved CASPASE-3A in Der p 2-cultured primary epithelial cells. CD46 crosslinking could induce the formation of autophagosomes and LC3-II expression in primary respiratory epithelium cells. Furthermore, CD46 mAb suppressed hydrogen peroxide-induced epithelial cell apoptosis, and treatment with the autophagy inhibitor 3-MA reversed this effect. CD46 also decreased the hydrogen peroxide-induced production of 8-OHdG, IL-1β and IL-6 from the epithelial cells. In addition, silencing ATG5 in A549 cells decreased CD46-activated autophagy with LC3-II expressions. Taken together, these results suggest that CD46 could induce autophagy and decrease oxidative stress-mediated apoptosis in respiratory epithelium, and this may offer a new potential therapeutic strategy to treat allergic asthma.
Numerous studies have reported that ROS can increase airway inflammation, and that modification of airway oxidative stress may affect the pathological features of asthma^[@CR3]--[@CR13]^. It has also been reported that asthmatic airway epithelial cells are susceptible to oxidative stress, and that cumulative oxidative damage contributes to apoptosis in epithelium lining asthmatic airways^[@CR16]^. Complement has emerged as an important factor in the pathophysiology of asthma, and the identification of complement split products at the airway surface has been shown to be a common pathway for the induction of Th2-mediated inflammatory responses^[@CR29],[@CR30]^. CD46 acts as 'don't-eat me' signal and is down-regulated during apoptosis, and this leaves cells less protected against complement activation by oxidative stress^[@CR33],[@CR41]--[@CR43]^. It is known that respiratory epithelial cells express membrane-bound complement regulatory protein (CD46) to prevent complement-mediated autologous tissue damage. Mahtout *et al*. reported that *Porphyromonas gingivalis*, a major etiological agent of chronic periodontitis, causes shedding of CD46 expressed by epithelial cells^[@CR44]^. The allergen *Dermatophagoides pteronyssinus* 2 contains a cysteine protease, and it may cause proteolysis of CD46 with a subsequent increase in the apoptosis of respiratory epithelial cells.
Studies on bronchial epithelial cells in asthmatic patients are hampered by difficulties in obtaining suitable human samples. The concept of a "united airway disease" has been proposed between allergic rhinitis and asthma. Nasal epithelial cells have been used as surrogates for lower airway cells in which nasal and bronchial cells have a similar morphological appearance and uniform cytokine expressions^[@CR45]^. Varsano *et al*. demonstrated that the normal human respiratory tract from the nose to the alveoli expresses CD46, and that this expression was increased during inflammation and retained under cell culture conditions^[@CR46]^. We also found that the expression of CD46 increased in asthmatic respiratory epithelium. In addition, we also detected apoptosis of the fragile respiratory epithelium concurrently with a decrease in CD46 expression. Furthermore, primary nasal epithelial cells were susceptible to mite allergen-induced apoptosis following a decrease in CD46 expression. This suggests that CD46-inhibited oxidant-induced apoptosis may offer a new strategy to treat lung injuries linked to oxidative stress in asthma.
Many studies have established an important crosslink between oxidative stress and autophagy in the pathogenic processes of asthma^[@CR26],[@CR27]^. Poon *et al*. reported an increase in autophagy in human bronchial tissues of patients with asthma, and suggested an association between autophagy and reduced lung function in patients with moderately severe asthma^[@CR47]^. In addition, an experimental mice model showed that autophagy protein-deficient bronchial epithelial cells were hyperresponsive to methacholine exposure, and that this contributed to smooth muscle hyperreactivity^[@CR48]^. However, to date, no studies have documented the autophagy regulation of respiratory epithelium cells by CD46 stimulation. Importantly, we found that CD46 mAb could induce the formation of autophagosomes and LC3-II expression in primary respiratory epithelium cells. It is therefore reasonable to assume that increased autophagy would be necessary for epithelial apoptosis. Our results showed that hydrogen peroxide promoted epithelial apoptosis and that this was blocked by anti-CD46 mAb. In addition, we showed that treatment with the autophagy inhibitor 3-MA decreased the anti-apoptosis effects. These findings may help to explain the survival mechanisms by which CD46-activated autophagy plays a key role in the respiratory homeostatic mechanism that facilitates immune tolerance and establishment of respiratory tract integrity.
Several studies have reported that *ATG5* gene polymorphisms are associated with childhood asthma^[@CR28],[@CR49]^, and that the expression of the *ATG5* gene is increased during acute asthma exacerbations in nasal epithelial cells^[@CR49]^. Joubert *et al*. first demonstrated that crosslinking CD46 agonist antibodies (mAb) can directly trigger autophagy through ATG5^[@CR39]^. The molecular pathway by which CD46 induces de novo formation of autophagosomes relies on the scaffold protein GOPC^[@CR39]^. We further demonstrated that CD46 crosslinking by agonist antibodies induced the expression of GOPC in human lung epithelial A549 cells. Furthermore, we found that silencing *ATG5* in human lung epithelial A549 cells decreased CD46-activated autophagy with LC3-II. Therefore, we suggest that ATG5 plays an important role in the ability of respiratory epithelium to increase autophagy and protect against asthma.
During epithelial injury caused by oxidative stress in asthma, the epithelium becomes an important source of inflammatory cytokines that contribute to ongoing inflammation and airway remodeling^[@CR13],[@CR50]^. Autophagy can directly regulate the secretion of cytokines, and disruption of normal autophagy pathways by ROS has been linked with increased secretion of the proinflammatory cytokine IL-1β^[@CR51],[@CR52]^. Harris *et al*. demonstrated that autophagy controls IL-1β production through at least two separate mechanisms: by decreasing activation of the NLRP3 inflammasome, and by regulating PRO-IL-1β for lysosomal degradation^[@CR50]^. We found that CD46 could decrease H2O2-induced oxidative stress through 8-OHdG and the production of the inflammatory cytokines IL-1β and IL-6 from epithelial cells. We further demonstrated that CD46-induced autophagy inhibited IL-1β by H2O2-activated airway epithelial cells due to a decrease in the expressions of PRO-IL-1β and NLRP3. Therefore, CD46 may be effective in ameliorating asthmatic airway diseases through modulating the autophagy signaling pathway.
In conclusion, we found that CD46 was a target antagonizing the apoptosis of oxidative stress-associated respiratory epithelial cells through autophagy. Further studies are needed to clarify the effect of autophagy in asthma and the effect of modulating CD46 on lower airway inflammation. These findings may provide further evidence regarding the practical application of CD46 in clinical practice as a treatment for asthma.
Materials and Methods {#Sec11}
=====================
Subjects {#Sec12}
--------
A total of 60 adult patients with mild intermittent asthma with concomitant rhinitis and sensitivity to house dust mites (Der p) as proven by an IgE specific test result greater than third grade (\>3.5 kU/L) using a CAP system (Pharmacia, Uppsala, Sweden) who were referred for turbinectomy were enrolled in this study. The asthmatic patients in our study were initially diagnosed at the study hospital. Definition of mild asthma was based on symptoms and a forced expiratory volume in 1 s (FEV1) of ≥80% according to the Global Initiative for Asthma guidelines. Surgery was performed under strict clinical indications, and all patients had difficulty in nose breathing. The samples obtained from the asthmatic patients were randomly subdivided into different treatment groups for immunohistochemistry, confocal immunofluorescence, flow cytometry and Western blot analysis. Healthy controls (n = 30) with normal serum IgE levels who visited the hospital for reasons unrelated to the study were enrolled as controls. Patients with either congenital or acquired immune deficiency and who were receiving systemic immune suppressive therapy were excluded. Nasal and inhaled corticosteroid treatment was stopped 4 weeks before surgery. Informed consent was obtained from each subject before participating in the study. The study was approved by the Institutional Review Board (No:101103) of Changhua Christian Hospital, and all methods were performed in accordance with the relevant guidelines and regulations.
Tissue Sample, Cells, Antibodies and Reagents {#Sec13}
---------------------------------------------
Nasal biopsy specimens were cut into small pieces and placed in trypsin (0.025%)/EDTA (0.01%; Gibco, Grand Island, NY) for 3 hours at 37 °C and 5% CO~2~. Cells were strained through 70-mm nylon mesh (Becton Dickinson Labware, Franklin Lakes, NJ), washed, seeded at a density of 4 × 10^3^ cells/cm^2^ in T-75 cell culture flasks (Hyclone, GE Healthcare, USA), and cultured in bronchial epithelial cell medium (Hyclone) supplemented with 100 U/mL penicillin, 100 mg/mL streptomycin, and 0.25 mg/mL amphotericin B (Gibco) in a humidified atmosphere containing 5% CO~2~ at 37 °C. Confluent monolayer primary nasal epithelial cells or A549 cells (human bronchial epithelial cell line, American Type Culture Collection, Rockville, MD) were cultured with or without anti-human CD46 mAb (5 ug/ml) (Clone: MEM-258) (GeneTex, San Antonio, Texas, USA) in RPMI-1640 medium containing 10% fetal bovine serum (Gibco). Recombinant *Dermatophagoides pteronyssinus* 2 (Der p 2) (Indoor Biotechnologies, Cardiff, UK) served as the allergen. The following antibodies were used for Western blot analysis: anti-human CD46 mAb (Genetex), anti-cleaved CASPASE 3 A (Genetex), anti-ATG5 mAb (Genetex), anti-LCB3-I mAb (Genetex), anti-LCB3-II mAb (Novus Biologicals, Littleton, CO), anti-GOPC mAb (Genetex), anti-IL-1β mAb (Abcam, Cambridge, MA), anti-NLRP3 mAb (Genetex), IgG (Abcam) and β-ACTIN (Abcam).
Histology and Immunohistochemistry {#Sec14}
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Paraffin-embedded nasal tissue samples were soaked in xylene and then sequentially in solutions of 100%, 95%, and 70% ethanol to remove the paraffin wax and for rehydration. Antigen unmasking was performed by heating the slides in retrieval buffer, and then cooled to room temperature. H2O2 block (Lab Vision, Fremont, CA) and protein block (Lab Vision, Fremont, CA) were then applied to the tissues to prevent non-specific protein binding and to block endogenous peroxidases. Rabbit monoclonal anti-human CD46 antibody (GeneTex) was diluted 1:500 with antibody diluent (Lab Vision, Fremont, CA) and applied to the tissues for 30 minutes at room temperature. Immunohistochemical staining was performed using an UltraVision Quanto Detection System HRP (Thermo Fisher Scientific, Waltham, MA). Visualization was achieved using the diaminobenzidine (DAB) method. Slides were counterstained with hematoxylin.
Confocal Immunofluorescence {#Sec15}
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Cells were incubated with diluted Autophagy Reagent A according to the manufacturer's recommendations in a FlowCellect™ Autophagy LC3 Antibody-based Assay Kit (Millipore, Billerica, MA). This kit contains two key detection reagents to help facilitate the monitoring of lipidated LC3-II in a given cell system. Briefly, the use of selective permeabilization solution discriminates between cytosolic LC3 from autophagic LC3 by extracting the soluble cytosolic proteins, while protecting LC3 which has been sequestered into the autophagosome. Primary nasal epithelial cells were incubated with Reagent A at 37 °C and 5% CO~2~ for 60 min. Cells were washed and resuspended in 100 μL of Reagent B, centrifuged immediately, and resuspended in 100 μL of Assay buffer with 1:20 diluted FITC-conjugated anti-LC3 antibody. LC3-II was photographed live on a Confocal Olympus FV1200 fluorescent microscope. The number of GFP-LC3 vesicles in primary nasal epithelial cells was calculated from 200 cells for each experiment. Quantification of GFP-LC3 puncta per cell was assayed. For terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) assay, we used an ApopTag Plus Peroxidase *In Situ* Apoptosis Detection Kit (Takara, Shiga, Japan) according to the manufacturer's instructions. In order to detect apoptosis of CD46-expressing cells, confocal microscopic analyses between intact and fragile primary nasal epithelium with TUNEL (FITC), CD46 (PE), and 4′,6-diamidino-2-phenylindole (DAPI) (nuclear stain) were performed. To evaluate whether CD46 crosslinking could induce autophagy in primary upper airway epithelial cells, epithelial cells were incubated for 4 hours in complete medium either in the presence of anti-CD46 mAb (5 μg/ml), isotype control antibody (IgG), or in nutrient-deprived media (starvation), and quantification of GFP-LC3 puncta (autophagosomes) in the nasal epithelial cells was performed using confocal microscopy.
Flow Cytometry and Annexin V/Propidium Iodide Double Staining {#Sec16}
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To detect the role of CD46-induced autophagy in primary upper respiratory epithelial cells after exposure to hydrogen peroxide, an FITC Annexin V/propidium iodide Apoptosis Detection Kit I (BD Pharmingen, USA) was used. Anti-CD46 mAb (5 μg/ml) and/or autophagy inhibitor 3-methyladenine (3-MA) (10 mmol/L) (Sigma-Aldrich, St. Louis, MO) was co-incubated with primary nasal epithelial cells (1 × 10^5^ cells) and then cultured with H2O2 (0.5 mM) for 1 hour, followed by 8 hours recovery. The treated cells were then stained with propidium iodide and Annexin V-FITC for 15 minutes according to the manufacturer's instructions, and then subjected to flow cytometry analysis (FC500, Beckman Coulter, Fullerton, CA).
Enzyme-Linked Immunosorbent Assay (ELISA) {#Sec17}
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The concentrations of IL-1β and IL-6 in cell supernatants were determined using a commercially available ELISA-based assay system (R&D Systems, London, UK). The expression of the oxidative stress marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) induced by oxygen radicals was measured using a highly sensitive 8-OHdG ELISA kit (JalCA, Fukuroi, Shizuoka, Japan). Supernatant from anti-CD46 mAb (5 μg/ml) pretreated primary nasal epithelium cells from the asthmatic patients after exposure to H2O2 (0.5 mM) were analyzed with 8-OHdG and IL-1β and IL-6 ELISA-based systems.
Gene Silencing {#Sec18}
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The mechanism of the CD46 mAb-mediated de-novo formation of autophagosomes has been shown to be regulated by *ATG5* gene-induced autophagy^[@CR39]^. Small interfering RNAs (siRNAs) targeting human *ATG5* (Sense: (5′-\>3′) GAACCAUACUAUUUGCUUUtt; and Antisense: AAAGCAAAUAGUAUGGUUCtg) or control siRNA (GeneDirex) were purchased from Cell Signaling Technology. Cells were transfected using the siRNA transfection reagent Lipofectamine™ RNAiMAX according to the manufacturer's instructions (Invitrogen, Carlsbad, CA). Diluted siRNA (final = 20 nM) added in 2 ml Opti-MEM I Medium (Invitrogen, Carlsbad, CA) without serum in the 100 mm culture plate. Mixed gently (30 µl Lipofectamine™ RNAiMAX to each well containing the diluted siRNA molecules) and incubate for 20 minutes at room temperature. A549 cells (1 × 10^5^ cells/mL) solution in antibiotic-free complete medium and mixed with siRNA- Lipofectamine™ RNAiMAX complexes after 24 hours, replace the transfection medium with complete medium and continue incubation 72 hours for assay.
Western Blot Analysis {#Sec19}
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Protein levels of CD46, cleaved CASPASE 3A, ATG5, LCB3-I and LCB3-II, GOPC, PRO-IL-1β and NLRP3 were determined by Western blot analysis. Equal amounts of proteins in each study groups were ascertained using a Bio-Rad protein assay kit (Bio-Rad, Hercules, CA). Cellular proteins were resolved by 10% SDS-polyacrylamide gel. After electrophoresis, protein levels were determined by Western blot analysis.
Statistical analysis {#Sec20}
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All data were presented as mean ± SD. As the continuous variables were not in normal distribution, nonparametric statistics including the Wilcoxon rank-sum test was used for comparisons. Groups of datasets in each treatment group were compared using the Kruskal-Wallis test, followed by the Duncan test. A *p* value less than 0.05 was considered to be statistically significant.
Electronic supplementary material
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{#Sec21}
Supplement figures
**Publisher\'s note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yung-Sung Wen, Jiu-Yao Wang and Kuender D. Yang contributed equally.
Electronic supplementary material
=================================
**Supplementary information** accompanies this paper at 10.1038/s41598-018-31317-5.
This work was supported in part by grants from the Ministry of Science and Technology, Taiwan, ROC (MOST 103-2314-B-371-006 and 106-2314-B-371-008 and MOST 107-2314-B-371-011-MY2) and Changhua Christian Hospital(Y_104_0252 and Y_104_0127 and Y_105_0246 and Y_105_0023 and Y_105_0050).
Drs Y.G.T., Y.S.W., J.H.L. and C.Y.L. conceptualized and designed the study, performed the experiments, drafted the initial manuscript, and approved the final manuscript as submitted. Drs K.D.Y., J.Y.W. and H.L.S. carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
Competing Interests {#FPar1}
===================
The authors declare no competing interests.
|
歡迎光臨shielis41在痞客邦的小天地
I bet once you woke up this morning, you had a beautiful honourable mental object of how your day would unfold. You'd give somebody a lift a shower, go to work, view tv - whatever it is you habitually do minus much initiative. It's features of like mortal on autopilot. You already know indisputable trial will transpire, even up to that time they happen. What we normally forget though, is thatability we are unremittingly fashioning choices - roughly speaking Everything - even if those choices are passive, and even once we don't mull over we have any judgment at all.
So what juncture do you disrespectful on the autopilot electrical switch in the morning? If you're look-alike peak people, likelihood are this happens location betwixt the short while your thought start to once you're brush your teeth! We kick into the flow, category of same awheel a breeze, not quite sure wherever we'll end up - perceptive and reacting during the course of instruction of our day - and once it's over, we're recurrently left moving and de-stressing, so we can do it all once again mean solar day. Sounds like fun, no?
Don't get me wrong, there's a lot to be aforementioned for a homelike repeated. Going beside the go is fabulous - as yearlong as you've pre-pavedability your end. And definite conduct ladle us in good health (i.e. exploit dressed, ingestion meals, etc). If we were to truly engrossment on everything, we credible wouldn't have the activeness to set up those material possession which are truly principal to us. The trouble arises still once our full day passes as a variety of involuntary darken - once we make a contribution the identical soft publicity to moments thatability could be life-transformingability as we do to hair care our pelt.
Remember, once it comes to Law of Attraction, what you snap your zest and engrossment to is what you get. Everything you have in your duration accurately now, you have created - the good, the bad, and the workaday. So the request for information deserving interrogative is "Do you have everything you want?" If you do, you in all probability don't need to publication any further. But if you have this reaction thatability in attendance may possibly be something more - something that, should it 'pop,' would brand your being violently fulfillingability - later sustenance reading, because it won't nick a giant application to step what shows up in your existence.
One technique I use to stopover the stencil of aware by failure to pay - and embezzle fund the controls of my vivacity - is attractive 5-10 minutes up to that time I go to sleep to 'create my day' (those of you who have seen 'What The Beep Do We Know' may be acquainted with next to the posit). I slog next to iv clean-cut areas in being which are historic to me - career, health, relationships, and material possession (you can manual labour beside any, and as many areas as you wishing). I consciously let the Existence cognise what I desire to have start in respectively region for the following day (of course, you can do this in the antemeridian once you stir up if you like). Once I'm complete, I let everything go, disappearing the 'hows' to the World. That's a unfavorable splinter to the Law of Appeal problem. Your solely job is to allege what you want, and judge you will acquire it. Then it's up to the Universe to verbalize it in the high-grade way attemptable.
