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--- abstract: 'We use a numerical solution of the deterministic TDGL equations to determine the response induced by a probe field in a material quenched into a superconducting state. We characterize differences in response according to whether the probe is applied before, during, or after the phase stiffness has built up to its final steady state value. We put an emphasis on the extend to which superfluid response requires a non-negligible phase stiffness, which for the considered quench has to build up dynamically. A key finding is that the time dependent phase stiffness controls the likelihood of phase slips as well as the magnitude of the electromagnetic response. Additionally, we address the electromagnetic response expected if the probe itself is strong enough to activate phase slip processes. If the probe is applied before phase stiffness is sufficiently build up we find that phase slips occur so that the vector potential is compensated and no long term supercurrent is induced, while if applied at sufficient phase stiffness a weak probe pulse will induce a state with a long-lived supercurrent. If the probe is strong enough to activate the phase slip process the supercurrent state will only be metastable with a lifetime that scales logarithmically with the amplitude of fluctuations in the magnitude of the order parameter. Finally, we study the response to experimentally motivated probe fields (electric field that integrates to zero). Interestingly, depending on the relative time difference of the probe field to the build up of superconductivity, long-lived supercurrents can be induced even though the net change in vector potential is zero.' author: - 'D. M. Kennes' - 'A. J. Millis' title: 'Electromagnetic Response during a Quench Dynamics to Superconducting State: Time-Dependent Ginzburg-Landau Analysis' --- Introduction ============ Quench dynamics, in other words the response of a system to sudden changes in parameters, is of great current interest in the context of cold atomic gases[@Bloch08] and correlated electron systems.[@Gogolin16; @Essler16; @Vidmar16] Quench dynamics may be studied experimentally by measuring the response to a weak applied probe field. One expects different responses according to whether the probe is applied prior to the quench, during the quench, or long enough after that the system has relaxed into a thermal or prethermal state. Recent reports of optically induced high transition temperature superconductivity[@mankowsky2015coherent; @mitrano2016possible] along with theoretical interpretations[@Komnik16; @Sentef16; @Knap16; @Kennes16; @Babadi17; @Babadi17; @Sentef17; @Nava17] give a particular topicality to the question of the electromagnetic response of a material quenched into a superconducting state. In Ref. we studied this question within a BCS model that allowed for a time dependent magnitude of the order parameter but assumed perfect phase stiffness at all times. This analysis provided a reasonable account of the transient response at energy scales of the order of the superconducting gap or for probe fields applied a reasonable time after the quench. However, the low frequency response is controlled by the behavior of the phase of the superconducting order parameter. The importance of the phase stiffness and of phase slips can be seen from the general expression for the supercurrent $j=\nabla \phi-2eA$ in terms of the gradient of the superconducting phase $\phi$ and the vector potential $A$. If a superconductor is quenched in the presence of a vector potential then the phase adjusts (to the extent possible) so that $\nabla \phi=2eA$ and the supercurrent is small, whereas if the vector potential is applied long after the superconductor is quenched then the phase is fixed, typically such that $\nabla \phi=0$, and the supercurrent is proportional to $-2eA$. The key issues of the timing of the probe relative to the establishment of phase rigidity, and the strength of the probe relative to the field required to drive phase slips were beyond the scope of this previous work. In this paper we investigate the interplay between the timing of the quench and the application of a probe field via solutions of the time-dependent Ginzburg-Landau (TDGL) equations.[@Cyrot73; @Gorkov75; @Ivlev84] While TDGL equations have been extensively studied,[@Cyrot73; @Gorkov75; @Ivlev84] this particular issue seems not to have been previously considered. We concentrate mainly on the case of a one-dimensional system with periodic boundary conditions, but present a few results for the two dimensional case. The main conclusions we draw are not crucially affected by the dimensionality or geometry of the system considered but we note and discuss those aspects that are particular to the one dimensional case. We thus use the one-dimensional case solely due to reasons of numerical convenience. We study the fully determininstic TDGL equation. The inclusion of noise (full model A dynamics) will be seen not to significantly affect the phenomena of interest here (see Refs. for a recent interesting study of quenches using model A dynamics). The rest of this paper is organized as follows. In section \[sec:Formalism\] we present the equations to be solved and the methods of solution. In section \[sec:quench\] we describe those aspects of the physics of a quench that are relevant to our analysis in sections \[sec:response\] and \[sec:PhysicalPulse\] of the response to differently tailored probe fields. Section \[sec:conclusion\] is a summary and conclusion. An Appendix gives details of our numerical procedure and verifies convergence. Formalism\[sec:Formalism\] ========================== We use the deterministic TDGL equations[@Gorkov75; @Ivlev84] to describe the dynamics of the complex superconducting order parameter $\Delta=\left\|\Delta\right\| e^{i\phi}$, along with the charge density $\rho$ and current density $\vec{j}$ in the presence of electromagnetic fields represented by the vector potential $\vec{A}(t)$ and scalar potential $\Theta(t)$. We choose units such that $\hbar=c=e=1$, implying that the superconducting flux quantum $\Phi_0\equiv hc/2e=\pi$. The equations are $$\begin{aligned} &\frac{1}{ D}\left(\partial_t+2i\Psi\right)\Delta=\frac{1}{\xi^{2}\beta}\Delta\left[r(t)-\beta \|\Delta\|^2\right]\notag\\ &\phantom{\frac{1}{ D}\left(\partial_t+2i\Psi\right)\Delta=}+\left[\vec{\nabla} - 2i\vec{A}(t)\right]^2 \Delta \label{eq:TDGL} \\ &\rho=\frac{\Psi-\Theta}{4\pi\lambda_{\rm TF}^2} \label{eq:rho} \\ &j=\sigma\left(-\nabla \Psi-\partial_t A(t)\right)+\frac{\sigma}{\tau_s}{\rm Re}\left[\Delta^\left(\frac{\nabla}{i}-2A\right)\Delta\right] \label{eq:j}\end{aligned}$$ Here $D$ is the normal state diffusion constant, $\Psi$ is the electrochemical potential per electron charge, $\xi=\sqrt{6 D\tau_s}$ is related to the superconducting coherence length $\xi_0=\xi/\sqrt{r/\beta}$, where $\tau_s$ is the spin-flip scattering time, $\lambda_{\rm TF}$ is the Thomas-Fermi static charge screening length and $\beta$ is a system dependent constant that sets the magnitude of the order parameter. The quench is specified by the time dependence of the parameter $r(t)\sim[T_c(t)-T]$, with $T$ and $T_c$ the temperature and the superconducting critical temperature. We consider an “interaction quench” in which the system Hamiltonian is changed in such a way as to vary the transition temperature from less than to greater than the physical temperature. For definiteness we measure lengths in units of $\xi$ and time in units of $\xi^2/D$ (which we write simply as $D^{-1}$ since $\xi$ is our unit of length) and choose parameters $\beta=1$, $\sigma=1 $, $\tau_sD=\frac{1}{6}$ and $\lambda_{\rm TF}^2/\xi^2=1$. We chose those units for definiteness, but we verified that none of the general conclusions depend on this choice of parameters unless otherwise stated. The TDGL equations must be supplemented by the continuity equation $$\partial_t \rho+\vec{\nabla}\cdot\vec{j} =0 \label{eq:continuity}$$ and the Poisson equation for the scalar potential $$\nabla^2\Theta=-4\pi\rho.\label{eq:Poisson}$$ We solve the coupled partial differential equations Eqs. - with periodic boundary conditions in one or two dimensions using a finite difference approach. We discretized time in steps of $D\Delta t =0.001$ and space in units $\Delta x/\xi=1$ and checked numerically that the results obtained are converged with respect to $\Delta t$ and $\Delta x$ on the scale of the plots shown (see Appendix \[Appendix:a\]). The partial differential equations require initial conditions. We assume that for $t<0$ the parameter $r<0$ so there is no superconductivity, and that at $t=0$ $r$ is suddenly switched to a positive value (we chose $r=0.1$, so $\xi_0=1/\sqrt{0.1}$). The pre-quench state at $t \leq 0$ is characterized by small thermal fluctuations, which for positive $r$ will grow exponentially, leading eventually to an equilibrium superconducting state. We therefore choose as initial condition at $t=0$ a state with random, small order parameter values. We considered two cases: (i) absolute values of the order parameter drawn randomly from a uniform distribution $\|\Delta\|\in [0,\Delta_{\rm ini}]$ and phase values drawn randomly from a uniform distribution $\phi\in(-\pi,\pi]$ on the different lattice sites (see Appendix \[Appendix:a\] left panel of Fig. \[fig:ini\_cond\_1\]) and (ii) fixed magnitude $\|\Delta\|=\Delta_{\rm ini}$ with phase values randomly drawn from a uniform distribution $\phi\in(-\pi,\pi]$ (see Appendix \[Appendix:a\] right panel of Fig. \[fig:ini\_cond\_1\]). Both initial conditions give very similar results (see Appendix \[Appendix:a\]) and all of the results in the following are obtained by assuming that the initial conditions are characterized by a fixed small magnitude and a random phase. Quench Dynamics \[sec:quench\] ============================== In this section we recapitulate basic aspects of the quench dynamics in the absence of applied probe fields, in order to set the stage for the subsequent discussion of the response to probe fields. We consider a quench into a superconducting state achieved by instantaneously changing the interactions so that at time $t<0$ the transition temperature $T_c$ is less than the sample temperature $T$ while at time $t>0$ the transition temperature is greater. An example of two experiments for which such a study of a quench might be relevant are given in Refs. We suppose that the quench occurs in the presence of a spatially uniform, time independent vector potential $\vec{A}$. The non-superconducting state is characterized by small fluctuations in the superconducting order parameter. After the quench these fluctuations grow and at sufficiently long times the system evolves to a homogeneous superconducting state. The system of main interest here is one dimensional, with periodic boundary conditions for numerical convenience. This system has the topology of a ring and an applied vector potential corresponds to a flux $\Phi= L A$ threading the ring. It is convenient to measure the vector potential in units of the superconducting flux quantum $\Phi_0=hc/2e=\pi$ (with the last equality following from the convention $\hbar=c=e=1$), writing $A=\Phi/L$ and the gauge-invariant gradient as $\vec{\nabla}-2\pi i \Phi/\left(L\Phi_0\right)$. The possible homogeneous superconducting states are characterized by a phase winding number $n=\oint\nabla \phi/(2\pi)$ implying a nonzero phase gradient $d\phi/dx=2\pi n/L$. The magnitude of the order parameter is[@Ivlev84; @Kramer85] $\left\|\Delta(n)\right\|=\sqrt{\frac{r}{\beta}-\left( \frac{2\pi\xi}{L}\right)^2\left(n-\frac{\Phi~}{\Phi_0}\right)^2}$. The corresponding free energy gain is $-\beta\|\Delta(n)\|^4$ so the true ground state will have winding number $n$ given by $2\pi$ times the nearest integer to $\Phi/\Phi_0$ but depending on initial conditions and subsequent dynamics the actual state reached may be a metastable state with different winding number. From Equation \[eq:j\] we find that in the equilibrium state at winding number $n$ the supercurrent circulating around the ring is $$\vec{j}_n=\frac{2\pi \sigma \tau_s}{L} \left( n-\frac{\Phi~}{\Phi_0}\right)\left\|\Delta(n)\right\|^2. \label{eq:curr_wind}$$ Changes in the winding number occur via phase slip processes at which the amplitude of the order parameter is driven locally to zero and the phase difference across the region with locally zero order parameter changes by a multiple of $2\pi$.[@Vodolazov02; @Yu08; @Ludac08; @Ludac09; @Michotte04; @Baranov11] In the deterministic dynamics studied here phase slips occur when the local amplitude of the current is greater than an energy barrier determined by the local magnitude of the order parameter. (Note that the random initial conditions mean that this magnitude will be different on different sites and that the random currents implied by the random phases will lead to different order parameter magnitudes at intermediate times even if the initial condition is a space independent order parameter magnitude). Phase slips may occur as the system equilibrates, and will be more common soon after the quench when the order parameter is small and the energy barrier to phase slips is less. In model A stochastic dynamics there will be a small amplitude for phase slips even if the drive is not large enough to overcome the energy barrier; for small noise the resulting corrections are exponentially small in the reciprocal of the noise amplitude and will not be considered here. Fig. \[fig:plot1\] shows two examples of the evolution of the system following a quench with $A=0$. The left column shows the time evolution of the order parameter magnitude on the $100$ different sites in the system (for $L=100\xi)$, computed from two different randomly chosen initial conditions. The initial stages of the growth are exponential with the differences between different sites arising from the randomness in the initial conditions. The middle panels show the current on the $100$ sites. The currents are almost identical on every site because the charge fluctuations decay