Now if this sounds at all look-alike meditation, it is - kind of. But for those of you who twinge at the specified bring up of 'meditation', I'll let you in on a in person covert. Meditatingability (in the conventional undergo) holds just about as a great deal ecstasy for me as watching turf bud. All I'm unsophisticatedly doing is taking a few minutes to consciously focus, and truly get in air beside what I want. By doing so, I'm raising my wave stratum in dictation to like a shot plain what I whim. In fact, any instance you brainstorm yourself off course during your day, it helps to bring out yourself rear legs to the query "What do I want?" Once you do, you'll brainstorm your shaking well-nigh directly leaps to high terrain.
Once you get into the tradition (see, customs can be good!) of creatingability all day, you'll insight the international will corroborate up otherwise for you. At first, the changes may give the impression of being elusive - slim 'coincidences' you see thatability distribute you a little bit human to what you've asked for. Next to every fine-tuning, those teensy dealings will get larger serendipitiesability. It will consciousness like the Universe is protection up for you, birthing fallen a red carpet, and invitatory you to tactical maneuver readdress. It's not magic, but it can definitely surface thatability way!
So flippingability the electrical switch - moving from unconsciousness to winning calmness of you existence - is in fact massively basic. It lonesome requires several awake creation, paid fame to what unfolds about you, past attractive accomplishment which moves you soul to all you desire. The nice piece going on for Law of Glamour is you've pretty substantially been doing this all along - remember, you've already been attracting everything - the variation is now you turn a intended creator, instead than travel your fingers and hoping material possession curved shape out ok. I can generate you a guarantee: no concern what you do, material possession will always rotate out ok. But once you harness Law of Attraction, you increase the ascendancy to build exactly what you want. So snatch the controls and genuinely fly! |
What would happen if you took a group of healthy, young people and subjected them to months of sleep deprivation, piles of work, extreme pressure to succeed and hazing from superiors and peers? Oh, and during that time, a single mistake could mean the difference between saving a life or inadvertently killing someone.
That's basically what happens for thousands of Americans each during their medical internship.
After medical school, which itself is super stressful, graduates spend about two years practicing under supervision at a hospital. Reports have shown that many of them face depression, anxiety and other mental health issues.
University of Michigan researchers have been studying the problem for more than a decade, enrolling over 2,000 medical interns from schools around the country every year, then studying how they fare over time.
"During the first year of training, rates of depression [go] up, risk of suicide goes up, anxiety goes up and part of what we're studying is why that is and who's at risk and what environmental elements put them at risk," Dr. Srijan Sen, professor of depression and neurosciences, said in an interview with CNBC.
The problem seems to start in medical school, where a survey found that roughly 10 percent of students had thought about killing themselves within the previous year. This population also suffers from suicide at rates 15 to 30 percent higher than the general population. It continues, and for some gets a lot worse, during the internship.
"We find that many of the interns start out fine, and about half get depressed by the end of the year," said Sen.
Now the study is getting a technology boost. The interns are getting a Fitbit.
Fitbit got involved with the study through its own research efforts, which involve looking at consumer-generated data for signals of depression. The company thinks its data could be useful in analyzing things like sleep interruptions and varying activity levels, which might contribute to mental health problems. If an intern is running on particularly low levels of sleep and exercise, a Fitbit could pick it up.
"We see indications that sleep can get pretty erratic, especially for medical interns who are shift workers," said Jonathan Charlesworth, a research scientist at Fitbit and a trained neuroscientist. "We're seeing that correlate to depressive symptoms." |
"Inspired by actual events" "My name is Thorkild Bonnesen." "I'm 47 years old." "And I just emptied a bottle of whisky." "I'm not dancing because I'm celebrating anything." "On the contrary." "I've lost everything." "And I haven't even hit rock bottom yet." "To fall so low you've got to start at the top." "Let's go one year back." "I had it all." "A big Jaguar, a mobile phone..." "Do you hear me?" "I'll try going over here." "... a big mansion and a lovely lady." "Black, even." "Grace." "Grace!" "No!" "We met in Ghana." "I had to give her dad a cow for him to allow the marriage." "I was on top of the world." "But the '80s had only just begun." "1983 is going to be a good year." "I was making a bundle as head of a large Danish electronics company." "But a new market is emerging." "But the owners were clueless." "They turned all my ideas down." "Had I proposed the microwave, Rubic's cube, video games, the Walkman or..." " Voilà." " 'The home computer bound to suit yer'." "A computing solution for private use." "This is the future." "Ordinary people will never use computers." " Trust me." "This is gonna be huge." " Your ideas are just too nutty." "Focus on the company, okay?" "Not on promoting yourself." " I quit." " Thorkild, calm down." "No!" "My ideas are obviously too big for this hillbilly company." " I never let adversity crush me." " Thorkild, wait!" "I came from nothing and grew up in an orphanage." "They belted you if you had any good ideas." "The better the idea, the harder the beating." "I won't let anybody boss me around anymore." "There's always a new adventure if you just look for it." "You charge an arm and a leg." "There you go." " Are you okay?" " Yeah." " What on earth is that?" " An electric bike." " Powered by a battery." " Smart." "I invented the battery myself." "Five times as powerful as a car battery." " But it can't power this guy, can it?" " No." "A car's heavy." "But it's an amusing thought." "We'll come back to this original." "But the idea was born." "I want to make the world's first electric car." "No, it's not for the disabled." "This could turn out to be the biggest car venture in Scandinavia." "Great ideas are those others reject." "Then you have them for yourself." "Yes, I have heard of Volvo." "And Saab." "Of course." "Imagine a car that doesn't run on gas." "You'd come home and charge it." " It would be damn cheap." " Listen to the voice of reason." "If you insist on making a car, make one that runs on fucking cocaine." " Then I'm game!" " Won't that be more expensive?" "The voice of reason is Per Lawman." "He handles my finances and he's a bona fide yuppie." "Nose candy?" "Holy moly." " Got any more ice?" " We're out of ice?" "Søs, Thorkild wants ice." "Who the hell do I have to beat up to get one sorry ice cube in Thorkild's drink?" "!" "He holds the record for attorneys who've busted out of jail." "Sayonara, motherfuckers!" "Anyway, I needed to assemble a crack team." "I'll drive." "No, not these guys." "Not these either." "These guys." "The best are those everyone else dismisses." "Those intent on breaking the mold." "Welcome." "Henrik wasn't hard to convince." " Good to see you." " Thanks for putting me on the team." "My go-to guy." "Smart, young, hip with his finger on the pulse." "It's Tuesday, and you're tuned into your fave channel." "Wham bang thank you ma'am, have a grrrreat day." "Is that your lower lip or are you wearing a turtleneck?" "He oughta be on the radio!" "The next guy was Vonsil." " I'm Vonsil." " We met by chance." "I've only got one arm." "But I can do almost anything by mouth." "Right, almost anything by mouth." "Welcome to the South Harbor." "Vonsil didn't look successful." "I'm staying at the garage at the moment, or rather illegally going on five years." "Brewski?" "Cheers." "But I needed his skills." " About that fiberglass..." " Right." "How's about that?" "First you mold the shape." "Then I coat it with fiberglass, liquid epoxy, for a smooth surface." " Smooth surface?" "May I?" " Sure." "It withstands almost anything." "I use it for boats." " But this is an ass, right?" " You bet." "It's Samantha Fox's ass." "A replica." "One to one." "Times two." " I've never tried that before." " It doesn't weigh a thing." " That sure is a light ass." " My case worker told me:" ""You're a lightweight"." "Okay, so I'll build one." "Vonsil's okay." "He just takes some getting used to." "It sure takes balls to go for black upholstery with a pink lining." " Who's the guy with the battery?" " He's an electrical engineer/professor." " Is he coming?" " Yes." "And finally Jens Knastrup, Knas." "The original from the gas station." "Mr. Battery." "Hello." " Kirsten?" "Where are you?" " We're in the sun lounge, Jens." "He was hardest to convince." "But he had his battles at home." " We haven't got a sun lounge." " No, because you haven't built it yet." "I've got great news." "I'm meeting a man today who wants to use my battery for an electric car." " That's the dumbest thing I ever heard." " He seems to have great faith in it." " We're meeting..." " You and your lame little battery?" "Jens, get real." "Just build that sun lounge you promised me over a year ago!" "Nice day in school?" "You'll be going to high school soon." "A new chapter." "Not that Daddy liked high school much, but after that comes the university." "That'll be better." "Or..." "I'm a very persuasive guy." "All you need is charm and a great offer." " This is my wife, Kirsten." " Hello, Kirsten." "And who's this?" " Fanny, our daughter." " At school they call her Elefanny." "That's what you get for stuffing yourself with candy and soda, Fanny." " Right..." "Did you forget our meeting?" " I thought you were having me on." " Having you on?" " That's what Kirsten said." "Kirsten, isn't there something you really want?" " You want a sun lounge." " I'll take care of that, okay?" "I'll get you a sun lounge if you'll let me borrow your genius, Mr. Battery." "Kirsten, you made the right decision." "Knas, let's go." "We're busy." " Nice to meet you, Kirsten." " Bye." "Let's go." "When you set out to revolutionize the auto industry, you have to go all in." "The big money is found out of town." "A BUFFET OF OPTIONS VOTE FOR KAI OVE" "Nothing spells big money like a small-town mayor." "RESTAURANT PEDER OXE" "I gather Bjerringsund is interested in new business ventures." "Yes, Bjerringsund Municipality holds great potential." "I always compare it to a buffet." "With cold and hot dishes." "Three kinds of herring, battered plaice with tartare sauce egg and shrimps, chicken-and- asparagus tartlets, warm liver pa..." "Don't interrupt when we're discussing local politics!" "Three kinds of cheese." "We need room." "We have plenty of room." "But what's in it for me as mayor?" "A small-town mayor is easily impressed." "Especially away from home." "Reedtz-Thott!" "Ladies and gentlemen, the first Danish strawberries." "Fantastic!" "Who's tempted?" "800 kroner per kilo." " 800 kroner?" " We'll have a box." " There you go, sir." " Here's 1,000." "Keep the change." " May I document the occasion?" " Of course." "Well, Kai Ove?" "Have we got a deal?" "Now we just needed to break the story." "The world's first electric car." "Any questions?" "Yes." "Say you're plastered and ram into a pensioner at a bus stop won't you get an electric shock?" " That's one for you, Knas." " No, you won't." "You may get acid all over." "There was a serious acid accident in Sheffield..." "Let me stop you right there." "Safety is our main priority." "I bet." "When will we see the car on the road?" " In less than a year." " Less than a year?" "You're a dreamer, Thorkild." "Your work hasn't even started." "Wanna bet?" "In less than a year" " I'll deliver the first strawberries in the world's first electric car or I'll buy every one of you a bottle of whisky." "Our production will take place in Bjerringsund." " If there are no more questions..." " Bjerring what?" "Great to see so many photographers." "We'll gladly pose for pictures." " Put on a happy face, will you?" " Are we moving out of town?" " Kirsten won't be pleased." " Any chance of getting laid there?" "When I say we're going to Bjerringsund, we are." "Just one more, with all of you jumping for joy." "Ready?" "One, two, three..." "New venture comes to Bjerringsund" "Well?" "Welcome to our new home, honey." "Yeah..." "People are staring." "They're just dazzled." "Hello, hello." "What do you call the critter that's been warming your ballsack all the way?" " Freddie." " Fresh Freddie?" "Nej, Freddie Mercury." "Jens, what am I supposed to do here?" "Stop kicking me all the time, Fanny." "Unbelievable!" "Wow, Thorkild." " I like the premises." " Impressive." "We'll do fine here." "Welcome to Bjerringsund and to the future." "How about a toast?" " Cheers, cheers." " Cheers." " Henrik, show us what we're making." " Here you go." " This is how I envision our car." " What?" "It looks like a bumper car for idiots." ""Look at me in my retard jeep."" "It's not a car for the disabled." "I think it's sexy." " What color did you have in mind?" " Denim, for sure." "Denim blue." "Yeah." "I was thinking mouse grey like a mouse's fur." "I was thinking black." "Sure, with Blackie running about at home bare-assed and in a banana skirt." "I was thinking a nice and friendly pastel shade." " Banana." " Pastel shade?" "I'm not riding around in a pastel-colored car." "Think I'm a homo?" " What are we talking about?" " Good morning." "Kai Ove." "Welcome." "This is Kai Ove, Mayor of Bjerringsund." "This is the team." "On behalf of the town " " I'd like to welcome you all to Bjerringsund." "I've taken the liberty of bringing you a small welcome present." "A calendar adorned with pictures of the city council." "I'm November." "Funny you should say that." "This is our November." " Indeed." " This is the electric car." "An electric car?" "I see." "I thought you were making an electric kettle." "For boiling water." "No, an electric car." "We'll turn Bjerringsund into Scandinavia's Detroit." "I'd go with the electric kettle." "People can better relate to that." "Well, I've got to run." "I'll just leave the same way I came in." "What the hell?" "It's time to find an international name for the car." "Let's have a brainstorm." "A brainstorm is where you say all the ideas that come to mind." " Boy, oh boy." "This could get ugly." " What's on your mind, Knas?" "I'm scared I'll say the wrong thing and you'll use it." " But it's a brainstorm." " Come on." "Ratata?" " Ratata?" "No." " I knew it." " Are we gonna go with Ratata now?" " How about Dan Dream?" "Dream because it goes like a dream, and Dan because we're from..." "Denmark." "Because we're from Danmark." "It was my idea." "Dan Dream has a nice ring to it." ""There goes a Dan Dream."" " Dan Dream." "What do you think, Knas?" " Dalton." "The Dalton Car." " What's with the Lucky Luke references?" " I have no imagination." "We're calling it Dan Dream!" "Bye." " Hi." " Good morning." "Four croissants, please." " What?" " I'd like four croissants, please." "What?" "Four croissants, please." " Nobody eats that around here." " I do." "I eat croissants." "When car buyers from all over the world come, they'll want croissants, too." "So, four croissants." "No, I'll try something new." "Four ordinary rolls." "Right." "Good morning." "My name is Thorkild." "I've opened the electric car factory." "We're from Copenhagen." "As I guess you can hear." "But you'll find that we're just like you." " Hi, Henrik." "Hi, Henrik." " Hi, Thorkild." "Henrik, I'm having a pool party tonight." "Henrik." "Henrik!" "I'm having a pool party tonight." "Pool party!" " Why don't we have a pool like them?" " I thought you wanted a sun lounge." "You're such a drag, Jens." "Let's get this pool party started." "There are two rules for a pool party." "Rule no. 1:" "No glasses in the pool." "Very important." "Rule no. 2:" "Hell, there aren't any rules for a pool party." "Henrik!" "The rule says you have to wear a bathing suit." " I am!" " Henrik, you're so funny!" "And we're off!" "Cheers!" "Well, Kirsten." "Are you happy with your sun lounge?" "Sure, but I'd rather have a job." "I'm a librarian but they're not hiring." " Oh, I see." " Can't you pull some strings?" " I'm not a librarian." " No, but you know everyone." "We'll have to look into that." "So, spending some dough out of town, are you?" "Manufacturing a car costs." "I'm counting on you to handle my finances." " Sure, I've got a handle on it." " Wanna hear something wicked?" " For fuck's sake, Knas!" " Ever heard Bifrost?" "Jesus, you've got a dead one there." "Want a refill?" " Yeah." "Rumble in the jungle!" " Cut it out, Vonsil!" "Grace, it's all in good fun." "City fuckers!" "Hey!" "Someone's messing with the cars." "There's someone out there!" "Why did you kill the music?" " What's going on?" " Look out the window." " What about it?" " Somebody's messing with the cars." " I can't see anyone." " Fine, then forget it." " What's up?" " Nothing." "Go back to the party." "You're such a drag!" "Oh my God, Jens." "Did you crap in the bidet?" " No." " Then who did?" "Dunno." "You're alright, man." "Knas crapped in the bidet!" " You big idiot." " Hey!" "Knas crapped in the bidet!" "Cheers." "Good one!" " On the count of three, get dressed!" " Nope." " One, two, three." "Get up, Kit!" " You'll have to come and get me." " You're welcome to jump in." " I never swim in chlorinated water." "I'm a Bjerringsund boy." "I've swum in the bay all my life." " So go jump in the bay, Kai Ove." " I intend to as a matter of fact." " But the bay's far away." " I know my town, thank you very much." "It's only 400 yards, so I'll be back in 10 minutes." " I'll just grab a towel." " Have fun, Kai Ove." " Ole Abildgaard, Mads Ulrik, me and..." " You all went to Submarina?" "Yeah, we all hit Submarina." "Well, well..." "That stays between us, okay?" "We don't want Knas to get confused." " Who kisses who is nobody's business." " You've got it." " Who's kissing who?" " Kirsten's kissing that waiter, Bjørn." "Henrik, shut the fuck up." " I'm pissed." "It's great." " Sure." "Get home safely." "Thanks." "Let's see if we can find the car now." " Bye for now, Vonsil." " Well, I'll be off, too." "I'm borrowing your slippers." "I can't find my shoes." " Why don't you sleep over?" " Got to be in Copenhagen in 3 hours." " A major contractor's up the creek." " Can you make it in time?" "Sure, I'll be in Copenhagen in 40 minutes." "40 minutes?" "No, Per Lawman, how...?" "Per?" "You can fly a chopper?" "Sure, what's the big deal?" "Right, left, up, down." "See you!" "Here you go, honey." "Man!" "What a night, huh?" "Anything wrong?" "Vonsil grabbed my butt." " He doesn't respect me." " It's because you have a great ass." " It's because I'm African." " That you have a great ass?" "That he doesn't respect me." " Kai Ove?" "Are you okay?" " Sure." "Why?" "I just went out for a swim, but then I changed my mind." " Well, it's quite far away." " Oh, it's not that bad." " Is Kit still here?" " No, she left." "Sure." "Boring Kit." "Always leaves early." " She left at three." " Well..." "Thank you for a lovely evening." "You're welcome." "FUCKER" "Man, I'd love to hump September!" " Vonsil?" " Yes?" "Got a minute?" "I want to talk to you in my office." "Vonsil, Grace is a bit pissed off because you grabbed her ass." "Oh that." "Come on, man." "She's a Negro." "They love a good ass-grabbing, don't they?" "Sure they do, but lay off anyway, okay?" " Sure." "Whatever you say, Thorkild." " I know you don't mean any harm." "But Grace is afraid we don't respect her." " Didn't she used to be a prostitute?" " No." "She worked at a hotel." " As a hooker." " No." "She's got a degree." " As a stripper?" " No, in hotel management." " For real?" " Yes." "Goddamn!" "I've got a good one for you." "A Negro went to the job center:" " "Got a job for me?"" " Thorkild!" "Thorkild!" "Thorkild!" " Freddie's been kidnapped!" " Who?" "Freddie!" "Calm down, Henrik." "I'll