away almost instantaneously, leading to a state with $\vec{\nabla}\cdot\vec{j} =0$. From panel (c) we see that at early times the current is very small because the magnitude of the order parameter is very small; at intermediate times we see a current pulse associated with the equilibration of the phase degrees of freedom while the current vanishes at long times because the long-time limit of the winding number $n=0$. Panel (e) shows that after an intially complicated evolution the phase locks into a common value at all sites, corresponding to the zero current state shown in panel (c). Panel (d) shows that for a different choice of initial conditions the long-time limit corresponds to a non-vanishing current. In this case, at large times the phase is stiff and the magnitude of the order parameter is sufficiently large that the induced supercurrent is not large enough to drive a phase slip. Panel (f) shows the phase in the polar plot described above. The non-vanishing phase gradient is revealed as a phase monotonically increasing as one moves around the ring. A quench in the presence of a static vector potential (flux) may be understood in a very similar way. The minimum energy state has a phase winding $n$ given by the nearest integer to $\Phi/\Phi_0$ and particular initial conditions may lead to long-time states characterized by a winding number $n$ which differs from this value. If $\Phi/\Phi_0$ is not an integer the ground state will have some residual supercurrent. The generalization of this picture to higher dimensions involves additional considerations. Random initial conditions may lead to states with vortices and antivortices (in dimension $d=2$) or vortex loops ($d=3$), whose long-time evolution involves interesting coarsening dynamics. These issues were recently discussed.[@Kobayashi16a; @Kobayashi16b] Here we focus on response to applied fields. Fig. \[fig:plot2\] compares a one and two dimensional case, showing that despite the issues of vortex/antivortex pairs the basic evolution of the gap amplitude (panels (a) and (b)) and supercurrent (panels (c) and (d)) are very similar in the two cases. We therefore believe that for the purposes of understanding the response to probe fields, consideration of the one dimensional model suffices. Response to Short Electric Field Pulse\[sec:response\] ====================================================== We now turn to the application of an electric field pulse along the wire which we describe as $$\vec{E}(t)=\vec{A}\frac{1}{T_0\cosh\left(\frac{t-t_p}{T_0}\right)^2},\label{eq:Epuls1}$$ where $A/T_0$ is the maximal field strength, $t_p$ is the center time and $T_0$ is the width of the pulse. This electric field pulse is difficult to apply experimentally, but provides substantial physical insight (note Ref. ). We will consider experimentally relevant probe pulses profiles in the next section. For simplicity we concentrate the discussion on the case where the phase winding is zero before the pulse is applied. The relation $\vec{E}=- \partial_t \vec{A}$ means that the E-field pulse of Eq. \[eq:Epuls1\] leads to a long time increase in the vector potential $\Delta \vec{A}=\vec{A}(t\rightarrow \infty)-\vec{A}(t\rightarrow -\infty)$. Integrating Eq. \[eq:Epuls1\] gives $$\Delta \vec{A}(t)=-\vec{A}\frac{1+\tanh\left(\frac{t-t_p}{T_0}\right)}{2}.$$ The presence of a vector potential will lead to a supercurrent; if the current is sufficiently large, phase slips will occur, allowing the phase gradient to adapt to the vector potential and the current to relax. The phase slip dynamics depend crucially on the magnitude of the applied field and on the timing of the pulse relative to the development of the phase stiffness of the superconducting state. If the pulse is applied at very early times, the small value of the order parameter means that phase slips are easy to drive and the phase will adapt to the vector potential, leading to minimal current at long times. On the other hand, if the pulse is applied at later times, the phase stiffness will be fully established and phase slips will only be generated if the supercurrent is sufficiently large. Fig. \[fig:plot3\] shows the results of applying an E-field pulse at a time $Dt_p=1000$ long after the superconducting state is established. We see that in both the one and two dimensional cases a supercurrent is rapidly established after the pulse and persists. The concomitant decrease of $\Delta$ is also visible. No phase slips occur. For E-field pulses that are stronger, or applied earlier, phase slips may occur. The stability analysis performed in[@Ivlev84; @Vodolazov02; @Ludac08; @Ludac09] reveals that within the deterministic TDGL dynamics for fully established phase