ask around." "Freddie!" "Freddie!" "Freddie." "Well, well, well." "The fancy gentleman's paying our humble diner a visit?" "Hand over the rabbit, and we're out of here." "Too posh to eat a sloppy joe?" "Just hand over Henrik's rabbit, and we're out of here." " Who says this is the faggot's rabbit?" " I'm not a faggot." "The rabbit is his." "It obeys him." " Put the rabbit down." "Call him over." " It's a special call." " Call him over." "Call the rabbit over!" " Alright." "Come on, Freddie." "That's it, come on, Freddie." "Yes, come on." "Come, come." "Good boy, Freddie!" "Good boy!" "Damn!" " Did you fire that?" " Yes." "Are you the guy from Copenhagen?" "Are you building a nuclear bomb?" " Nonsense." " That's what people are saying." " And they say you're screwing a rabbit." " What a load of nonsense." "City fucker!" " Hello, Kai Ove." "Is this a bad time?" " No, not at all." "I'm just changing the water in the fish tank." "I want to do an open house at the factory." " Okay?" "What did you have in mind?" " People can come and ask questions." " I'll serve oysters and champagne." " For God's sake, no!" "Free beer, hot dogs and happy jazz will have them crawling out of the woodwork." "Kai Ove?" "We have to get going." "Oh hi, Thorkild." " Hi, Kit." "Nice to see you again." " You too." " What happened to your eye?" " Oh that..." "Well, that's little Kit for you." "She's such a klutz." "She bumped into a knee." "Yes, well..." "We've got to get going." "We do folk dancing." " I'm ready." " No." "You're not wearing any pants." "Get in here." "How many times have I told you..." "Welcome." "Welcome to Dan Dream." "Hi there, Fanny." "Vonsil, put the calendar away." "We've got kids here." " They can't see what month it is?" " Just do it." "Great do, Thorkild." "Now you see where beer, happy jazz and hot dogs will get you in this town." "You just met Brownie." "That's what we call her." " Her nipples are huge and brown." " Oh." "How do you know?" "She's cheap." "Real cheap." "Now, these are the galvanized screws." "But these are the non-galvanized screws." "You reek of sweat." "You reek of sweat." " Don't you shower anymore?" " Sure I do, Kirsten." "I showered..." "Where's the calendar?" "I showered..." "Good grief!" "She's bored." "I think Bjerringsund bores her." "So I'm really glad you promised her that librarian job." " We just talked about it." " It changes everything." " It'll make Kirsten happy again." " Maybe you ought to change things." " In what way?" " Prepare a romantic dinner." "I do it all the time with Grace." "A nice dinner and dessert in the bedroom." " If you know what I mean...!" " Lemon curd?" "Let's take one of me inside the car." " We don't need to." " It's no bother." "Front-page material." "Welcome to open house at Dan Dream the world's first electric car." "I have a dream." "I have a Dan dream a Dan Dream, I have a dreamy Dan Dream." "I want to make a good electric car, but safety is a top priority as well which our technical supervisor will tell you more about:" "Jens Knastrup." "We're going to perform a crash test by ramming the car into a concrete wall at 30 mph." " Help!" " Then we'll check the crash test dummy." "How damaged is it?" "Vonsil, will you do the honors?" "Vonsil, go over and check the damage." "Shit." "Don't worry." "I only hit my head really bad." "Electric car and heaps of free hot dogs" " What a success!" " The mood changed completely." "People loved it." "I saw a woman drinking a Coke with two straws." "That's one horny chick." " This calls for champagne, doesn't it?" " Sure." "Take a look at this." "That's my stump." "I made the papers, man." "Hi, Kirsten." " What are you doing home?" " I made a romantic dinner." "Oh." " Who are you?" " He..." "He's... teaching me how to play the trumpet." " The trumpet?" " Yes." "I take trumpet lessons twice a week with Bjørn." " Oh?" " Yes." "I'm Bjørn." "Trumpet Bjørn." "Where's the trumpet?" "You've got a nerve!" "I'm out of work and trying to learn an instrument." "Spare me your pathetic questions!" " Is your daughter's name really Fanny?" " Yes." "You do know it means vagina, right?" "Not that I mind." "It was Kirsten's idea." "I wanted to name her Rikke." " You can't make fun of that." " Rikke-Dick." "Good morning." "Gather round." "I've got great news." " A library job for Kirsten?" " No, it's got nothing to do with that." "Look." " Well?" " World premiere at Forum?" " Look, Freddie!" " Shit!" "We've been cooped up here long enough." "Let's show the world our creation." "Is it true that Prime Minister Schlüter is coming to Forum?" "The PM himself will present the electric car from Bjerringsund the home town of Kai Ove." "It doesn't get any bigger than that." " We're presenting it in 14 days?" " Yes." "We aren't ready." "The car isn't finished." "The world press is coming." "You'll just have to work around the clock." "But I've got problems at home." "Kirsten's on my back about that job." "Keep your eye on the ball here." "This is a huge chance." "Let's take it." "Let's finish the world's first electric car!" "Am I right?" "Get to work!" " 14 days, Thorkild." " Come on!" "Give me five!" "This is a great ride." "I think it's chic." "And I love that it doesn't make a sound." "Hell yeah." "It doesn't make a sound." "The brakes don't work." "The fucking brakes don't work!" " Hit the brakes!" " I am, for fuck's sake!" " Use the handbrake." " I only have one arm, for fuck's sake!" " Why don't they work?" " Knas, where's the fucking handbrake?" "Oh shit!" "Goddammit!" " Sit still." " Alright!" "Why aren't you working?" "What happened to you?" " Well, you can thank Knas." " Where is Knas?" "Kirsten called to say he wasn't coming." "Do I have to go pick him up myself?" "Thanks a lot!" "Hi, Fanny." " Knas, why aren't you at work?" " Jens is helping me pack." "We're moving back to Copenhagen so I can get my library job back." " But I need Knas." " I need a job." " I promise I'll get you that job." " So get it now." " Right now?" " Yes!" "Let's go to the library." " Get me that job!" " But..." "Alright, let's do it." " Can I go to work then?" " No." "Not until I've got a job." "I'm driving." "Fanny, let's go." " Thanks." " There she is, Thorkild." " The Brownie?" " The Brownie?" "Hello." " We're closed." " Can I come in for a moment?" "I scratch your back..." "Okay, then." "Let's get it over with." " Didn't we have some mints?" " Fanny probably ate them." " This is taking ages." " That means she didn't say no." " You start tomorrow at 10." " Great." "Happy now, Kirsten?" " I can't believe we made it." " You'd think we were rock stars." " With a party bus." " We're riding in the Dynamite Express!" "Just wait until we return from Forum." "What a triumph!" "Let's go." " Congratulations, Thorkild." " Thanks." "We've got a driver, a driver, as crazy as MacGyver in the bus, yeah in the bus, yeah." "We've got a driver, a driver, as crazy as MacGyver in the bus where we hang out." " Cheers!" " Listen, everyone." "I've booked a table for us at Baron Von Dy." "No way am I gonna dip my skewer where you dip yours, if you get my drift!" "I don't." "Anyway, it's at 7 pm." "Vonsil, please double-check tomorrow that there are two wedges under the front wheels, so it won't roll." " Aye-aye, captain." " Thank you." "Grace, when you've driven five laps..." "Knas?" "When Grace has driven five laps tomorrow, she'll go to pit and then I want people to ask you questions, okay?" " Yes." " Good." " Can Freddie come?" " Sure." "As long as he doesn't poop on the PM." "Poop or no poop, I can't wait to meet Prime Minister Schlüter." " You have to cook it first." " Nice and tender." " You have to cook it in the pot first." " It needs cooking?" " You can't eat raw chicken." " Why didn't you say so?" "Oh shit." "I'd like to thank my wife for being a real trooper about all this." "Because you are, Kirsten." "You've settled in in Bjerringsund." "Not only have you got yourself a job but a hobby, too." " So I got you a present." " My goodness!" "I wonder what it is." " Wow." " Shit, man!" "Alright." " Well, well." "You take trumpet lessons?" " No, not at all." " Sure you do." "Twice a week." " Play a fanfare." " Grace wants a fanfare." " But I haven't..." " You can do it." " Show them how good you are." "Play the one, you know..." "Come on now, Kirsten, Kirsten, Kirsten and Kirsten, Kirsten, Kirsten, Kirsten." "Play it!" " We promise to sing along, Kirsten." " We really want to hear." "Kirsten, who the fuck's giving you trumpet lessons?" "Trumpet Bjørn." "The waiter." "He sidelines as a trumpet teacher." " Trumpet Bjørn, you know..." " Well, that was lovely." " We'll get much joy out of that." " I'd like to propose a toast." "Here's to a fantastic international presentation tomorrow." "Cheers." "I've got a big day tomorrow." "Thousands are going to celebrate my battery." "It's gonna make a splash." "It might even make the front page of The Engineer." "We're a good team." "Me and my battery, you and your trumpet." " I don't play the trumpet." " Don't be so hard on yourself." " It's a difficult instrument." " I don't take trumpet lessons." "I had an affair with Bjørn." "You're never here." "What the hell did you expect?" " So you haven't tooted the trumpet?" " No, damn it." "I tooted Bjørn's horn, for God's sake." " Twice a week for four hours?" " I'm going to my mom's, Jens." " Thorkild, got a moment?" " Sure." "Look, I didn't get to look at your accounts until this morning." " You've spent all your money." " What?" "Renting Forum, checking buyers into the D'Angleterre sun hats, happy jazz." "It all adds up." "Sure, but once the buyers see the car, we're gonna be rolling in money." " I'm glad to her that." " Per Lawman, you have a nosebleed." " Sure all that coke isn't dangerous?" " If it was, no one would be doing it." "Hey there!" "You got your period!" "Your first?" "Thorkild, something just crossed my mind while I was in the can." "Did you say Grace was driving the car?" "Yes." "It's not uncommon to have beautiful women present a car." "No, but there's no getting around she's a Negro." "A Negro in an electric car." "Can't you hear how crazy that sounds?" "It's cuckoo." "It's like a hat wearing a hat or cheese with cheese." " It's 1983." "I think people are ready." " You're still in Denmark." "Beer and hot dogs work." "Don't start getting fancy ideas." " Are you okay?" " My stomach's rumbling again." "I think I'm allergic to this fondue." "This is nasty." "I think I'm gonna need a towel." " Thorkild, aren't you coming to bed?" " Sure." "I'm just worried about tomorrow." "If this fails..." "What?" "Everything is impossible until it's been done." " Nelson Mandela says so." " And isn't he in prison?" "Papa T. Come to bed." " Come on." " You're right, Grace." "Thanks, Grace." " I love you." " I love you too, darling." " What's that?" " The mayor." "Or maybe Kirsten's practicing the trumpet." "But she doesn't play." "No." "She's bad." "Who'd have thought little Denmark would build its own car?" "Dan Dream." "People are coming from near and far including journalists from 41 countries." "Dan Dream will be doing the rounds here at Forum all thanks to entrepreneur Thorkild Bonnesen and his dream team." "Hi, Thorkild." "Wagner Sørensen from Silkeborg Municipality." "I ordered 30 of your new car." "So we're pretty excited to see what we ordered." " Yeah." " Shit, look at her." "Pitch-black." "You never get used to that." "Well, so long." "Hi, Papa T. Everything looks great!" "Look, I've been thinking." "You're not driving the car." " Why not?" " We can't afford any mishaps." " I'm an experienced driver." " I know." "I've been talking to people, and we have to remember what people want." " They don't want anything strange." " What do you want?" " What matters is what they want." " What do you mean?" "Buyers have come from West Germany, the Netherlands, Belgium but not Uganda." "And so what?" "And so what?" "It's going to be too weird, period." "It's like a hat wearing a hat." " A hat wearing a hat?" "What's that?" " Like cheese with cheese." "It's weird." "Like if you take a cheese sandwich with bread, butter and cheese and top it with cheese." "It's weird." " Are you sick?" "What's up?" " No, Grace." " Put that hand away." " Fine." "Grace, try to see it my way." "Boys, Grace isn't driving the car." " Okay." "Want me to drive?" " I'll do it." "No, think of the stakes." "The car must be the main focus." "You're too conspicuous." "We need an ordinary Danish man to drive it." "I'll do it." "The police won't stop me here." "Per Lawman, no thanks." "Knas will drive the car." " Where is Knas?" "Haven't you seen Knas?" " He hasn't showed up yet." "Goddammit!" "He's right." "You're too conspicuous." " Look who's talking." " Where are my shoes?" "Knas!" "Knas!" "Knas, dammit!" "We've got a presentation in 30 minutes at Forum!" " You're driving the car." " Me?" "Yes." "Is that a problem?" "Put on your shoes and get going." "Kirsten's had an affair with Trumpet Bjørn." "That'll have to wait." "Put on your shoes in the taxi." " Hurry!" " Alright." "Shut the door." " It's hot in here." " In a minute you drive five laps." "And we'll be a world sensation, okay?" "Isn't that a good plan?" "Sure, let's stick to that." "Thorkild." "Shut the door." "Shut it." "What?" "Maybe Kirsten tooted or smooched Trumpet Bjørn's horn..." " Or his wiener." " Get a grip!" "Should I get a divorce?" "What about Fanny?" "Stop!" "We don't know what happened." "It's probably something Kirsten made up." "You have been away a lot." "You have." " Okay, now focus." " I have been away a lot." " She made it up." " Let's concentrate on the car." "Ready?" " Yes." " Roll up the window." " Thorkild, the PM's here." " Ladies and gentlemen:" "The PM!" "How much we've seen in the world and in Denmark since World War 2." "Sheltered by peacetime, we built up a new, modern Denmark." "Together, we can strengthen Danish research and the development of products for the future." "Denmark's first electric car is about to drive its first lap." "Very exciting!" "There it is." "Wait until you hear how silent it is." "Don't worry." "You'll all get a close look at it." "The PM sure has a full head of hair." "Just like a real Kennedy." "But I never got to meet him." "Of course not, after you tried to run him down with your stupid car." "I told you to make an electric kettle!" "Then the worst-case scenario would have been accidentally scalding the PM!" " Did you fall asleep, Knas?" " No." " You must have dozed off." " No." "Knas, you were fast asleep." "I was blinded by the photographers' flashes." "I don't notice the car rolling." "When I do, I'm a yard from the barrier." "Oh, that bloody fondue stomach!" "I crapped my pants." "Get me a new pair of pants." " The press is waiting." " There's a shop in Kværndrup." " We're not going to Kværndrup." " Right." "I'll wait in the bathroom." "I'm a size 46." "My political career is on the line." " Grace, get him some pants." " No." "It's too weird." "Like a hat wearing cheese or a cheese that's a hat or whatever." "Do I have do everything myself?" "!" "Hello there." "I need a size 46 of something like that." "Very well." " That'll be 140 kroner." " Here's 150." "Driver!" "Open the back door!" "But, Thorkild, it's a denim jacket!" " Kai Ove, got time for a few questions?" " No comment." " You must have some comments." " I'm afraid not." "Sure, but give us a break." "Of course I understand, but..." "You can't be serious, Claus." "We made a deal." "I didn't wreck the car." "My hopeless technical supervisor Knas did." "You're asking me how to spell Knas?" "Call yourself a journalist?" "Very impressive." "The tabloids keep calling." "And the idiot from Silkeborg canceled the deal, too." "He's the third one today." "What the hell's happening?" "How about the buyers from Germany, Belgium, the Netherlands?" "No foreigners are gonna buy a Danish car that the Danes don't even believe in." "Surely you can see that." "You're not that stupid, are you?" "The money's gone, Grace." "Not a penny left." "All gone." "You're singing?" "What the hell is there to sing about?" "You like the pool, too." "You like a good steak, handbags new shoes and what have you." "Now it's all..." "Thorkild, it's your own fault." "You got scared at Forum." "You were afraid to let an African drive." "You didn't walk the line." "Too scared to go all the way for what you believe in." "I sold my house, okay?" "I moved to this hellhole." "I've spent 60 million kroner." "I work day and night." "I even had to screw the Brownie librarian to get Kirsten a job, so Knas would go to work to get the car ready." "That sure as hell is going all in!" "Grace, don't do that." "Stop, Grace." "Grace!" "I didn't like doing it." "Okay?" "I did it for our sake." "Grace, come back!" "Grace." "Damn, it's sweet!" "Grace!" "Grace, I broke a bottle in the pool." "Come back." "There's broken glass everywhere." "I can't deal with bottles now as well!" "Grace!" "Who's gonna call the pool guy?" "There's broken glass everywhere!" "I went to the garage and fixed the bumper and put in a new windshield that'll deflect flash." "Anti-flash." "In case of photography." "Flash?" "How about getting some matches for your eyelids?" " Thorkild, what now?" " What are you talking about?" "We're gonna go on as planned." "One more round and we go on." "Tommy, another round of beers." "Has anyone seen Grace?" "That's so Grace." "I bet she went back to Africa." "That's just so Grace." "Always taking the easy way out." "I pampered her from head to toe and she just takes off." "No fucking way." "I'm gonna call her." "I'm gonna call Africa." "Quiet, please." "I'm trying to call Africa." "Hey, stand still!" "Thanks." "What the fuck does it say?" "There." " What does that say?" " 2, 1." "Not that!" "Okay, from the top." "Thanks a lot, Henrik." " What does it say?" "There." " 0, 0..." "I can read the numbers 1-10." "Stop huffing, for fuck's sake." "You sound like a bellows." "I'm not trying to light a fire." "I'm calling Ghana." "Give me a break!" "4..." "Goddammit." "I hate to interfere, but the word is she's at the women's shelter in Gørlund." " Where?" " The Witch's Lair in Gørlund." "Let's go, guys." "Get a move on!" "I bet there are a lot of neglected, hence horny, women at that shelter." "What a mean thing to say." "These women are in distress." "My point exactly." " Look, I'm here to get my girlfriend." " Let me say it again." " Men are not allowed here." " Oh cut the crap!" "Hey!" "Let's go, guys!" " There she is!" " Grace!" "Grace!" "Grace, my darling." " Hell, that's not Grace." " Are you sure?" " Yes." " We came all this way." "Just take her." " Oh come on." " Attack!" "Kit?" "Let's go to the pub." "No, I want to go home." "Kirsten's back." "Oh, shut up." "She had an affair." "Everybody knows it." "If only you'd got her that job, it wouldn't have happened." "So now it's my fault?" "Fine!" "Let's call the whole thing off!" "Thorkild." "We quit our good jobs to move over here with you." "Good jobs?" "You were scrubbing floors at a strip joint when I met you." "Vonsil's right." "A lot of things would have been easier for me if I'd stayed." "I've fucking had it!" "Get out of the car!" "Get the fuck out, Knas." "I'm calling the whole thing off." "Get out when I tell you to!" " It's my car." " Oh right." "And so we're back where we started." "Shitfaced, lost everything and I haven't even hit rock bottom yet." "Thorkild Bonnesen?" "You're under arrest for assault at the shelter." "You're coming with me to the police station." " Listen to the music." " Please come along." " You have to come with me." " No way." "I'm going in the pool." " Come here." "Bonnesen!" " Hurray!" "I'm going in the pool!" "Bonnesen?" "And so I hit rock bottom." " Good morning, Thorkild." " Good morning." "He made the front page." "Shit, the whole station's laughing at him." " The man just fell asleep." " He had an enginear-death experience!" "An enginear-death experience, get it?" "He's the laughing stock of the country." "What a fucking idiot." "Well..." " Isn't it early for strawberries?" " I think they're the first this year." "Hey!" "Hey!" "Hey, come back." "Hey!" "I want to talk to my lawyer." " Thanks for letting me borrow them." " What have you been up to?" "I quit cocaine." "I'm bored, Thorkild." " I'm bored as hell." " Great." "You have to get me out of here." "There's something I need to do." "Help me." "Please." "Maybe I can help the both of us." "My life is boring as hell anyway." "I'll do a double