stiffness the critical value for the vector potential is $A_{c}=\Delta_0/(2\sqrt{3}\xi )\approx 0.091/\xi$. In Fig. \[fig:plot3\] we present the order parameter evolution after a quench at $t=0$ followed by the application of a stronger electric field pulse $A=0.1/\xi>A_{c}$. The upper panels shows the results when the pulse is applied the early time, $Dt_p=10$. Comparison of panel (a) to the corresponding panel of Fig. \[fig:plot2\] shows that the time evolution of the magnitude is almost unaffected by the change in the vector potential: the phase simply rearranges to compensate the external vector potential to the extent possible given the quantization of the phase winding. The evolution of the current reveals similar physics: we see that after an initial current pulse visible as the vertical region adjacent to the $t=0$ axis, the current is very small (corresponding to the very small order parameter amplitude) and then increases as the order parameter increases, eventually saturating at the value given by optimal winding number. The lower panels of Fig. \[fig:plot3\] show results when the pulse is applied at a late time, $Dt_p=600$, after the superconducting state is almost fully established. In this case the initial response of the system is to keep the phase fixed ($\nabla\phi=0$), to reduce the order parameter to the value (dashed line) corresponding to $\nabla \phi=0$ and the given $A$, and to build up a supercurrent $\sim \Delta^2 A$. We see however that this large-current state is only an intermediate time regime: at a longer time phase slip events occur that relax the system back to the minimum energy state, with minimal current and maximal order parameter amplitude. To understand the degree to which phase slips occur we computed the long-time limit of the winding number and current following from 100 randomly chosen initial conditions, for electric field pulses applied at a series of times ranging from very early, when the magnitude of the superconducting order parameter is negligibly small, to late, when the superfluidity is well established. We chose a pulse strength $\xi A=0.05$ and a system of length $L=100\xi$, so the flux $\Phi=\frac{5}{\pi}\Phi_0$. This choice of flux puts the system very close to the crossing point of the parabolas (as indicated in the inset of Fig. \[fig:cross\]). For each initial condition we computed the long time limit of the winding number and the current. The diamonds connected by a solid line in Fig. \[fig:cross\] (green on-line, numerical values given on the right axis) show the long time limit of the current $\bar j$, averaged over all 100 initial conditions and plotted as a function of the time the E-field pulse was applied. A pulse applied at an early time leads to a small current; a pulse applied at late times leads to a large current. We have also analysed the statistics of phase slip events. The squares, circles, down triangles and up triangles show the percentage of initial conditions (left axis) leading to states with winding number $n=-1,0,1,2$ respectively for a probe field applied at the given time. If the electric field pulse is applied early we find that the phase conforms to the vector potential, whose long time limit corresponds to a flux $\Phi=\frac{5}{\pi}\Phi_0\approx 1.59\Phi_0$ yielding a high percentage of states with $n=2$ and $n=1$ phase winding. As the time of application of the electric field pulse is increased, the phase stiffness increases and the likelihood of phase slips (needed to reach the $n\neq 0$ states) go down. We see that the probability of finding a long time state with winding number $n=2$ rapidly decreases; and as the time of application of the pulse further increases the vast majority of the states have $n=0$ with a small probability of $n=\pm 1$. Finally, we turn our attention to the lifetime of the supercurrent plateau obtained for stronger electric field pulses. If $A>A_{c}$, dynamic phase slips become activated leading to transitions to lower-current, energetically favored states. For $A>A_c$ the typical situation is shown in panel (d) of Fig. \[fig:plot3\]: we have a supercurrent plateau that lasts for a time $\tau$ before a set of phase slip events occur that cause the system to transition back to a state of zero winding number and vanishing current. We calculated $\tau$ of the supercurrent (as defined in Fig. \[fig:plot3\]) for a total of $100$ initial conditions $A$ and different center times $Dt_p$ of the electric field pulse. Fig. \[fig:Fluc\] shows that $\tau$ has a systematic dependence on the strength of the applied field. Stronger E-field pulses leave larger vector potentials, which more easily drive phase slips. We also see that if the pulse is applied