line." " Welcome back, buddy." " Hey." " This is it, Papa T." " What's going on?" " Let go of me!" "Not the keys." " Run, Thorkild!" "Run!" "You may ask what a lawnmower like this has to do with modern transport." "Well, this is no ordinary lawnmower." "It moves on the grass with the help of an air cushion." "Hello, Kirsten." "Hi, Fanny." "Hi, Knas." " What do you want?" " I want to talk to Knas." "I forgive you for Forum." "You didn't have a chance." "You were in the dark in the car, and the PM's speech was long and boring." "I forgive you, and I'm sorry you were the laughing stock of Denmark." " "An enginear-death experience."" " It's a load of crap." "But, Knas?" "You and I are going for an important ride in our Dan Dream car." "Come on!" " Now?" " Right now!" "No, Jens." "Ever since that hustler came along, things have gone haywire." "And I'm reduced to being the woman married to the Forum idiot." "I'm not making any more sacrifices." "Sacrifices?" "Shut your dirty mouth, Kirsten." "You only got the job because Thorkild fucked the chief librarian." "For 20 stiff minutes, Thorkild had to ram his penis in the librarian's red, hairy vagina!" "In the childrens' book department!" " To get you a job!" " Knas..." "Not now!" "He didn't even climax." "Did you, Thorkild?" "He didn't enjoy it anyway." "We're leaving now, Kirsten and nothing you can say can stop me." "And get off Fanny's back." "You're making her life hell." "She's not unhappy because she's fat, She's fat because she's unhappy!" "And you're not really fat, Fanny." "It's just puppy fat." "You're the most beautiful girl in Bjerringsund." "Thanks, Dad." "This almond tart is for you." " I'll drive." " Bye, Miss Fanny." "Kirsten." "These are the first Danish strawberries, We're gonna deliver them to Peder Oxe." " Why deliver them to a restaurant?" " Because we promised." "To prove the car's alright." "It didn't crash because it's a bad car." " Knas fell asleep." " No, I was blinded." "Relax, it was my fault." "I got scared and chose the wrong driver." "Knas." "I let you down, too, and I'm sorry." "I apologize." " We love you, Thorkild." " Back off, sweet Prince Henrik." "Okay, but what about the car?" "It's only got a 100-km range." " We need 30-40 batteries." " You're not going anywhere." "Your little shit box ruined the good reputation of Bjerringsund!" "I guarantee you that no one's gonna help you." "Oh yes." "I'll give you a battery." "Before Thorkild came to town, this town was a lifeless hole." " He gave us all faith in..." " Sit down!" "No, Kai Ove." "Dear citizens of Bjerringsund your mayor, Kai Ove Jakobsen, beats his wife, that is me." "That's a downright lie!" "Sit down, I tell you!" "Hey, hey, hey!" "Hello!" "Sit down!" "You're the dumbest idiots I ever saw, but you sure have given us a laugh." " Hell, I'll give you a battery." " Thanks." " Me too." " I guess I owe you one, too." " Thanks, Trumpet Bjørn." " I'll give you a battery as well." " And me." " Me too." "Thanks a lot." "Great." "Thanks, Bjerringsund!" " Where are the strawberries?" " In the back." " This is a genuine adventure." " Straight out of the 'Famous Five'." " But there's only four of us." " Not counting Freddie." "'Five and the Spazz Jeep'." " Did you talk to Grace?" " No." "I don't know where she is." " I treated her badly." " I hope she isn't dead." "No, she's just somewhere else." "Maybe Africa." "Africa?" "In that case she is dead." "Ever heard the one about the two Negroes at the steak joint?" ""Two well-done, thanks." "I can see that, but what'll it be?"" "You gotta drop the Negro jokes." "It's all in good fun." " I'm sick of them." " Relax, will you?" "No!" "You're the only one that thinks they're funny." "The only one laughing." " Oh come on." " Okay, listen." "Keep telling Negro jokes until you stop laughing and get it out of your system." " And then we'll continue, okay?" " Okay." "Okay, here goes." "What do you call a Negro with a wooden leg?" "A stick in a turd." "What does a Negro who's got the shits say? "Help, I'm melting!"" "What do you say to a Negro in a uniform?" ""Two Whoppers, please."" "What does a Negro with 12 warning triangles up his ass look like?" "A Toblerone." "I'm done." "They don't make me laugh anymore." " Then let's go." " Yes." "Ever heard the one about the two Eskimos who pass by a bar?" "And the last battery, Henrik." "Is it enough, Knas?" "I think so." "What's happening?" " The battery's dead." " Shit." "Okay." "We'll wait here until a car approaches." "Then we stop it, grab their battery and go on." "Okay." "No fucking way!" "Wait here." "I think I'm ready to settle down." "I'm tired of messing around with a new chick every night." "Every night?" "You haven't been with a chick for as long as I've known you." "You haven't been with a chick either." "No." "And I think you know why." " It's not exactly a secret anymore." " Knas, haven't you got a secret?" " No." " Get it off your chest." "Yes." "I don't really like cutlets." " That's your secret, Knas?" " Yes." "I can squeeze down a rissole." "But not cutlets." "Well, now you know." "What the hell?" "Is that Thorkild?" "We'll take this battery!" " It's a live one." " I'm a bit worried." "It's 25 times as powerful as a car battery." "We're gonna go too fast." " But that's great." " No, the car's tested up to 35 mph." " We'll pull the handbrake as we go." " I'd strongly advise against that." " Well, we're gonna." "Let's go." " It's a bad idea." "Henrik?" "I had a bad experience with a harvester." "Just a few years ago." " How awful." " Horrible." "You're gay?" "That's terrible." "When did that happen?" "Know what happens if a gay guy mistakes wallpaper paste for vaseline?" "His wallpaper falls off." "Wallpaper!" "Let's go!" "Let's stick together." "Oh let's stick together." "Oh let's stick together" "You know it's summer when Nanna sings 'Let's Stick Together'." "Baron Reedtz-Thott just picked up the first box of Danish strawberries and is on his way in his Ferrari to Restaurant Peder Oxe." "Damn!" " Let's drop the handbrake." " No!" "It's only tested to 35 mph." " But we have to." " No!" "Who's technical supervisor here?" " We have to!" " No." "It's too dangerous." " Shut up, Knas." " No, no!" "It went like a dream, Knas." "Dan Dream is the car of the future!" "Shit, man." "This is it." " I don't believe it." " What the hell's happening?" "I can see the restaurant from here." " Grace." " Hi, Papa T." " It's Grace!" " Are you sure?" " How did you know I was here?" " You're the talk of Bjerringsund." "They're calling you a hero." "And they said you were looking for me." "Everything is impossible until it's been done." "Grace, I want you to drive the car." "100%." "Guys, out." " We'll push." "Come on." " Hi, Grace!" " Okay." " Ready, guys?" " And push!" " One, two, three." "Yes, onwards." "That's it, Knas." " Here comes trouble." "Are you squatters?" " No, no." "We're Dan Dream." " Did Reedtz-Thott bring strawberries?" " No, we're all waiting for him." " Yes!" " We did it!" "Well done." "You drove your electric car all the way to Copenhagen." "Thanks, but don't praise me." "These three gentlemen built the car." " Talk to them." " I will." " Congratulations, honey." " It all worked out fine?" "I need to do something." "Excuse me?" "Can I have your attention?" "A year ago we promised to bring the first Danish strawberries in the world's first electric car." "We succeeded." "Some people say:" ""Who do you think you are?"" "Tell them:" ""We know who we are." "We matter!"" "Ladies and gentlemen:" "I give you the first Danish strawberries." "They made it!" "What the hell?" " Fucking rabbit!" " Okay, fair enough." "The electric car Hope Whisper crashed at Forum on October 14th, 1983." "The cause of the crash is still uncertain." "After the crash, buyers and investors lost faith in the project." "Pre-orders worth millions were canceled and the people behind lost everything." "Later, electric cars turned out to be a pretty good idea." "Dedicated to the real Thorkild, Thure Barsøe-Carnfeldt and the rest of the Hope Whisper Pioneers." "Subtitles:" "Helle Schou Kristiansen Dansk Video Tekst" |
Tools & Resources:
Description
This custom 3536+/- Sq Ft log cabin sits among majestic oak trees with a magnificent view of the York Mountain appellation. As you enter this magical property, you drive through a nicely maintained oak forest, cross a bridge over a running creek, continue past the lap pool, hot tub, bocce ball court, amazing gardens, pond and gazebo and up to the beautiful setting. There are paths to meander through and explore all over with an abundance of wildlife and fruitful gardens to enjoy. The home has a wrap around deck, overhang and patio space to sit outside and relax or entertain and take in the breathtaking views. The home itself has been updated to a designer's delight and yet is comfortable and welcoming at the same time. This property has been loved by the owners and guests who visit. Situated just a few minutes from award winning Epoch Winery, only 10 minutes to downtown Paso Robles, and 20 minutes to Cambria. Tranquility awaits you at "Logs" retreat.
Features
# of Parking Spaces: 2.00
Appliances: 6 Burner Stove, Double Oven, Microwave, Refrigerator
Appliances YN: Yes
Area: TTON - Templeton
Baths: 3
Bedrooms: 4
Carport Spaces: 2.00
Community Features: Rural
Cooling: Central
Cooling YN: Yes
Country: US
Directions: Highway 46 West, take York Mtn to the right, follow until you hit Shadow Canyon and go right. Prop |
Familien Stammbaum Karte
Informationen zu diesem Breeder:
A boutique luxury cannabis seed bank from California focused on creating new varieties of cannabis with exotic terpene profiles and unique visual appeal. Haute Genetique’s first series release consists of the Raspberry Collection which includes the XO Raspberry Glue and the Raspberry Cookies. The male used in the raspberry series hails from Northern California, also known as the "WOW" and is rumored to be a rare OG cross that has the classic OG power and flavor while adding a bit of purple coloring to the mix . The "Wow" AKA Pink Champagne is a coveted clone only that was acquired in 2010 then out-crossed to a strawberry diesel male then back-crossed to the original clone 5 times to produce a true Raspberry "WOW" male. The award winning Gorilla Glue #4 cut was then pollinated by this male to produce the XO Raspberry Glue. The XO Raspberry Glue has all the power and flavor of the Gorilla Glue as well as the dense structure but has a sweet overtone with beautiful purple hues when ripe. The Raspberry Cookies is a cross with the Raspberry Male and Epik cookies which is a clone only out of central California. The plant has classic cookie structure with deep purple coloring and a pungent nose that is truly unique. , |
Q:
Reactive Programming using RxScala
I have a Observable that connects to a service via a Socket protocol. The connection to the socket happens through a client library. The client library that I use has java.util.Observer with with I can register for events being pushed into it
final class MyObservable extends Observable[MyEvent] {
def subscribe(subscriber: Subscriber[MyEvent]) = {
// connect to the Socket (Step: 1)
// get the responses that are pushed (Step: 2)
// transform them into MyEvent type (Step: 3)
}
}
I have two open questions that I do not understand.
How can I get the result of Step: 3 in my Subscriber?
Every time when I get a MyEvent, with a subscriber like below, I see that there is a new connection being created. Eventually Step 1, Step 2 and Step 3 are run for each incoming event.
val myObservable = new MyObservale()
myObservable.subscribe()
A:
Unless I'm misunderstanding your question, you just call onNext:
def subscribe(subscriber: Subscriber[MyEvent]) = {
// connect to the Socket (Step: 1)
// get the responses that are pushed (Step: 2)
// transform them into MyEvent type (Step: 3)
// finally notify the subscriber:
subscriber.onNext(myEventFromStep3)
}
and code that subscribes would do something like:
myObservable.subscribe(onNext = println(_))
|
IUI's, IVF, DEIVF and finally we are parents to twins. Welcome to our story...
Saturday, September 19, 2009
weigh in
-0.6 pounds. However, I have lost body mass so I am forgetting the numbers till I'm off meds. My WW leader wants me to not look at the weigh in results for the next three weeks. I understand why. She is trying to teach me to trust my body. Well, honey bunch, I don't.
Today is a wonderful fall day. Its sunny, a little chilly but not cold at all. I slept for 9 hours last night and had real coffee this morning. Bloody wonderful.
1 comment:
Trust your body? Is she nuts? We learn not to trust our bodies, our RE's, twinges, cramps, 2 week waits, medications....I don't blame you a bit. But ahhh, fall in NYC! Wonderful. We've been hit with a heat wave this week and the idea of chilly weather sounds like heaven. Enjoy! |
Ca2+/S100 proteins inhibit the interaction of FKBP38 with Bcl-2 and Hsp90.
FKBP38 (FK506-binding protein 38), a membrane-anchored TPR (tetratricopeptide repeat)-containing immunophilin, regulates signalling pathways such as cell survival, apoptosis, proliferation and metastasis. However, the mechanisms that regulate the activity of FKBP38 are, at present, poorly understood. We previously reported that Ca2+/S100 proteins directly associate with the TPR proteins, such as Hop [Hsp70 (heat-shock protein of 70 kDa)/Hsp90-organizing protein], kinesin-light chain, Tom70 (translocase of outer mitochondrial membrane 70), FKBP52, CyP40 (cyclophilin 40), CHIP (C-terminus of Hsc70-interacting protein) and PP5 (protein phosphatase 5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore we have hypothesized that Ca2+/S100 proteins can interact with FKBP38 and regulate its function. In vitro binding studies demonstrated that S100A1, S100A2, S100A6, S100B and S100P specifically interact with FKBP38 and inhibit the interaction of FKBP38 with Bcl-2 and Hsp90. Overexpression of permanently active S100P in Huh-7 cells inhibited the interaction of FKBP38 with Bcl-2, resulting in the suppression of Bcl-2 stability. The association of the S100 proteins with FKBP38 provides a Ca2+-dependent regulatory mechanism of the FKBP38-mediated signalling pathways. |
My day with Beer part 5
October 15, 2009
All good things must come to an end and here-in endith the beer fair postings…
Here are some Panel Questions from the Symposium:
Someone asked about working at Anchor Steam and we found out that it’s a very small company but that part-time work might be available. And they compensate with beer as well as money.
But if you want to work in the industry then you go to Davis and get a degree in brewing.
A few comments were made about sour beer being unsellable but there are now sour beers being sold by certain brewers. This is meet with revulsion from the panel. They say that well… you can sell sour beer but it’s not a very good idea.
So they used to drink beer with straws… do we know what the straws were made of? The Anchor Brewmaster knows that royalty used gold straws and there are some examples. The Professor they talked about reeds being used by most people. The big reason for straws was because of the unfiltered nature of beer. Using a straw meant you didn’t have to slurp through “the gunk and floating stuff”.
The history of beer focuses on the Middle East because there are more records to pull from there.
Were there different recipes for different classes? Did the wealthy drink vastly different beer from the poor? None of the experts thought so. There were different recipes but it wasn’t about class so much as what ingredients were available. No specific spices were written in the Sumerian text / recipes.
There is no such thing as a good year for beer. The golden rule is consistency. Blending of ingredients allows for a consistency of taste from one batch to the next. They work with International Bitterness Units and Scoville Heat Units to work on a blend to match the taste they are looking to match.
Society likes to have something to bring it together.
For Anchor’s 30 year Anniversary of their new building they are putting out a Humming Ale on draft in a few places in the next month.
There is a story in England about organizing workmen… to get them together to you sober them up and have a meeting or offer them free beer and have a meeting? |
The ceilings of many homes and apartments are not painted, but instead are coated with a substance that has a bumpy texture. It looks like this:
This treatment is normally called a textured finish or an acoustic finish by builders, but most people refer to it as popcorn. This sort of ceiling treatment is popular for several reasons:
It keeps you from having to plaster and sand the ceiling. If you've ever done it, you know that plastering a ceiling is no fun.
It hides lots of imperfections in the ceiling. The ceiling is a huge, flat, uninterrupted and well-lit expanse. Any imperfection is immediately obvious. The texturing hides imperfections very effectively.
It helps eliminate echo in a room. If you have ever talked in a room before and after carpeting, you know what a big difference carpet makes on echoes. An acoustic finish is like carpeting the ceiling.
There are many different ways to put a texture on a ceiling, but the most common technique involves mixing some sort of lumpy aggregate -- either vermiculite or polystyrene -- with ceiling paint. The mixture is then sprayed onto the ceiling using a special spray gun like the hopper texture gun from Lemmer. It goes on in one coat, and once it dries (like normal paint), you're done!
These links will help you learn more: |
Page:The Amazing Emperor Heliogabalus.djvu/114
him, or, as Xiphilinus puts it, in order to induce them to receive him into their city at all. Had there been time, we might have had another medal, in correspondence with the Parthian fraud, announcing the victory of Macrinus at Immae ; but stragglers began to come in, and with them the news that Antonine would arrive shortly at the head of the whole army, an announcement which caused bloodshed and strife in the city, and decided Macrinus to reconstruct his plans. He would not stay, he decided, where he was not wanted ; he would make his way to Rome, in the hope that his kindness to the Senate would at least secure them as a bodyguard — though what use some 600 portly and middle-aged gentlemen were going to be to him against the legions of a military empire was a question that had not yet occurred to his distracted mind ; but at any rate Antioch was no place for him or his son. The latter he entrusted to Epagathos, one of the few men on whom he could rely, with orders to take him to the King of Parthia for safe keeping ; whilst he himself, having cut off his hair and beard, and laid aside the purple and imperial ornaments for his successor's use, set out for the capital city by the route used for the ordinary post. It is a most significant fact that this man, the acknowledged Emperor, should on the very day of the battle itself have distrusted all his own lieutenants, governors, and civil officials to such an extent that he felt the only safe mode of progress was, disguised as a countryman, to travel by the public carriage. It presupposes that by this time |
Bridgestone Arena
Bridgestone Arena (originally Nashville Arena, and formerly Gaylord Entertainment Center and Sommet Center) is a multi-purpose venue in downtown Nashville, Tennessee, that was completed in 1996, and is the home of the Nashville Predators of the National Hockey League.
Ownership
Designed by HOK Sport in conjunction with the Nashville-based architecture/engineering firm Hart Freeland Roberts, INC., it was designed at an angle on the corner of Broadway and 5th Avenue in Nashville in physical homage to the historic Ryman Auditorium, the original home of the Grand Ole Opry.
Bridgestone Arena is owned by the Sports Authority of Nashville and Davidson County and operated by Powers Management Company, a subsidiary of the Nashville Predators National Hockey League franchise, which has been its primary tenant since 1998.
Events
The Predators hosted the NHL Entry Draft here in 2003; it was also the location for the 2016 NHL All-Star Game.
In 1997, it was the venue of the United States Figure Skating Championships, and in 2004 hosted the USA Gymnastics National Championships. It was the home of the Nashville Kats franchise of the Arena Football League from 1997 until 2001, and hosted the team's revival from 2005 to 2007, when the Kats folded.