at relatively early times $Dt_p\lesssim 400$ the waiting time for a phase slip is relatively short $D\tau \lesssim 700$ the systematics are less clear. In this regime the phase stiffness is small enough that phase slips occur relatively easily. For pulses applied at late times, we also see a systematic dependence on the magnitude of the order parameter fluctuations. These fluctuations are parametrized by $\sigma_\Delta$, the root mean square order parameter fluctuation, computed at the time at which the pulse is applied. The dependence on $\sigma_\Delta$ is logarithmic. The outliers to this logarithmic dependency are cases either where phase stiffness is not yet established at the time of the electric field pulse (approximately $Dt_p<500$) or if the winding number before the application of the electric field pulse happens to be $n> 0$. Response to Physical Electric Field Pulse \[sec:PhysicalPulse\] =============================================================== Many time-domain experiments,[@Averitt00; @Larsen11; @Matsunaga12a] utilize an electric field probe pulse of approximately the form (we also give the corresponding vector potential) $$\begin{aligned} E_{\rm probe, 1}(t)&=A_0\left(1-2\frac{(t-t_p)^2}{T_0^2}\right)e^{-(t-t_p)^2/T_0^2}\\ A_{\rm probe, 1}(t)&=-A_0\frac{t-t_p}{T_0}e^{-(t-t_p)^2/T_0^2},\end{aligned}$$ with the peak electric field $E_0=A_0/T_0$. In Ref. we proposed a second form of the probe field $$\begin{aligned} E_{\rm probe, 2}(t)&=2A_0\frac{(t-t_p)}{T_0}e^{-(t-t_p)^2/T_0^2}\\ A_{\rm probe, 2}(t)&=A_0e^{-(t-t_p)^2/T_0^2},\end{aligned}$$ These functional forms are depicted in Fig. \[fig:funcft\]. In the following we will denote them as type-I and type-II probe pulses, respectively. The form $E_1$ is more convenient experimentally, but $E_2$ allows for the reconstruction of the time dependent superfluid stiffness via a time integral of the induced current. The parameter $a$ tunes the width of the probe pulses. Fig. \[fig:Resp1\] and fig. \[fig:Resp2\] summarize the current response to a type-I and type-II electric field probe pulse, respectively. If the phase is not stiff the current response to an electric field probe is very weak. As the phase stiffens the response’s line shape increasingly starts to corresponds to the input vector potential until at large probe times $t_p$ the current perfectly follows the potential change as expected from $j\sim A(t)$ at $\nabla \phi=0$. In Ref. we argue that assuming the phase is stiff the integrated current $$I(t)=\int\limits_{t_{\rm l}}^td\tau j(\tau)\label{eq:I}$$ resulting from a type-II probe pulse can be linked to the superfluid stiffness. Here we introduce a lower cutoff $t_{\rm l}$ such that we do not integrate over the current resulting out of the quench dynamics. Thus $t_{\rm l}$ must be larger then the time needed to build up the phase stiffness (for the paramter used here $Dt_{\rm l}\approx 500$) to relate the integrated current to the superfluid stiffness. At large times where the phase is indeed stiff the integrated current should reach the asymptotic value $$I(\infty)=-2\sigma\tau_s\xi A\sqrt{\pi T_0}\left[\Delta_0^2-\frac{4}{\sqrt{3}}(\xi A)^2\right].\label{eq:Iinf}$$ We include here the $A^3$ correction resulting from the $\Delta$ dependence on the supercurrent, which was neglected in Ref. . The integrated current $I(t)$ for a type-II probe field applied at large times $Dt_p=1500$ is shown in the inset of Fig. \[fig:Resp2\]. We choose $Dt_{\rm l}=1000$ to cutoff the small contribution to the current arising due to the quench dynamics. As the upper dashed line we give the value predicted from Eq. and as the lower dashed line the same but keeping only the linear order in $A$. The former agrees perfectly, while the later shows small deviations as expected for the shown small value of $\xi A_0=0.05$. We note an interesting feature in the current response. While for both pulse types, the time integral of the electric field vanishes at long times (so no long-time vector potential is induced), the time dependence of the superconductivity means that the integral of the product of the electric field and the superfluid response need not vanish. In physical terms, in a nonequilibrium situation the supercurrent created during the second part of the electric field cycle need not cancel supercurrent created in the first part, leaving a net supercurrent even for a type I or II pulse. The effect is most pronounced for a relatively wide type II pulse with center time corresponding to the time over which the phase stiffness is becoming established. In this case the negative half of the electric field pulse might be in the regime where the phase is not stiff and a negligible supercurrent is