The arena has hosted college basketball events, including both men's (2001, 2006, 2010) and women's tournaments of the Southeastern Conference and the Ohio Valley Conference. Nashville will serve as a primary venue for the SEC Men's Basketball Tournament nine times between 2015 and 2025 (2015–2017, 2019–2021, and 2023–2025) after the SEC signed a long-term agreement with the Nashville Sports Council in 2013. It hosted the 2014 NCAA Women's Final Four and hosted the 2018 women’s tournament. And will host again in 2022, and 2026.
In odd-numbered years, the arena was regularly one of eight sites to host the first and second rounds of the men's NCAA Basketball Tournament for the first ten years of its existence, though it was taken out of the rotation for several years, partly due to the obsolete octagonal mid-1990s-style scoreboard that hung above the arena floor. It was replaced in the summer of 2007 by a new $5 million scoreboard and digital control room. The NCAA Tournament returned to Nashville in 2012.
Since 2002, the arena has hosted a Professional Bull Riders Built Ford Tough Series event every year (except in 2005 and 2006) until 2010. The event moved to the Arena in 2002 after having previously occupied the Municipal Auditorium from 1994 to 2001; during the venue's first year hosting this event, the Built Ford Tough Series was known as the Bud Light Cup.
The venue has also hosted numerous concerts and religious gatherings. Beginning in 2006, the Country Music Association Awards have been held in the arena, after the awards show moved from the Grand Ole Opry House with a one-year stop in New York City at Madison Square Garden in 2005.
Due to the 2012–13 NHL lockout, the Predators did not host any games that season until January 19, 2013. Instead, the arena hosted a Southern Professional Hockey League preseason game between the only other Tennessee pro hockey franchise, the Knoxville Ice Bears, and their cross-border rivals Huntsville Havoc on October 20.
Seating capacity
Bridgestone Arena has a seating capacity of 17,159 for ice hockey, 19,395 for basketball, 10,000 for half-house concerts, 18,500 for end-stage concerts and 20,000 for center-stage concerts, depending on the configuration used. It has also hosted several professional wrestling events and a boxing card since its opening.
The seating configuration is notable for the oddly-shaped south end, which features two large round roof support columns, no mid-level seating, and only one level of suites, bringing the upper-level seats much closer to the floor.
The arena can be converted into the 5,145-seat Music City Theater, used for theater concerts and Broadway and family shows, by placing a stage at the north end of the arena floor and hanging a curtain behind the stage and another to conceal the upper deck. The arena also features of space in a trade show layout. Mumford & Sons set the attendance record on March 22, 2019, with 19,047 fans in attendance. Kacey Musgraves set the record for the highest attendance for a female headliner with 18,373 fans during the Oh, What a World: Tour.
Arena construction
During construction of the arena there was a major time loss accident October 5, 1995 when a temporary column collapsed. Lead ironworker connector Daniel Lane Foreman suffered a shattered pelvis and was hospitalized for 10 days at Vanderbilt University Hospital. Ironworker Raymond Vance Foreman received minor injuries and was treated and released.
Notable events
Besides hosting the Nashville Predators, because of its location near Music Row and Nashville's role as the center of country music, Bridgestone Arena has seen many other famous performers and events:
CMA Awards (annually 2006–present)
CMT Music Awards (annually 2000–2005; 2009–2016; 2018-present)
2003 NHL Entry Draft June 21, 2003
61st National Hockey League All-Star Game January 31, 2016
2017 Stanley Cup Finals Game 3, 4 and 6; June 2017
Awards and nominations
The Bridgestone Arena was nominated for the 2007 Pollstar Concert Industry Venue of the Year Award. This is the fourth time the venue has been nominated. The first was in 1998 as the Nashville Arena, and then in 1999 and 2000 as the Gaylord Entertainment Center. In 2017 it was named loudest arena in sports.
Naming rights
The arena's original name when opened in 1996 was Nashville Arena.
In 1999, the arena was renamed Gaylord Entertainment Center after a 20-year, $80 million naming rights contract was signed between the Predators and Nashville-based Gaylord Entertainment Company, which at the time was a minority owner of the team.
In February 2005, it was announced that the Predators and Gaylord (which had earlier sold its stake in the team) had reached an agreement terminating any further involvement between them, and that the Gaylord name would remain on the building only until a new purchaser could be found for the naming rights. As a result, many in the Nashville media quickly reverted to calling the facility by its original name. With the beginning of the 2006 season, the Predators began referring to the arena by its original name as well. In doing so, the team replaced the "Gaylord Entertainment Center" wordmark on the center ice circle with the original "Nashville Predators" wordmark from the inaugural season. The "Gaylord Entertainment Center" name, however, was still displayed on the building's exterior signage at that point.
The facility was officially renamed Nashville Arena again, and all Gaylord signage was removed from the building's exterior on March 16, 2007.
On May 18, 2007, Sommet Group, a Franklin-based collection of companies whose services included human resources administration, payroll processing, software development, computer repair, insurance, and risk management bought the naming rights to the arena, and it became known as Sommet Center. Terms of the deal were not disclosed. The company had previously been the corporate title sponsor for the Predators during the 2007 Stanley Cup Playoffs. The agreement had lasted little more than two years when the Predators sued the Sommet Group on November 25, 2009 for breach of contract, alleging the latter had failed to make numerous payments under the naming rights agreement. As part of the suit, the Predators stated intentions to seek a new title sponsor for the arena. Sommet Group's headquarters were later raided by the FBI and IRS due to suspicion of fraudulent activities, and the company subsequently filed for bankruptcy and was liquidated. Sommet's founder, Brian Whitfield, was eventually convicted of fraud, including using some of the fraudulent funds to secure the arena naming rights. He was sentenced to 20 years in prison.
Unlike the Gaylord parting-of-ways, Sommet Group's name was stripped from all signage inside and outside the arena as soon as the team was legally allowed to do so. The building briefly resumed using the Nashville Arena moniker until February 23, 2010, when it was announced that the Predators had signed a naming rights deal with Nashville-based Bridgestone Americas, Inc., the North American subsidiary of tire manufacturer Bridgestone. The arena became known as Bridgestone Arena.
Renovations
In the summer of 2007 a number of renovations were made to what was then called the Sommet Center at a cost of several million dollars. Renovations included changes to concession stands and public areas, as well as major changes to infrastructure. The most obvious change was the August 2007 replacement of the original center-hanging scoreboard (at a cost of $3.6 million) with a new scoreboard made by ANC Sports. The original analog scoreboard had become outdated and was no longer supported by the original manufacturer, making parts difficult to come by. The new scoreboard is referred to as the "megatron" by arena and Predators staff. In addition, the TV–media control room was renovated at a cost of $2.6 million.
During the summer of 2011, a new NHL-mandated ice and dasherboard system was constructed and installed in the arena. In addition, the south side of the upper concourse was redesigned as a "fan zone". The wall separating the arena and that part of the upper concourse was removed.
In the summer of 2015, the Predators began replacing all of the arena's seating. This project was completed in Summer of 2016.
In the summer of 2019, the scoreboard above center ice was replaced with a new model known as "FangVision" which measures high and wide, along with the replacement of urinals in the men's toilets with waterless versions.
References
External links
Bridgestone Arena Seating Charts
Category:1996 establishments in Tennessee
Category:Arena football venues
Category:Basketball venues in Tennessee
Category:Bridgestone
Category:College basketball venues in the United States
Category:Convention centers in Tennessee
Category:Indoor ice hockey venues in the United States
Category:Nashville Predators
Category:National Hockey League venues
Category:Professional wrestling venues in Tennessee
Category:Sports venues completed in 1996
Category:Sports venues in Nashville, Tennessee
Category:Indoor arenas in Tennessee |
construction
Key to the stiffines: custom elliptical carbon tubes
Using our own elliptic tubes allows maximum rigidity of the boom whilst delivering minimal weight. We use tubes with variable wall thickness: the front area of the boom has extra thick wall for maximum stiffnes, while middle part has reduced wall thickness to keep the weight down. On upper side of extension tube we also use thicker wall to guarantee better connection with the adjust pin.
We use mostly natural cork grip for its superior feel while holding the boom, endurance and warmth during cold weather sailing. To keep the highest quality of our booms we use the best possible components like Ronstan® rollers, Clamcleat® cleats and a boom head of your choice.
Focus on detail
Each boom type has special tube dimension: formula, race and slalom boom 28 x 31,5 mm for best rigidity, slalom slim 26,5 x 28 for more control and wave boom 25,5 x 27 mm for better handling.
New 3D printed clips fits perfect to each tube dimension, to provide best connection between main tube and extesion tube.
Think different: oversized tail end
A chain is only as strong as its weakest link. On most booms the end piece is the weakest point of the boom, because of smaller diameter of tubes. So we decide to go the opposite way and make our back end the strongest part of our boom. We use a bigger diameter tail end to connect with the front part. This achieves the ultimate rigidity.
Back end
The width of the tail section has got to match each boom size and its use. A wider tail end generates more power, but for greater control, a narrower tail is recommended.
Our Slalom Slim boom has a narrower tail width to give greater control. Our Formula Extra Wide tail width increases to 29cm, this allows to reduce the outhole and makes the sail profile deeper. |
$input v_uv0
#include <filter.sh>
#include <filter/blur.sh>
uniform vec4 u_blur_p0;
#define u_blur_lod u_blur_p0.x
uniform vec4 u_blur_kernel_0_3;
uniform vec4 u_blur_kernel_4_7;
#define u_kernel_0 u_blur_kernel_0_3.x
#define u_kernel_1 u_blur_kernel_0_3.y
#define u_kernel_2 u_blur_kernel_0_3.z
#define u_kernel_3 u_blur_kernel_0_3.w
#define u_kernel_4 u_blur_kernel_4_7.x
#define u_kernel_5 u_blur_kernel_4_7.y
#define u_kernel_6 u_blur_kernel_4_7.z
#define u_kernel_7 u_blur_kernel_4_7.w
void main()
{
#ifdef GAUSSIAN_HORIZONTAL
gl_FragColor = blur_7(s_source_0, v_uv0, u_blur_lod, u_kernel_0, u_kernel_1, u_kernel_2, u_kernel_3, u_kernel_4, u_kernel_5, u_kernel_6);
#endif
#ifdef GAUSSIAN_VERTICAL
gl_FragColor = blur_5(s_source_0, v_uv0, u_blur_lod, u_kernel_0, u_kernel_1, u_kernel_2, u_kernel_3, u_kernel_4);
#endif
}
|
Friday afternoon, the Justice Department released an indictment that’s part of the investigation into Russian interference in the 2016 election led by special counsel Robert Mueller.
The indictment outlines the lengths Russia went to influence the election in favor of Donald Trump and against Hillary Clinton — including by supporting Bernie Sanders (and, later, Jill Stein).
The Russian operations on social media were meant to communicate derogatory information about Hillary Clinton and other candidates, including Ted Cruz and Marco Rubio. And they were supposed to support Sanders and Trump.
“Use any opportunity to criticize Hillary and the rest (except Sanders and Trump—we support them),” they were directed, according to the indictment.
This was because the Russians involved really didn’t like Hillary Clinton.
Around September 14 in 2016, for example, one “account specialist” of a Russian-controlled Facebook group called “Secured Borders” was reprimanded for having a “low number of posts dedicated to criticizing Hillary Clinton.”
The specialist was also told, “it is imperative to intensify criticizing Hillary Clinton.”
Later on, Russian operatives used accounts they controlled — including an account called “Woke Blacks” and “Blacktivist” — to urge Americans to vote for third-party candidates or not to vote at all. “Choose peace and vote for Jill Stein,” one such message read. “Trust me, it’s not a wasted vote.” |
which suicide method to use
I originally searched for a forum where people could just discuss suicide, not necessarily a help forum like this but this is all I could find.
So if you want to help me spare the motivation and pep talk, it doesn't do anything. I have had CHRONIC (not random or acute) depression since I was a fucking little kid. Okay, it's nonstop..so before you try to give me any encouragement, ask yourself why you think YOU can help me.
All I want to know is if anyone here has the knowledge if an overdose on morphine would be pleasant (like the high from lower doses) or would it be miserable like all other ways of dying? I want it to look like an accident. So obviously a gun is out of the question. I think I've had enough pain and misery that it's not too much to ask for a pleasant death. I can't seem to find the information I'm looking for on the net. I have no reason to believe it would be unpleasant, but you never know, and I want a for sure deal. I'd rather not have to ever make another trip to the emergency room and have to stay the night in the hospital followed by meaningless counseling.
Also, my birthday is in 14 days. I think it would be really convenient to do it on my birthday because for one everyone who knows me knows that I was addicted to opiates for several years, so it's perfectly logical to assume that I would want to celebrate my birthday by doing some morphine, this would make it look more accidental. They will think that I forgot to factor in how my tolerance had gone down after being clean for so long, it happens to "ex" junkies all the time right?
There has to be something better than death. ANYTHING. TRY ANYTHING but that. The fact that you want it to look like an accident shows you still care about something. Lets build from there. If this is a physical problem why not keep trying new meds. I am praying for you.Try that too. You may not like me saying that but I need to. Please dont do this. I know people whove seen overdoses before and it is traumatic for them. It is a bad thing. Whatever is inside you that wants this can be defeated. Who put all that negatvity in you? Dont let it win. Dont let them win. Im here anytime you want to talk. Like it or not I care and wont stop trying to convince you that it is wrong and a mistake to hurt yourself. I have lost so much in my life, but I cant give in.Please dont you either. I have a right to say this because I care and i dont want to see another wasted life. Ive seen too many. Let us help please . TELL US EVERYTHING and we WILL figure a way out.
ive had severe depression my entire life, im not saying its a guarantee i can help, but i can relate and im here if you wanna talk or something....
i might not be able to change how you think, trust me i know this one, i think in a similar fashion and noone has been able to completely make me want to continue on, but for bits of time i have felt better by talking to people, i reccomend trying it
weve been dealt a shitty card, and unfortunately theres no real concrete way to make it better, honestly i dont think its about getting better at this point, its about just dealing with it and surviving...kinda
Okay well, I can already tell that it would probably be best for me to not stick around here. You want to help and I appreciate that, but there is simply nothing we can talk about that will make the slightest bit of difference. I don't see the point in telling you all my life story.
And the ONLY reason why I want it to look like an accident is because a lot of people I know think that suicide is "weak" and I don't want to give them the power of thinking they were stronger than me because they'd never "stoop so low" or something like that. It is not about devastating "loved ones" because I have no loved ones. I pretty much hate everyone. Including the so-called "loved ones" like family members. In fact, I want them to feel my pain and it makes me angry that they get to live happy-go-lucky lives and will NEVER understand this pain. I blame them for a lot of it. Maybe my stupid mother shouldn't have prescribed me ritalin when I was 10 years old, which just so happened to be around the same time I became severely depressed? I'm not saying that that is totally conclusive, but yeah, that MIGHT be the reason why I am STILL depressed. Why I have never been happy SINCE then. So the whole idea of hurting loved ones basically has no effect on my conscience, or lack of.
I honestly don't see why it's such a bad thing to help facilitate someone's urge to end their own life, is THAT not helping them?
right, first off, this is a pro-life forum, so no one will give you help in achieving death, whether it be how much to take of something, or a peaceful way to die.
Secondly, I think if there was a "peaceful" way of doing it, most of us here, would have done it by now.
Thirdly, alot of us here have dealt with long term depression, so we can help in some way I would think. We may all have different reasons for being depressed, but we know what its like.
so reach out to us. tell us whats got you to this place? what have you tried to fix your predicament? what can help you live?
My brother shot himself 12 years ago on his bday, which also happened to be Thanksgiving. While I'm depressed myself, and think about suicide alot, I also know that it is selfish, and a permanent soulution to a temporary problem. But I do understand where you're coming from. Its just that my mom told me if I'm going to kill myself I better come and take her w/ me cause she couldn't go through losing another child. (She has been depressed and attempted suicide way before I was born)
I'm sorry you have so much anger. I'm more sorry that other pushed all that anger into you. You have been a scapegoat and a sacrifice. DONT let them win by acting that sacrifice out. You are turning that anger on yourself. Why not work it out and survive as a way to show them. Their lives may not be so happy if you could be in their skin. If they did all that to you how can they REALLY be happy. I wouldnt care what these people thought of me if they are soooo judgemental they will think badly no matter what. Dont give them that power. I'm sorry about the meds so young. That must have been terrible. You seem like a GREAT person to me. A strong person. Use that strength and make a great life and then the others will know what they did to you didnt work. Why not realize your potential as a STRONG and INTERESTING, Insightful, Smart person. I for one like you. Hang here and maybe you could help me too.COME ON. PLEASE stay. Youll probably laugh at me but Im actually starting to cry. JUST STAY. PLEASE
Okay well, I can already tell that it would probably devastating "loved ones" because I have no loved ones. I pretty much hate everyone. Including the so-called "loved ones" like family members.
Click to expand...
I have an opposite problem. I have a father I care about, and he's had medical troubles. In fact, his stroke was caused (in part) because he worked himself over what has happend with me. Plus, he's had a poor diet and smoked almost all his life. If I kill myself, he'll probably die over it as well.
Makes me pretty much fucking stuck. It would be easier if no one gave a shit, I'll tell you that.
Are you serious? You find someone who is suicidal funny? You think suicide is a laughing matter?
Click to expand...
I find the Ten Minute Guide to which I linked to be funny, because it is not precisely what it purports to be. For example, it contains advise such as (not exact words):
An improperly written suicide note can tarnish your memory/intentions eternally (they supply an example). To ensure that you're properly understood (ya know, for posterity), you should send your draft suicide note to all of your friends, who can possibly suggest revisions!
I think even the original poster could catch the intention behind that tidbit.... If not, they should certainly try it... |
Effects of glucocorticoids on glutamine metabolism in skeletal muscle.
The effects of dexamethasone on nitrogen and amino acid metabolism in the dog were studied in order to gain insight into the role of glucocorticoids in accelerated proteolysis and altered metabolism of glutamine in catabolic illnesses. After dexamethasone administration at a dose of 0.44 mg X day-1 X kg-1, nitrogen balance shifted from slightly positive (+0.126 g N X day-1 X kg-1) to markedly negative (-0.278 g N X day-1 X kg-1). This was associated with a 23% fall in total free amino acid nitrogen in skeletal muscle, with 80% of the decline accounted for by a decrease in glutamine. Plasma glutamine concentration decreased by 26%, although total plasma free amino acid nitrogen was unchanged because of a 49% increase in alanine. The alterations in intracellular and circulating levels of glutamine were not accompanied by measurable changes in glutamine synthetase or glutaminase activities in skeletal muscle. Hindquarter amino acid flux measurements demonstrated that the decline in intracellular glutamine concentration was associated with a marked increase in glutamine efflux from skeletal muscle. This occurred in spite of minimal changes in the intracellular/extracellular glutamine gradient. It is concluded that accelerated muscle glutamine release caused by glucocorticoids is a major contributor to the decreased glutamine levels in muscle that occur during critical illnesses. |
Q:
Build Yocto sources
I need the source packages for a Yocto project. I have already all the sources for the whole project, but they also include the development tools.
I would like to have a way of generating the (patched) sources of all the packages which will be built for the target image. So, for example, if the target image contains busybox, I'd like to have a copy of the busybox source package with the patches applied. I don't need the compiled package.
Is it possible to do this easily?
I couldn't find a hint in the bitbake manual and there's no API (at least I couldn't find one) to work with recipes.
A:
The 'archiver` class is what you're looking for.
If you want the patched sources, you likely want something close to this in local.conf:
INHERIT += "archiver"
COPYLEFT_RECIPE_TYPES = 'target'
Yocto Project documentation on maintaining open source compliance. The archiver.bbclass file itself has docs on how to use it. (i.e. dumping configured sources, creating srpm's, dumping the source code for more than the target, etc).
|
July 14, 2017
Is Killing "Leaders" Useful Or Not - CentCom Can't Make Up Its Mind
A contrasting juxtaposition in my twitter feed:
bigger
First the U.S. Central Command tweet with this statement by the commander of the U.S. Forces in Afghanistan, General Nicholson:
GENERAL NICHOLSON STATEMENT ON THE KILLING OF THE THIRD ISIS-K EMIR BY U.S. AND AFGHAN FORCES IN THE LAST 12 MONTHS
...
"This operation is another success in our campaign to defeat ISIS-K in Afghanistan in 2017," said Nicholson. "Abu Sayed is the third ISIS-K emir we have killed in the last year and we will continue until they are annihilated. There is no safe haven for ISIS-K in Afghanistan." [bold added]
Then the Micah Zenko tweet with this interview with the commander of U.S. Central Command, General Votel. Votel is the direct superior of the above Nicholson:
Q: ISIS leader Abu Bakr Al-Baghdadi — dead or alive? And does it matter anymore? Votel: [..] I hope that he is (dead), frankly. [..] That said, we've been doing this long enough to know that leaders are killed and we've killed plenty of them. And that there's always somebody who is going to step up into those positions so we shouldn't think that just killing Baghdadi is the key here. He can be replaced. So in that regard, it may not matter as much. [bold added]
Nicholson says he can win the war against XYZ by killing a bunch of successive XYZ "leaders". Votel rightly says that this is clearly not so. During sixteen years of War of Terror and constant killing of various "emirs" special boilerplate statements were prepared for the typical "victory" announcements. Votel seems to have understood that such killings do not matter. His direct subordinate Nicholson did not. Shouldn't they talk to each other about such issues?
But it may well be that Votel would have sounded very different if his troops had killed Baghdadi and not a Russian(!) air strike.
Posted by b on July 14, 2017 at 21:11 UTC | Permalink
Comments |
# -*- coding: UTF-8 -*-
#
# Copyright 2011-2019 by Dirk Gorissen, Stephen Rauch and Contributors
# All rights reserved.
# This file is part of the Pycel Library, Licensed under GPLv3 (the 'License')
# You may not use this work except in compliance with the License.
# You may obtain a copy of the Licence at:
# https://www.gnu.org/licenses/gpl-3.0.en.html
import ast
import importlib
import logging
import marshal
import math
import sys
import tokenize as tk
import openpyxl.formula.tokenizer as tokenizer
from networkx.classes.digraph import DiGraph
from networkx.exception import NetworkXError
from pycel.excelutil import (
AddressMultiAreaRange,
AddressRange,
build_operator_operand_fixup,
coerce_to_number,
EMPTY,
ERROR_CODES,
get_linest_degree,
in_array_formula_context,
NAME_ERROR,
PyCelException,
uniqueify,
)
from pycel.lib.function_helpers import load_functions
from pycel.lib.function_info import func_status_msg
ADDR_FUNCS_NAMES = '_R_', '_C_', '_REF_'
class FormulaParserError(PyCelException):
"""Error during parsing"""
class UnknownFunction(PyCelException):
"""Functions unknown to PyCel"""
class FormulaEvalError(PyCelException):
"""Error during eval"""
class Tokenizer(tokenizer.Tokenizer):
"""Amend openpyxl tokenizer"""
def __init__(self, formula):
super(Tokenizer, self).__init__(formula)
self.items = self._items()
def _items(self):
"""Convert to use our Token"""
t = [None] + [Token.from_token(t) for t in self.items] + [None]
# convert or remove unneeded whitespace
tokens = []
for prev_token, token, next_token in zip(t, t[1:], t[2:]):
if token.type != Token.WSPACE or not prev_token or not next_token:
# ::HACK:: this is code to make the tokenizer behave like
# this change to the openpyxl tokenizer.
# https://bitbucket.org/openpyxl/openpyxl/pull-requests/345
# If the pull request gets merged, we can the update our
# openpyxl requirements and remove this code.
if (token.matches(type_=Token.FUNC, subtype=Token.OPEN) and
':' in token.value):
# split the address on the ':'
addr, func = token.value.rsplit(':', maxsplit=1)
tokens.append(Token(addr, Token.OPERAND, Token.RANGE))
tokens.append(Token(':', Token.OP_IN, ''))
token.value = func
tokens.append(token)
elif (token.matches(type_=Token.OPERAND,
subtype=Token.RANGE) and
token.value.startswith(':')):
# split the address on the ':'
tokens.append(Token(':', Token.OP_IN, ''))
token.value = token.value[1:]
tokens.append(token)
# drop unary +
elif not token.matches(type_=Token.OP_PRE, value='+'):
tokens.append(token)
elif (
prev_token.matches(type_=Token.FUNC, subtype=Token.CLOSE) or
prev_token.matches(type_=Token.PAREN, subtype=Token.CLOSE) or
prev_token.type == Token.OPERAND
) and (
next_token.matches(type_=Token.FUNC, subtype=Token.OPEN) or
next_token.matches(type_=Token.PAREN, subtype=Token.OPEN) or
next_token.type == Token.OPERAND
):
# this whitespace is an intersect operator
tokens.append(Token(token.value, Token.OP_IN, Token.INTERSECT))
return tokens
class Token(tokenizer.Token):
"""Amend openpyxl token"""
INTERSECT = "INTERSECT"
ARRAYROW = "ARRAYROW"
EMPTY = "EMPTY"
class Precedence:
"""Small wrapper class to manage operator precedence during parsing"""
def __init__(self, precedence, associativity):
self.precedence = precedence
self.associativity = associativity
def __lt__(self, other):
return (self.precedence < other.precedence or
self.associativity == "left" and
self.precedence == other.precedence
)
precedences = {
# http://office.microsoft.com/en-us/excel-help/
# calculation-operators-and-precedence-HP010078886.aspx
':': Precedence(8, 'left'),
' ': Precedence(8, 'left'), # range intersection
',': Precedence(8, 'left'),
'u': Precedence(7, 'left'), # unary operator
'%': Precedence(6, 'left'),
'^': Precedence(5, 'left'),
'*': Precedence(4, 'left'),
'/': Precedence(4, 'left'),
'+': Precedence(3, 'left'),
'-': Precedence(3, 'left'),
'&': Precedence(2, 'left'),
'=': Precedence(1, 'left'),
'<': Precedence(1, 'left'),
'>': Precedence(1, 'left'),
'<=': Precedence(1, 'left'),
'>=': Precedence(1, 'left'),
'<>': Precedence(1, 'left'),
}
@classmethod
def from_token(cls, token, value=None, type_=None, subtype=None):
return cls(
token.value if value is None else value,
token.type if type_ is None else type_,
token.subtype if subtype is None else subtype
)
@property
def is_operator(self):
return self.type in (Token.OP_PRE, Token.OP_IN, Token.OP_POST)
@property
def is_funcopen(self):
return self.subtype == Token.OPEN and self.type in (
Token.FUNC, Token.ARRAY, Token.ARRAYROW)
def matches(self, type_=None, subtype=None, value=None):
return ((type_ is None or self.type == type_) and
(subtype is None or self.subtype == subtype) and
(value is None or self.value == value))
@property
def precedence(self):
assert self.is_operator
return self.precedences[
'u' if self.type == Token.OP_PRE else self.value]
class ASTNode:
"""A generic node in the AST used to compile a cell's formula"""
def __init__(self, token, cell=None):
super(ASTNode, self).__init__()
self.token = token
self.cell = cell
self._ast = None
self._parent = None
self._children = None
self._descendants = None
@classmethod
def create(cls, token, cell=None):
"""Simple factory function"""
if token.type == Token.OPERAND:
if token.subtype == Token.RANGE:
return RangeNode(token, cell)
else:
return OperandNode(token, cell)
elif token.is_funcopen:
return FunctionNode(token, cell)
elif token.is_operator:
return OperatorNode(token, cell)
raise FormulaParserError('Unknown token type: {}'.format(repr(token)))
def __str__(self):
return str(self.token.value.strip('('))
def __repr__(self):
return '{}<{}>'.format(type(self).__name__,
str(self.token.value.strip('(')))
@property
def ast(self):
return self._ast
@ast.setter
def ast(self, value):
self._ast = value
@property
def value(self):
return self.token.value
@property
def type(self):
return self.token.type
@property
def subtype(self):
return self.token.subtype
@property
def children(self):
if self._children is None:
try:
args = self.ast.predecessors(self)
except NetworkXError:
args = []
self._children = sorted(
args, key=lambda x: self.ast.nodes[x]['pos'])
# args.reverse()
return self._children
@property
def descendants(self):
if self._descendants is None:
self._descendants = list(
n for n in self.ast.nodes(self) if n[0] != self)
return self._descendants
@property
def parent(self):
if self._parent is None:
self._parent = next(self.ast.successors(self), None)
return self._parent
@property
def emit(self):
"""Emit code"""
return self.value
class OperatorNode(ASTNode):
op_map = {
# convert the operator to python equivalents
"^": "**",
"=": "==",
"<>": "!=",
}
@property
def emit(self):
xop = self.value
# Get the arguments
args = self.children
op = self.op_map.get(xop, xop)
if self.type == Token.OP_PRE:
return self.value + args[0].emit
parent = self.parent
# don't render the ^{1,2,..} part in a linest formula
# TODO: bit of a hack
if op == "**":
if parent and parent.value.lower() == "linest(":
return args[0].emit
if op == '%':
ss = '{} / 100'.format(args[0].emit)
elif op == ' ':
# range intersection
ss = '_R_' + ('(str({} & {}))'.format(args[0].emit, args[1].emit)
.replace('_R_', '_REF_')
.replace('_C_', '_REF_')
)
elif op == ':':
# range union
ss = '_R_' + ('(str({} | {}))'.format(args[0].emit, args[1].emit)
.replace('_R_', '_REF_')
.replace('_C_', '_REF_')
)
else:
if op != ',':
op = ' ' + op
ss = '{}{} {}'.format(args[0].emit, op, args[1].emit)
# avoid needless parentheses
if parent and not isinstance(parent, FunctionNode):
ss = "(" + ss + ")"
return ss
class OperandNode(ASTNode):
@property
def emit(self):
if self.subtype == self.token.LOGICAL:
return str(self.value.lower() == "true")
elif self.subtype == self.token.EMPTY:
return 'None'
elif self.subtype in ("TEXT", "ERROR") and len(self.value) > 2:
# if the string contains quotes, escape them
return '"{}"'.format(self.value.replace('""', '\\"').strip('"'))
else:
return self.value
class RangeNode(OperandNode):
"""Represents a spreadsheet cell or range, e.g., A5 or B3:C20"""
@property
def emit(self):
return self._emit()
def _emit(self, value=None):
# resolve the range into cells
sheet = self.cell and self.cell.sheet or ''
value = value is not None and value or self.value
if '!' in value:
sheet = ''
try:
addr_str = value.replace('$', '')
address = AddressRange.create(addr_str, sheet=sheet, cell=self.cell)
except ValueError:
# check for table relative address
table_name = None
if self.cell:
excel = self.cell.excel
if excel and '[' in addr_str:
table_name = excel.table_name_containing(self.cell.address)
if not table_name:
logging.getLogger('pycel').warning(
'Table Name not found: {}'.format(addr_str))
return '"{}"'.format(NAME_ERROR)
addr_str = '{}{}'.format(table_name, addr_str)
address = AddressRange.create(
addr_str, sheet=self.cell.address.sheet, cell=self.cell)
if isinstance(address, AddressMultiAreaRange):
return ', '.join(self._emit(value=str(addr)) for addr in address)
else:
template = '_R_("{}")' if address.is_range else '_C_("{}")'
return template.format(address)
class FunctionNode(ASTNode):
"""AST node representing a function call"""
"""
A dictionary that maps excel function names onto python equivalents. You
should only add an entry to this map if the python name is different from
the excel name (which it may need to be to prevent conflicts with
existing python functions with that name, e.g., max).
So if excel defines a function foobar(), all you have to do is add a
function called foobar to this module. You only need to add it to the
function map, if you want to use a different name in the python code.
Note: some functions (if, pi, and, or, array, ...) are already taken
care of in the FunctionNode code, so adding them here will have no effect.
"""
# dict of excel equivalent functions
func_map = {
"abs": "x_abs",
"and": "x_and",
"atan2": "xatan2",
"gammaln": "lgamma",
"if": "x_if",
"int": "x_int",
"len": "x_len",
"max": "xmax",
"not": "x_not",
"or": "x_or",
"min": "xmin",
"round": "x_round",
"sum": "xsum",
"xor": "x_xor",
}
def __init__(self, *args):
super(FunctionNode, self).__init__(*args)
self.num_args = 0
def comma_join_emit(self, fmt_str=None, to_emit=None):
if to_emit is None:
to_emit = self.children
if fmt_str is None:
return ", ".join(n.emit for n in to_emit)
else:
return ", ".join(
fmt_str.format(n.emit) for n in to_emit)
@property
def emit(self):
func = self.value.lower().strip('(')
if func and func[0] == func[-1] == '_':
func = func.upper()
if func.startswith('_xlfn.'):
func = func[6:]
func = func.replace('.', '_')
# if a special handler is needed
handler = getattr(self, 'func_{}'.format(func), None)
if handler is not None:
return handler()
else:
# map to the correct name
return "{}({})".format(
self.func_map.get(func, func), self.comma_join_emit())
@staticmethod
def func_pi():
# constant, no parens
return "pi"
@staticmethod
def func_true():
# constant, no parens
return "True"
@staticmethod
def func_false():
# constant, no parens
return "False"
def func_array(self):
return '({},)'.format(self.comma_join_emit('({},)'))
def func_arrayrow(self):
# simply create a list
return self.comma_join_emit()
def func_linest(self):
func = self.value.lower().strip('(')
code = '{}({}'.format(func, self.comma_join_emit())
if not self.cell or not self.cell.excel:
degree, coef = -1, -1
else:
# linests are often used as part of an array formula spanning
# multiple cells, one cell for each coefficient. We have to
# figure out where we currently are in that range.
degree, coef = get_linest_degree(self.cell)
# if we are the only linest (degree is one) and linest is nested
# return vector, else return the coef.
if func == "linest":
code += ", degree=%s)" % degree
else:
code += ")"
if not (degree == 1 and self.parent): # pragma: no branch
code += "[%s]" % (coef - 1)
return code
func_linestmario = func_linest
@property
def _build_reference(self):
if len(self.children) == 0:
address = '_REF_("{}")'.format(self.cell.address)
else:
address = self.children[0].emit
address = address.replace('_R_', '_REF_').replace('_C_', '_REF_')
if address.startswith('_REF_(str('):
address = address[10:-2]
return address
def func_row(self):
return 'row({})'.format(self._build_reference)
def func_column(self):
return 'column({})'.format(self._build_reference)
SUBTOTAL_FUNCS = {
1: 'average',
2: 'count',
3: 'counta',
4: 'xmax',
5: 'xmin',
6: 'product',
7: 'stdev',
8: 'stdevp',
9: 'xsum',
10: 'var',
11: 'varp',
}
def func_subtotal(self):
# Excel reference: https://support.office.com/en-us/article/
# SUBTOTAL-function-7B027003-F060-4ADE-9040-E478765B9939
# Note: This does not implement skipping hidden rows.
func_num = coerce_to_number(self.children[0].emit)
if func_num not in self.SUBTOTAL_FUNCS:
if func_num - 100 in self.SUBTOTAL_FUNCS:
func_num -= 100
else:
raise ValueError(
"Unknown SUBTOTAL function number: {}".format(func_num))
func = self.SUBTOTAL_FUNCS[func_num]
return "{}({})".format(
func, self.comma_join_emit(fmt_str="{}", to_emit=self.children[1:]))
class ExcelFormula:
"""Take an Excel formula and compile it to Python code."""