induced while for the positive half of the electric field pulse the phase is stiff and a current is induced. To analyze this in more depth we present in Fig. \[fig:Resp22\] the long time current $\bar j$ averaged over $100$ initial conditions for the same parameters as in Fig. \[fig:Resp2\] and two widths of the type-II electric field probe pulse $T_0=100$ and $T_0=300$. As the center time $t_p$ crosses through the build up time of the superconductor ($Dt\approx500$) the current first rises up and then returns to zero, in accordance to the picture drawn above. Conclusion\[sec:conclusion\] ============================ In this paper we have used the time dependent Ginzburg-Landau equations to address the response to a probe field of a system quenched into a superconducting state. The key issue is that a superfluid response requires a non-negligible phase stiffness, which has to build up dynamically after a quench. The value of the phase stiffness controls the likelihood of phase slips and the magnitude of the electromagnetic response. An important related issue is that the quench dynamics correspond to evolution in time from random initial conditions; these lead to a distribution of states, some of which are metastable states carrying a supercurrent even in the absence of externally applied fields. Such states have a different electromagnetic response than do non current-carrying states. A third important point is whether the probe is strong enough to activate phase slip processes. If the probe is applied before the superconducting order is established, phase slips occur so that the vector potential is compensated and no long term supercurrent is induced, whereas for a weaker probe pulse a state with a long-lived supercurrent is established. We find that the lifetime of a state with a long-lived supercurrent scales logarithmically with the amplitude of fluctuations in the magnitude of the order parameter. We considered the response to two types of probe line-shapes. One is the electric field pulse, in which the time integral of the field is non-zero so the vector potential is different at long times after the pulse than it was before the pulse. In the other (of which we considered two variants) the time integral of the electric field vanishes, so no vector potential is left at long times. The response to an electric field pulse provides useful physical insights, but pulses in which the time integral of the electric field vanishes are more easily achievable in experiments. We studied the changes in system response as the time of probe application is varied relativel to the time of the onset of superconducting phase stiffness. For the case where the probe is applied before the superconducting order builds up, we find that the phase of the superconducting order parameter adopts to the vector potential change and there is no clear superconducting response. In the opposite case where the probe is applied after phase stiffness is established, we find a canonical superconducting response. In the intermediate regime, where the center time of the probe pulse aligns with the build up time of the superconducting phase stiffness, we report that an asymptotic supercurrent can be induced at large times although the total vector potential does not change overall. This is because the one cycle of the electric field pulse applied at times where the phase is not stiff and can thus be compensated by the phase, while during the times of the second cycle the phase is stiff and thus the system will respond with the build up of a supercurrent. If that current is too small to activate the phase slip process it will have infinite lifetime. Several generalizations of our work would be of interest. Extending our analysis, which is based on simple theoretical models, to more realistic situations such as one dimensional wires with a finite transverse dimension, is important because the wire thickness will affect the energetics and dynamics of phase slips. Further consideration of experiments that might reveal the phase slip dynamics is important. The mesoscopic considerations of disorder and sample to sample fluctuations are also of interest. Further, our analysis of higher dimensional situations was limited. Our work indicates that the basic issues relating to the timing of the probe field relative to the onset of phase stiffness are not strongly dimension dependent, but the interplay of the timing of probe fields with other aspects of the quench physics including structure of vortex-antivortex pairs or vortex loops requires further analysis. Additionally, treating thermal fluctuations and the pinning of phase slip center by impurities is a fascinating and important avenue of