default_modules = (
'pycel.excellib',
'pycel.lib.binary',
'pycel.lib.date_time',
'pycel.lib.logical',
'pycel.lib.lookup',
'pycel.lib.text',
'math',
)
def __init__(self, formula, cell=None, formula_is_python_code=False):
if formula_is_python_code:
self.base_formula = None
self._python_code = formula[1:]
else:
self.base_formula = formula
self._python_code = None
self.cell = cell
self.lineno = 1
self.filename = ''
self._rpn = None
self._ast = None
self._needed_addresses = None
self._compiled_python = None
self._marshalled_python = None
self.compiled_lambda = None
self.msg = None
def __str__(self):
return self.base_formula or self.python_code
def __getstate__(self):
# build the python code
self.python_code
# Throw everything away except the python code
state = dict(self.__dict__)
remove_names = 'compiled_lambda _compiled_python _ast _rpn ' \
'base_formula _needed_addresses'
for to_remove in remove_names.split():
if to_remove in state: # pragma: no branch
state[to_remove] = None
return state
@property
def rpn(self):
if self._rpn is None:
self._rpn = self._parse_to_rpn(self.base_formula)
return self._rpn
@property
def ast(self):
if self._ast is None and self.rpn:
self._ast = self._build_ast(self.rpn)
return self._ast
@property
def needed_addresses(self):
"""Return the addresses and address ranges this formula needs"""
if self._needed_addresses is None:
# get all the cells/ranges this formula refers to, and remove dupes
if self.python_code:
code = iter((self.python_code.encode(),))
tokens = tuple(tk.tokenize(lambda: next(code)))
addrs = []
for i, t in enumerate(tokens):
if t.type == 1 and t.string in ADDR_FUNCS_NAMES and (
tokens[i + 1].string == '(' and
tokens[i + 3].string == ')'):
addrs.append(AddressRange(tokens[i + 2].string[1:-1]))
self._needed_addresses = uniqueify(addrs)
else:
self._needed_addresses = ()
return self._needed_addresses
@property
def python_code(self):
"""Use the ast to generate python code"""
if self._python_code is None:
if self.ast is None:
self._python_code = ''
else:
self._python_code = self.ast.emit
return self._python_code
@property
def compiled_python(self):
""" Using the Python code, generate compiled python code"""
if self._compiled_python is None and self.python_code:
if self._marshalled_python is not None:
try:
marshalled, names = self._marshalled_python
self._compiled_python = marshal.loads(marshalled), names
except Exception:
self._marshalled_python = None
return self.compiled_python
else:
try:
self._compile_python_ast()
except Exception as exc:
raise FormulaParserError(
"Failed to compile expression {}: {}".format(
self.python_code, exc))
return self._compiled_python
def _ast_node(self, token):
return ASTNode.create(token, self.cell)
def _parse_to_rpn(self, expression):
"""
Parse an excel formula expression into reverse polish notation
Core algorithm taken from wikipedia with varargs extensions from
http://www.kallisti.net.nz/blog/2008/02/extension-to-the-shunting-yard-
algorithm-to-allow-variable-numbers-of-arguments-to-functions/
"""
lexer = Tokenizer(expression)
# amend token stream to ease code production
tokens = []
for token, next_token in zip(lexer.items, lexer.items[1:] + [None]):
if token.matches(Token.FUNC, Token.OPEN):
tokens.append(token)
token = Token('(', Token.PAREN, Token.OPEN)
if next_token.matches(Token.SEP, Token.ARG):
tokens.append(token)
token = Token('', Token.OPERAND, Token.EMPTY)
elif token.matches(Token.FUNC, Token.CLOSE):
token = Token(')', Token.PAREN, Token.CLOSE)
elif token.matches(Token.ARRAY, Token.OPEN):
tokens.append(token)
tokens.append(Token('(', Token.PAREN, Token.OPEN))
tokens.append(Token('', Token.ARRAYROW, Token.OPEN))
token = Token('(', Token.PAREN, Token.OPEN)
elif token.matches(Token.ARRAY, Token.CLOSE):
tokens.append(token)
token = Token(')', Token.PAREN, Token.CLOSE)
elif token.matches(Token.SEP, Token.ROW):
tokens.append(Token(')', Token.PAREN, Token.CLOSE))
tokens.append(Token(',', Token.SEP, Token.ARG))
tokens.append(Token('', Token.ARRAYROW, Token.OPEN))
token = Token('(', Token.PAREN, Token.OPEN)
elif token.matches(Token.SEP, Token.ARG):
if next_token.matches(Token.SEP, Token.ARG) or \
next_token.matches(Token.FUNC, Token.CLOSE):
tokens.append(token)
token = Token('', Token.OPERAND, Token.EMPTY)
elif token.matches(Token.PAREN, Token.OPEN):
token.value = '('
elif token.matches(Token.PAREN, Token.CLOSE):
token.value = ')'
tokens.append(token)
output = []
stack = []
were_values = []
arg_count = []
for token in tokens:
if token.type == token.OPERAND:
output.append(self._ast_node(token))
if were_values:
were_values[-1] = True
elif token.type != token.PAREN and token.subtype == token.OPEN:
if token.type in (token.ARRAY, Token.ARRAYROW):
token = Token(token.type, token.type, token.subtype)
stack.append(token)
arg_count.append(0)
if were_values:
were_values[-1] = True
were_values.append(False)
elif token.type == token.SEP:
while stack and (stack[-1].subtype != token.OPEN):
output.append(self._ast_node(stack.pop()))
if not len(were_values):
raise FormulaParserError(
"Mismatched or misplaced parentheses")
were_values.pop()
arg_count[-1] += 1
were_values.append(False)
elif token.is_operator:
while stack and stack[-1].is_operator:
if token.precedence < stack[-1].precedence:
output.append(self._ast_node(stack.pop()))
else:
break
stack.append(token)
elif token.subtype == token.OPEN:
assert token.type in (token.FUNC, token.PAREN, token.ARRAY)
stack.append(token)
elif token.subtype == token.CLOSE:
while stack and stack[-1].subtype != Token.OPEN:
output.append(self._ast_node(stack.pop()))
if not stack:
raise FormulaParserError(
"Mismatched or misplaced parentheses")
stack.pop()
if stack and stack[-1].is_funcopen:
f = self._ast_node(stack.pop())
f.num_args = arg_count.pop() + int(were_values.pop())
output.append(f)
else:
assert token.type == token.WSPACE, \
'Unexpected token: {}'.format(token)
while stack:
if stack[-1].subtype in (Token.OPEN, Token.CLOSE):
raise FormulaParserError("Mismatched or misplaced parentheses")
output.append(self._ast_node(stack.pop()))
return output
@classmethod
def _build_ast(cls, rpn_expression):
"""build an AST from an Excel formula
:param rpn_expression: a string formula or the result of parse_to_rpn()
:return: AST which can be used to generate code
"""
# use a directed graph to store the syntax tree
tree = DiGraph()
# production stack
stack = []
for node in rpn_expression:
# The graph does not maintain the order of adding nodes/edges, so
# add an attribute 'pos' so we can always sort to the correct order
node.ast = tree
if isinstance(node, OperatorNode):
if node.token.type == node.token.OP_IN:
try:
arg2 = stack.pop()
arg1 = stack.pop()
except IndexError:
raise FormulaParserError(
"'{}' operator missing operand".format(
node.token.value))
tree.add_node(arg1, pos=0)
tree.add_node(arg2, pos=1)
tree.add_edge(arg1, node)
tree.add_edge(arg2, node)
else:
try:
arg1 = stack.pop()
except IndexError:
raise FormulaParserError(
"'{}' operator missing operand".format(
node.token.value))
tree.add_node(arg1, pos=1)
tree.add_edge(arg1, node)
elif isinstance(node, FunctionNode):
if node.num_args:
args = stack[-node.num_args:]
del stack[-node.num_args:]
for i, a in enumerate(args):
tree.add_node(a, pos=i)
tree.add_edge(a, node)
else:
tree.add_node(node, pos=0)
stack.append(node)
assert 1 == len(stack)
return stack[0]
@classmethod
def build_eval_context(cls, evaluate, evaluate_range,
logger=None, plugins=None):
"""eval with namespace management. Will auto import needed functions
Used like:
build_eval(...)(expression returned from build_python)
:param evaluate: a function to evaluate a cell address
:param evaluate_range: a function to evaluate a range address
:param logger: a logger to use (defaults to pycel)
:param plugins: module paths for plugin lib functions
:return: a function to evaluate a compiled expression from build_ast
"""
if plugins is None:
modules = ()
elif isinstance(plugins, str):
modules = (plugins, )
else:
modules = tuple(plugins)
modules = tuple(importlib.import_module(m)
for m in modules + cls.default_modules)
logger = logger or logging.getLogger('pycel')
error_messages = []
def capture_error_state(is_exception, msg):
if is_exception:
import traceback
trace = traceback.format_exc()
else:
trace = '' # pragma: no cover
error_messages.append((trace, msg))
def error_logger(level, python_code, msg=None, exc=None):
""" Log a traceback, a msg, and reraise if asked
:param level: level for the logger "error", "warning", "debug"...
:param python_code: Code which caused the error
:param msg: Additional information for logging
:param exc: An exception to reraise, if desired
:return: the constructed error message if not reraising
"""
if exc:
capture_error_state(exc, msg)
assert 1 == len(error_messages)
trace, msg = error_messages.pop()
fmt_str = "{0}Eval: {1}" if msg is None else "{0}Eval: {1}\n{2}"
error_msg = fmt_str.format(trace, python_code, msg)
getattr(logger, level)(error_msg)
if exc is not None:
raise exc(error_msg)
return error_msg
def load_function(excel_formula, name_space):
"""exec the code into our address space"""
# the compiled expressions can call these functions if
# referencing other cells or a range of cells
name_space['_C_'] = evaluate
name_space['_R_'] = evaluate_range
name_space['_REF_'] = AddressRange.create
name_space['pi'] = math.pi
# function to fixup the operands
name_space['excel_operator_operand_fixup'] = \
build_operator_operand_fixup(capture_error_state)
# hook for the execed code to save the resulting lambda
name_space['lambdas'] = lambdas = []
# get the compiled code and needed names
compiled, names = excel_formula.compiled_python
# load the needed names
not_found = load_functions(names, name_space, modules)
# exec the code to define the lambda
exec(compiled, name_space, name_space)
excel_formula.compiled_lambda = lambdas[0]
del name_space['lambdas']
return not_found
def eval_func(excel_formula, cse_array_address=None):
""" Call the compiled lambda to evaluate the cell """
if excel_formula.compiled_lambda is None:
missing = load_function(excel_formula, locals())
if missing:
msg_fmt = 'Function {} is not implemented. '
excel_formula.msg = '\n'.join(
msg_fmt.format(f.upper()) +
func_status_msg(f)[1] for f in sorted(missing))
try:
with in_array_formula_context(cse_array_address):
ret_val = in_array_formula_context.fit_to_range(
excel_formula.compiled_lambda())
except NameError:
error_logger('error', excel_formula.python_code,
msg=excel_formula.msg, exc=UnknownFunction)
except Exception:
error_logger('error', excel_formula.python_code,
exc=FormulaEvalError)
if error_messages:
level = 'warning' if ret_val in ERROR_CODES else 'info'
error_logger(level, excel_formula.python_code)
return ret_val if ret_val not in (None, EMPTY) else 0
return eval_func
def _compile_python_ast(self):
""" Compile the python code into a lambda for execution
### Traceback will show this line if not loaded from a text file
If the compiler has been loaded from (json, yaml, etc) then python
expression will be shown in any tracebacks instead of the above
"""
local_line = sys._getframe().f_lineno - 6
source_code = "lambdas.append(lambda: {})".format(self.python_code)
kwargs = dict(mode='exec', filename=self.filename or __file__)
tree = ast.parse(source_code, **kwargs)
ast.increment_lineno(tree, (self.lineno - 1) or local_line)
names = set()
# edit the ast with a few changes to be more excel like
class OperatorWrapper(ast.NodeTransformer):
"""Apply excel consistent type conversions, fetch dependant names"""
def visit_Name(self, node):
""" Gather up all names needed """
node = ast.NodeTransformer.generic_visit(self, node)
names.add(node.id)
return node
def visit_Compare(self, node):
""" change the compare node to a function node """
node = ast.NodeTransformer.generic_visit(self, node)
return self.replace_op(
node, node.left, node.ops[0], node.comparators[0])
def visit_BinOp(self, node):
""" change the BinOP node to a function node """
node = ast.NodeTransformer.generic_visit(self, node)
if isinstance(node.op, ast.BitAnd) and self.is_addr_and(node):
return node
return self.replace_op(node, node.left, node.op, node.right)
def visit_UnaryOp(self, node):
""" change the UnaryOp node to a function node """
node = ast.NodeTransformer.generic_visit(self, node)
left = ast.Str(EMPTY)
return self.replace_op(node, left, node.op, node.operand)
def replace_op(self, node, left, node_op, right):
""" change the compare node to a function node """
op = ast.Str(s=type(node_op).__name__)
return ast.Call(
func=ast.Name(id='excel_operator_operand_fixup',
ctx=ast.Load()),
args=[left, op, right],
keywords=[],
lineno=node.lineno,
col_offset=node.col_offset,
)
def is_addr_and(self, node):
# reference intersection does not get fixup
return (isinstance(node.left, ast.Call) and
node.left.func.id == '_REF_' and
isinstance(node.right, ast.Call) and
node.right.func.id == '_REF_'
)
# modify the ast tree to convert Compare and BinOp to Call
tree = ast.fix_missing_locations(OperatorWrapper().visit(tree))
# compile the tree
self._compiled_python = compile(tree, **kwargs), names
self._marshalled_python = marshal.dumps(self._compiled_python[0]), names
|
Facebook Marketing Metrics that Matter with Blake Jamieson [Podcast]
This was one of those podcasts that was so much fun that it was difficult to edit it down to 30 minutes. So I only edited it to 38!
Blake Jamieson is a friend of mine whom I met at the AllFacebook.com Marketing Conference in New York City last December. His main claim to fame is the amazing work he did to build up a thriving Facebook presence in a challenging industry (read this post he wrote for me about how he used gaming to increase engagement). |
760 F.2d 254
U.S.v.Friona
84-1371
United States Court of Appeals,Second Circuit.
2/21/85
1
W.D.N.Y.
AFFIRMED
|
Transoral open reduction and fixation of mandibular condylar base and neck fractures in children and young teenagers--a beneficial treatment option?
To evaluate the possible benefits of open surgery, endoscopically assisted reduction and fixation using a transoral route was used in a selected series of pediatric patients with displaced condylar base and neck fractures. A cohort of 6 patients (1 male and 5 female; age range, 7 to 15 yr; mean, 13.4 yr) with displaced condylar base and neck fractures (n = 9) were included. Inclusion criteria were age younger than 16 years, fracture of the condylar base or neck, and displacement of the fracture by at least 45°. Fractures were classified using conventional radiography, cone-beam computed tomography, or computed tomography. Patients underwent transoral endoscopically assisted open reduction and fixation using miniplate osteosynthesis. Postoperatively, patients were followed clinically and radiographically for 18 months. Complete follow-up varied from 18 to 35 months (median, 24.5 months). All patients showed normal occlusion and pain-free unrestricted function of the temporomandibular joint at 3, 6, 12, and 18 months postoperatively. There were no signs of incomplete remodeling or deformation of the condyles. Transoral endoscopically assisted surgical treatment of severely displaced condylar base and neck fractures in children and young teenagers offers a reliable solution to preclude the sequelae of closed treatment, such as altered morphology and functional disturbances, eliminates visible scars, and lowers the risk of facial nerve damage compared with open reduction using an extraoral approach. |
An open review of politics in the city of Denver, Colorado, including little-reported governmental decisions and election campaigns.
Friday, March 16, 2007
Mayor: How am I doing?
Former mayor Ed Koch of New York was famous for asking city residents, "How am I doing?" Current Denver mayor John Hickenlooper has just done the same, albeit in a bit more rigorous and scientifically-valid method.
He spent nearly $25,000 to hire The Kenney Group, a large political consulting firm, to poll city residents on their feelings.
Their reactions were summarized in a news article this morning by Rocky Mountain News political reporter Daniel Chacon entitled "Hickenlooper Weathers Storms."
The centerpiece of the discussion was the mayor's handling of the snowstorm, which "found that 66 percent of voters rated Denver's performance managing snow removal as excellent, good or fair." While I'm sure that number is acccurate, the fact that The Kenney Group felt the need to lump together all three categories suggests a very high percentage of "good" or "fair" responses.
More pertinent excerpts from the article are included below:
When asked about the May election, 49 percent of respondents said they would definitely vote for Hickenlooper.
"The honeymoon may be over," Kenney said, "but the marriage is off to a very good start."
The mayor's approval rating is 84 percent - 10 percentage points higher than Gov. Bill Ritter, according to the survey.
"The mayor continues to have an astounding relationship with the voters of Denver," Kenney said. "I've not quite ever seen a number like this. Almost half have a 'very favorable' rating."
Hickenlooper, who said he hadn't yet seen the results of the poll, said he doesn't know why he connects well with voters.
"We've always tried to tell the truth, and when we've made mistakes, we've tried to work harder to correct them," he said. "I think that's what most people try to do and maybe that connects with people in some way."
Kenney, who often works for Democratic candidates, said his firm convened two focus groups in conjunction with the poll.
He said they viewed Hickenlooper as "an everyday guy."
"He's viewed as somebody they could invite over to their house or have a beer with," Kenney said.
Among the findings:
• 68 percent believe "things in Denver are generally headed in the right direction."
• 14 percent said education and schools are the most important issues facing Denver.
• 55 percent feel their quality of life is about the same as it was four years ago while 24 percent say it's much or somewhat better.
• 59 percent think local taxes are "about right" compared with the services they receive.
• 62 percent rate Denver's economy as fairly strong, but 43 percent said it's very or somewhat difficult to keep up with their bills. |
Mentorship in a community-based residency program.
The concept of mentorship has become a timely issue in surgical residency education. Traditionally, surgical training programs contained resident teams consisting of chiefs, seniors, juniors, and interns on 4- to 8-week blocks. With the new hour regulations, many programs have had to make changes in the format of their teaching programs to accommodate the new hour restrictions and yet still strive to maintain excellence in residency education. We examined a rotation with a mentor or a small group of surgeons in an apprenticeship model. This consists of one resident following one to three surgeons in a practice, in essence being their apprentice. One of the strongest advantages of this is the exposure the resident has to the true lifestyle of a practicing general surgeon. There is also strong continuity of care, because that one resident goes to office with their mentor, scrubs all their cases, rounds with them, and sees the patients in follow up. This continuity concept ultimately results in better outcomes for the patients. |
Introduction {#s1}
============
Chemotherapy has been utilized for the treatment of cancer for over 70 years ([@B1]), and cytotoxic chemotherapeutics (CCTs) form part of the treatment regimen for many patients with cancer. However, as single agents or as chemotherapy combinations, they rarely represent cures for advanced-stage disease ([@B2]), and the efficacy requires improvement in adjuvant and radiotherapy-combination settings. These classes of drugs target replicating malignant cells by disrupting features core to the cell cycle, including DNA replication and the inhibition of the dynamic processes of mitosis ([Figure 1A](#F1){ref-type="fig"}). Despite their use in the treatment of cancer for their cytotoxic properties, there is mounting evidence that they also promote an anti-tumor immune response ([@B3]--[@B10]). Given these observations, there may be significant opportunities for the inclusion of CCTs in immunotherapy regimens.
{#F1}
Immunotherapy has represented a paradigm shift in the way that oncologists approach the treatment of cancer. Unprecedented clinical benefit has been achieved in a variety of cancers using Immune checkpoint inhibitors (ICIs) that targets immune regulation of T-cell responses, such as antibodies which neutralize PD-1 or its ligand PD-L1, or CTLA-4 ([@B11]). However, there remains a majority of patients (up to 60--70%) who are refractory to the current therapies or acquire resistance ([@B12], [@B13]), and there is a notable variation in patient responses to ICIs across different tumor types ([@B14], [@B15]). Combining immune checkpoint blockade therapies improves patient outcomes using the currently-available therapies ([@B12], [@B16], [@B17]). Also, the number and location of anti-tumor cytolytic T-lymphocytes (CTLs) in the tumor microenvironment dictate the response to these therapies ([@B18]--[@B23]) ([Figure 1B](#F1){ref-type="fig"}). Harnessing the broad immune-stimulating capabilities of CCTs in combination with immune checkpoint therapies has shown great promise ([@B17], [@B24]), with improved clinical outcomes ([@B25]--[@B29]). There are also further opportunities for CCTs to be used more broadly in combination with the growing range of immunotherapies ([@B30]).
This mini review considers our current mechanistic understanding of the immune-stimulating capabilities of CCTs for improving the anti-tumor immune response and proposes that these drugs should be considered a versatile therapeutic option in the immunotherapy repertoire.
Immune Priming: Immunogenic Death of Tumor Cells {#s2}
================================================
The observation that cell death, in the absence of infection, can result in CD8^+^ T-cell responses against "dead cell" antigens, has been an area of significant research interest and has been coined "immunogenic cell death" (ICD) ([@B6], [@B31]). Key steps leading to, and dictating whether, an anti-tumor immune response occurs have been identified in an elegant series of studies by the field. CCTs have been demonstrated to be at least one initiator/potentiator of this process, which is not seen with all chemotherapy drugs, but has been most commonly characterized using anthracyclines ([@B32]), platinum compounds ([@B19]), and alkylating agents ([@B33]).
ICD requires an induction of endoplasmic reticulum (ER) stress and autophagy in the tumor cell by the CCT ([@B34]--[@B36]). Through the ER stress response, the reticular chaperone calreticulin (CRT) is presented on the cell surface as part of a complex with the disulphide isomerase ERp57, as an early pre-apoptotic event, preceding even the presentation of apoptotic markers such as phosphatidylserine ([@B34], [@B37]). Phagocytic cells then detect surface-presented CRT/ERp57 using CD91 (LDL-receptor related protein/α2-macroglobulin receptor) which provides a potent "eat me signal" for phagocytic engulfment of the cell ([@B38], [@B39]), which is pivotal for the generation of a subsequent immune response ([@B40], [@B41]). Interestingly, DNA damage by anthracyclines is not the initiating signal for this response, as enucleated cells (cytoplasts) exposed to mitoxantrone present surface CRT and are phagocytosed by dendritic cells (DCs) at an equivalent rate to that of nucleated cells ([@B39]). Cisplatin has also been demonstrated to be capable of inducing a DNA damage-independent ER-stress response in enucleated cells through a pathway which required calcium and the calcium-dependent protease calpain ([@B42]).
During the blebbing phase of apoptosis, release of adenosine triphosphate (ATP) from the dying cell potentiates ICD and provides a "find me" signal which attracts DCs and macrophages to the site ([@B43]), and stimulates their maturation ([@B44]). ATP signaling through the purinergic receptor P2X~7~ on phagocytic cells triggers activation of the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex (inflammasome), which subsequently results in the release of the pro-inflammatory cytokine IL-1β ([@B32], [@B45]). IL-1β then attracts IFN-γ secreting CTLs to the tumor site via IL-17-producing γδ T-cells ([@B41]). Interestingly, there is evidence that the IFN-γ expression by the CD8^+^ tumor infiltrating lymphocytes (TILs) is vital to the anti-tumor response elicited through ICD, as the immunological control of tumor growth by oxaliplatin has been demonstrated to be independent of perforin, and IFN-γ-dependent ([@B32]).
In the latter stages of cell death, there is a release of damage-associated molecular patterns (DAMPs) ([@B46]), which license ICD. Two key ICD-related DAMPs have been identified as nuclear non-histone chromatin protein high mobility group box 1 (HMGB1) ([@B47]) and surface heat shock protein 90 (HSP90) ([@B48]), which are capable of signaling as endogenous ligands of Toll-like receptor-4 (TLR-4) on DCs, leading to their processing and presentation of tumor-associated antigens, rendering the cell death immunogenic rather than tolerogenic. As clinical support for these observations, loss-of-function alleles of the *TLR4* gene are a negative predictor of benefit from adjuvant chemotherapy with anthracyclines or oxaliplatin ([@B47]). HMGB1 has also been demonstrated to facilitate the recruitment of neutrophils and natural killer (NK) cells into the tumor microenvironment of a xenograft model of breast cancer in athymic mice, where both populations were required for cyclophosphamide to control tumor growth ([@B49]). ICD requires multiple non-redundant licensing steps, as either blockade of surface CRT exposure ([@B39], [@B40]), HMGB1-dependent TLR4 signaling ([@B47]), or autophagy-depended ATP release ([@B35]) severely compromises ICD. Since robust immune-mediated tumor killing can be unmasked in a subset of patients through the use of ICIs in the absence of CCTs ([@B50]), and the rare cases of spontaneous tumor remission ([@B51]), it is likely that ICD can also occur without the need for an adjuvant. This is also supported in preclinical models where spontaneous anti-tumor immune responses, in the absence of therapeutic interventions, occur ([@B52]--[@B54]). However, harnessing CCTs as well as some targeted agents ([@B6]), to elicit ICD provide powerful therapeutic tools for use in patients with undetectable or weak anti-tumor immune responses ([@B31]). Further to this, tumors carrying a high mutational burden provide the immune system with neoantigens to mount such responses against, underscored by the observation that tumor mutational burden correlates with clinical benefit of ICIs targeting PD-1 and CTLA-4 ([@B55]--[@B57]). However, even non-mutated proteins can be antigenic when inappropriately expressed, such as the cancer/testis antigens ([@B58]). Pharmacodynamic markers which monitor for evidence of an ICD-type response to CCTs might provide useful information in tailoring treatment regimens to improve ICD as cancer therapy becomes more personalized ([Figure 1B](#F1){ref-type="fig"}).
Trafficking and Infiltration of T-Cells {#s3}
=======================================
There is a clear link between the presence of TILs and progression free and overall survival in a variety of cancers ([@B59]--[@B64]). The prevalence of TILs, the "Immunoscore," has been shown to reliably predict the risk of recurrence (3 year risk of recurrence, high vs. low Immunoscore hazard ratio 0.2, 95% confidence interval 0.1--0.38, *p* \< 0.0001) in a large international cohort study of patients with TNM stage I-III colon cancer ([@B65]). The presence of TILs also correlates with the clinical response to ICIs targeting both PD-1 ([@B66]) and CTLA-4 ([@B67]) receptors. Tumor microenvironments which lack T-cell infiltration have become known as "immunologically cold," which can result due to either exclusion mechanisms or a lack of a TIL-type of inflammation to attract these cells to the site ([@B18], [@B68], [@B69]). However, a potentially important biological response to CCTs is their ability to initiate a T-cell influx into the tumor microenvironment ([@B10], [@B70]--[@B74]) ([Figure 1B)](#F1){ref-type="fig"}. A high CD8/Foxp3 TIL ratio post-neoadjuvant chemotherapy is predictive for improved relapse free and overall survival in patients with breast cancer ([@B75]). Paclitaxel, at a dose of 200 mg/m^2^ every 2 weeks for 4 cycles, was shown to improve TIL numbers in 7 out of 21 patients with breast cancer ([@B70]). Intriguingly, in this study, T-cell infiltration tended to occur in patients whose tumors had a strong apoptotic response acutely (96 h) after receiving the first dose of paclitaxel ([@B70]). Others have observed chemotherapy-dependent CD8^+^/CD4^+^ T-cell infiltration in response to paclitaxel and gemcitabine in a murine model of ovarian cancer ([@B74]) and 5-FU in a murine model of breast cancer ([@B10]). In models of melanoma, temozolomide improved TIL recruitment into the tumor in a CXCR3-dependent manner ([@B72]). Others have also shown CXCR3 to be non-redundant to T-cell recruitment into the tumor ([@B76]). *In vitro* exposure of melanoma cell lines to either temozolomide, cisplatin, or dacarbazine resulted in their expression of T-cell chemokines CCL5, CXCL9, and 10. However, the response was not predictable, as different CCTs promoted T-cell chemokine expression in different cell lines ([@B72]), suggesting that tumor cell sensitivity is an important variable in this process. In another study, doxorubicin was shown to induce a rapid TLR3-dependent expression of interferon β1 (IFN-β1) from tumor cells, which was triggered by the release of self RNA by chemotherapy-stressed or dying cells ([@B77]). IFN-β1 then signaled in both a paracrine and autocrine fashion to promote the IFN-α/β receptor-dependent release of the T-cell chemokine CXCL10, alongside a concurrent expression of MHCI ([@B77]). The CCT-induced expression of tumor cell MHCI has also been shown by others using ovarian cancer cell lines exposed to gemcitabine, paclitaxel or carboplatin ([@B74]), and renders the tumor cells more susceptible to CTL killing ([@B78]). Using CCTs to promote T-cell infiltration into the tumor and convert previous immunological "cold" microenvironments "hot," is an important attribute of these drugs. However, as the response appears to be both dependent on the tumor cell and the chemotherapy it is exposed to ([@B72]), how to anticipate the response for efficient pairing of chemotherapy to each patient has yet to be established.
The Response of the Stroma {#s4}
==========================
The tumor stroma, the heterogenous population of non-cancerous cells, some of which can facilitate tumor progression, play significant roles both directly and indirectly in modulating the response to chemotherapeutics. Examples of populations that have been demonstrated to suppress the infiltration or activity of anti-tumor CD8^+^ T-cells include cancer associated fibroblasts ([@B18], [@B54]), tumor associated macrophages (TAMs) ([@B10]), myeloid-derived suppressor cells (MDSCs) ([@B79], [@B80]), and Tregs ([@B81]). There is evidence that CCTs can selectively target immune suppressive cell populations, for example preferential depletion of Tregs in response to paclitaxel ([@B82]), cyclophosphamide ([@B83]), or temozolomide ([@B84]) treatment. MDSCs have been shown to be preferentially depleted by doxorubicin ([@B85], [@B86]) and 5-FU ([@B85]), and TAMs by gemcitabine ([@B9]). CCTs can also activate NK cells ([@B87]), but also concurrently render tumor cells more susceptible to NK cell-mediated lysis, such as through promoting the expression of B7-H6, the ligand for the NK cell activating receptor NKp30, on the tumor cell surface ([@B88]). CCTs can also modulate MDSC differentiation/polarization, where paclitaxel promoted monocytic MDSC differentiation into a more DC-like phenotype ([@B89]) and docetaxel promoted their differentiation into a more pro-inflammatory macrophage phenotype ([@B90]).
TAMs are a prevalent cell type in the tumor and have been demonstrated to modulate the therapeutic efficacy of CCTs ([@B10], [@B37], [@B91]). Many of these effects are due to their immune suppressive capabilities ([@B10]). In the spontaneous MMTV-PyMT murine model of breast cancer, macrophage expression of heme oxygenase-1 (HO-1), an enzyme responsible for the breakdown of heme to generate the biologically active products biliverdin, ferrous iron (Fe^2+^) and carbon monoxide (CO) ([@B92]), was demonstrated to play a pivotal role in suppressing an anti-tumor immune response generated by 5-FU ([@B10]). However, TAM secretion of IL-10 has also been demonstrated to be important in suppressing paclitaxel-elicited CD8^+^ T cell responses indirectly by suppressing IL-12 release from DCs in the tumor microenvironment ([@B91]). Macrophage can also promote tumor cell survival in response to CCTs through their secretion of cathepsins B and S ([@B93]). Furthermore, tumor-polarized TAMs, in murine models of pancreatic ductal adenocarcinoma, have been demonstrated to release deoxycytidine which can be taken up by tumors cells to directly compete with gemcitabine, hindering the drug\'s efficacy ([@B94]). TAMs are highly plastic in their phenotype and biological response, and paclitaxel can skew the polarization to a pro-inflammatory phenotype through activation of TLR4 via an interaction of paclitaxel with the extracellular accessory protein MD2 ([@B95], [@B96]). However, this response is a murine-specific phenomenon, as paclitaxel binds mouse but not human MD2 ([@B95]). Nevertheless, another member of the taxane family, docetaxel, was shown to influence human macrophage polarization toward a more pro-inflammatory state characterized by increased HLA-DR, CD86 expression and their secretion of IL-1β and IL-8 ([@B97]).
Peripheral macrophages in the spleen also play a role in suppressing the apoptotic response of tumor cells distal to the spleen. Intravenous infusion of bone marrow-derived mesenchymal stromal cells exposed to carboplatin, oxaliplatin, and cisplatin released platinum-induced fatty acids (PIFAs), and conferred tumor resistance to platinum-based chemotherapeutics in murine models ([@B98]). Splenic macrophages (F4/80^+^ CD11b^low^) which had become activated by PIFAs via leukotriene B4 receptor 2 (BLT2) secreted polyunsaturated lysophosphatidylcholines (LPCs) which were capable of altering the DNA damage response in the distant tumor, and conferred therapy resistance ([@B99]).
The release of IL-1β by DCs in response to doxorubicin treatment plays an important role in recruiting IL-17 producing γδ T-cells which subsequently recruit anti-tumoral IFN-γ expressing αβ CD8^+^ T-cells into the tumor microenvironment ([@B41]). Conversely, expression of IL-1β by MDSCs in response to either gemcitabine or 5-FU was demonstrated to induce IL-17 expression by CD4^+^ T cells, which suppressed the chemotherapy-dependent control of tumor growth ([@B100]). Interestingly, IL-17 from γδ T-cells can induce both the suppressive activity of MDSCs and the tumor-derived release of CXCL5, which recruits MDSCs ([@B101]). As such, when MDSCs are present, and activated by IL-17, potentially their immune suppressive effects override the pro-inflammatory anti-tumor response of IL-17. These mechanisms provide examples of the importance of the immune landscape of the tumor when considering chemotherapy-elicited immune responses.
The Importance of Dose and Schedule {#s5}
===================================
CCTs target all replicating cells, leading to predictable effects on normal tissues with proliferating cell populations. For example, cytopenias commonly result from the impact of CCTs on the bone marrow, where pools of replicating cells drive hematopoiesis. One study in mice, analyzed the changes in gene expression after administration of cyclophosphamide and found bone marrow, spleen, and blood PBMCs, had 1123, 868, and 1083 differentially regulated genes respectively 1--2 days post administration, which in the bone marrow and PBMC fraction returned back to baseline at day 5 post-administration ([@B102]). In the clinic, CCTs are largely administered at the maximum tolerated dose which can be immunosuppressive as a result of myelosuppression. However, the recovery phase from chemotherapy-elicited lymphopenia can be an important window where anti-tumor immune responses become potentiated ([@B103]). Furthermore, low dose, but dose dense ("metronomic"), administration of paclitaxel and cisplatin in a subcutaneous HM-1 ovarian cancer model resulted in CD8^+^ T-cell dependent control of tumor growth that was superior to that observed at the maximum tolerated dose ([@B104]). The mechanistic understanding of why low dose metronomic chemotherapy regimens are generally more immune-stimulating is not entirely clear. However, maximum tolerated dose regimens are associated with a loss of CD8^+^ and CD4^+^ T-cells and NK cells from the tumor microenvironment, and pro-tumoral activation of cancer-associated fibroblasts ([@B105]). Whereas, low dose regimens preferentially target MDSCs (CD11b^+^ Gr-1^+^) and Tregs while concurrently increasing IFN-γ expressing T-cells ([@B104], [@B106], [@B107]), and activating NK cells ([@B108]). In a phase III trial of patients with advanced ovarian cancer a low dose metronomic paclitaxel regimen alongside carboplatin resulted in a significantly lengthened survival of 28 months compared to 17.2 months on the standard treatment regimen (hazard ratio 0.71; 95% confidence interval 0.58--0.88, *p* = 0.0015) ([@B109]). This observation in ovarian cancer patients has also been supported by others ([@B110]), however, the beneficial effects of the low dose dose-dense treatment regimen was only seen in those patients that had not received bevacizumab ([@B110]). Others have suggested medium intermittent dose regimens to strike the optimal balance between the cytotoxic roles of these drugs and the immune-stimulating effects ([@B111]). There is evidence to suggest that the dose and schedule are both important variables to efficiently harness the immune-stimulating effects of CCTs. However, further preclinical studies focusing on the biological mechanisms which account for dose and schedule effects are needed. It is likely that the optimal CCT dose is not equivalent for all patients due to tumor cell characteristics, efficiency of drug delivery, and microenvironment heterogeneity. Understanding how to clinically evaluate, and potentially predict, the optimal CCT regimen is an important question to be addressed.
Conclusions {#s6}
===========
CCTs have an intriguingly broad ability to modulate the anti-tumor immune response, providing benefit via several distinct mechanisms ([Figure 2](#F2){ref-type="fig"}) that influence the response to immunotherapy ([Figure 1B](#F1){ref-type="fig"}). Clinical outcomes with either CCTs or immunotherapies alone leave significant room for improvement, so there is a good rationale for exploring possible synergistic effects on the tumor microenvironment of the two combined modalities. The clinical evidence for combining ICIs with chemotherapy is already robust and supported by randomized trials ([@B112], [@B113]), comprehensively reviewed by ([@B114]). However, as the biological response of a tumor cell varies according to the CCT that it is exposed to ([@B9], [@B72], [@B78]), understanding how to predict these responses becomes increasingly important. CCT-elicited cell stress and apoptosis is clearly linked to ICD ([@B6]), and non-lethal "stress" can also render tumor cells vulnerable to T-cell killing ([@B115]). How to balance CCT dose to efficiently elicit the required immune-stimulating effects ([@B6], [@B115], [@B116]), preferentially eliminate immune suppressive cells ([@B82]--[@B86]), and avoid lymphodepletion ([@B104], [@B106]), highlight some of the potential variables in moving to an efficient use of these drugs as immunotherapies in a more personalized manner. The emerging importance of gut microbiota in dictating the efficacy of both ICIs ([@B117], [@B118]) and chemotherapy ([@B119], [@B120]) provide further confounding factors for rationally predicting clinical benefit. However, as our knowledge of the biological mechanisms underlying the immune-stimulating properties of CCTs continues to deepen, their utilization as immunotherapies with broad immune-stimulating effects offer significant promise for improving the number of patients benefiting from immunotherapy.
![Overview of the immune-modulating effects of cytotoxic chemotherapy. The depicted mechanisms, and chemotherapies shown to elicit these responses, summarize the results of the studies highlighted in the manuscript text. Red arrows indicate either an increased (pointing up) or decreased (pointing down) response. Blue flat ended lines represent an inhibitory effect relating to the mechanism depicted. The text boxes positioned near the arrows indicate the CCTs that were described to elicit the response. ATP, Adenosine triphosphate; CRT, Calreticulin; CTL, Cytotoxic T-lymphocyte; HLA, Human leukocyte antigen; HMGB1, High mobility group box 1; MDSC, Myeloid derived suppressor cell; NK, Natural killer; TLR4, Toll like receptor 4; Treg, T-regulatory cell ([@B6], [@B10], [@B32], [@B33], [@B36], [@B40], [@B41], [@B47], [@B49], [@B70]--[@B74], [@B76], [@B78], [@B83], [@B86], [@B88]--[@B90], [@B96]--[@B98], [@B100], [@B101], [@B104], [@B105]).](fimmu-10-01654-g0002){#F2}
Author Contributions {#s7}
====================
JO, DS, JEA, JS, and JNA wrote the manuscript.
Conflict of Interest Statement
------------------------------
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
**Funding.** JNA was funded by a grant from the European Research Council (335326). JO and JEA were supported by the UK Medical Research Council (MR/N013700/1) and were KCL members of the MRC Doctoral Training Partnership in Biomedical Sciences. DS was supported by a Cancer Research UK King\'s Health Partners Center studentship. The work was more broadly supported by the Cancer Research UK King\'s Health Partners Center studentship and Experimental Cancer Medicine Center at King\'s College London, and the National Institute for Health Research (NIHR) Biomedical Research Center based at Guy\'s and St. Thomas\' NHS Foundation Trust and King\'s College London.
[^1]: Edited by: Lionel Apetoh, Institut National de la Santé et de la Recherche Médicale (INSERM), France
[^2]: Reviewed by: Rodabe N. Amaria, University of Texas MD Anderson Cancer Center, United States; Celine Mirjolet, Centre Georges François Leclerc, France
[^3]: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
[^4]: †These authors have contributed equally to this work
|
Occasion Specification
Prints & Patterns Details
Wash Care Detail
Details of Sarees
Color Set Details
Color Family
: Yellow
Set Contents Attribute Women Apparel
Set Contents
: Single
Combo Attribute for Women Apparel
Combo
: No
Fabric Attribute for Ethnic
Fabric
: Cotton
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Configurational stability of chlorophosphines.
The configurational stability of chlorophosphines is investigated. Several mechanisms involving chlorophosphine monomer, dimers, and adducts with HCl are evaluated by density functional theory calculations. The presence of HCl in the medium is found to catalyze the P-center chiral inversion at room temperature. The reaction involves a two-step mechanism with low transition states (10 kcal.mol-1) and a stabilized achiral intermediate (-2.6 kcal.mol-1). Further calculations and experiments on the halogen exchange with HBr corroborate this mechanism, with bromophosphines being formed instantaneously. Finally, to avoid the racemization, the borane is found to be a very promising protecting group for the configurational stability of the P-chirogenic chlorophosphines. |
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