future research. [Acknowledgements:]{} AJM was supported by the Basic Energy Sciences Program of the US Department of Energy under grant 0012592. DMK was supported by DFG KE 2115/1-1. Simulations were performed with computing resources granted by RWTH Aachen University under project rwth0013. Numerical Procedure {#Appendix:a} =================== In this appendix we present some details of our numerical procedures. A quench involves an evolution forward in time from initial conditions that are determined by the fluctuations in the pre-quench state. In the superconducting case of interest here one has a two-component order parameter, which may be characterized by a magnitude and a phase or by the amplitudes of the real and imaginary parts. The actual initial conditions involve a distribution of both magnitude and phase (or equivalently of real and imaginary parts) which is random in space and time but correlated over length scales of the order of a bare coherence length $\xi$. Since the basic length scale in our theory and in our numerics is $\xi$ we simply take the order parameter to be random from site to site of our computational lattice. One may also as a simplification in the numerical consider initial conditions in which the magnitude of the order parameter is fixed and only the phase varies from site to site. The two choices of initial condition are represented in Fig. \[fig:ini\_cond\_1\]. We have found that the two initial conditions lead to equivalent results, which is shown in Fig. \[fig:plot02\]. We solve the TDGL equations by integrating forward in time using a first order Euler method. The algorithm requires a step size $\Delta x$ in space and $\Delta t$ in time. We have found that choosing $\Delta x=\xi$ suffices. To verify this we consider how the results shown in Fig. \[fig:plot1\] change as the step size is reduced. We compare numerically three values of $\Delta x/\xi=1,0.5,0.25$ keeping $L/\xi=100$ constant. This means that we define lattices of different number of lattice sites $100$, $200$ and $400$, respectively. To address the numerical convergence we need to choose the same initial conditions for all three values of $\Delta x$. To do so, we draw a random initial condition for our largest value of $\Delta x/\xi=1$ and then for the smaller values of $\Delta x$ copy the each value of the initial condition onto a pair of sites, for $\Delta x/\xi =0.5$, or a quadruple of sites, for $\Delta x/\xi =0.25$. The results are summarized in Fig. \[fig:conv\] showing the magnitude of the order parameter for a typical initial condition at one of the lattice sites. We see that decreasing the step size has no effect on the results Similarly we find that comparing $D \Delta t=0.01$ to $D \Delta t=0.001$ gives converged results and we choose the ladder. I. Bloch, J. Dalibard, and W. Zwerger, Rev. Mod. Phys. [80]{}, 885 (2008). C. Gogolin and J. Eisert, Rep. Prog. Phys. 79 (2016) 056001. F. H. L. Essler and M. Fagotti, J. Stat. Mech. (2016) 064002. L. Vidmar and M. Rigol J. Stat. Mech. 064007 (2016). R. Mankowsky, M. Först, T. Loew, J. Porras, B. Keimer, and A. Cavalleri, Phys. Rev. B [91]{}, 094308 (2015). M. Mitrano, A Cantaluppi, D. Nicoletti, S. Kaiser, A. Perucchi, S. Lupi, P. Di Pietro, D. Pontiroli, M. Riccò, S. R. Clark, D. Jaksch, A. Cavalleri, Nature [530]{}, 461 (2016). A. Komnik and M. Thorwart Eur. Phys. J. B [89]{}, 244 (2016). M. A. Sentef, A. F. Kemper, A. Georges, and C. Kollath, Phys. Rev. B [93]{}, 144506 (2016). M. Knap, M. Babadi, G. Refael, I. Martin and E. Demler, Phys. Rev. B [94]{}, 214504 (2016). D. M. Kennes, E. Y. Wilner, D. R. Reichman, and A. J. Millis, Nat. Phys. [13]{}, 479 (2017). M. Babadi, M. Knap, I. Martin, G. Refael and E. Demler, Phys. Rev. B [96]{}, 014512 (2017). M. A. Sentef, Phys. Rev. B [95]{}, 205111 (2017). A. Nava, C. Giannetti, A. Georges, E. Tosatti, M. Fabrizio, arXiv:1704.05613. D.M. Kennes, E.Y. Wilner, D.R. Reichman, A.J. Millis, arXiv:1703.07248. M. Cyrot, Rep. Prog. Phys. [36]{} 103 (1973). L. P. Gor’kov and N. B. Kopnin, Sov. Phys. Usp., [18]{} , 496 (1975). B. I. Ivlev and N.B. Kopnin, Sov. Phys. Usp. [27]{}, 206 (1984). Michikazu Kobayashi and Leticia F. Cugliandolo, Phys. Rev. [E 94]{}, 062146 (2016) Michikazu Kobayashi and Leticia F. Cugliandolo,EPL [115]{}, 20007 (2016) D. Y. Vodolazov and F. M. Peeters, Phys. Rev. B [66]{}, 054537 (2002). K.Yu. Arutyunov and D.S. Golubev and A.D. Zaikin, Physics Reports [464]{}, 1 (2008). M. Lu-Dac and V. V. Kabanov, Journal of Physics: Conference Series [129]{}, 012050 (2008). M. Lu-Dac and V. V. Kabanov, Phys. Rev. B [79]{}, 184521 (2009). L. Kramer and W. Zimmermann, Physica D [16]{}, 221 (1985). S. Michotte, S. Mátéfi-Tempfli, L. Piraux, D. Y. Vodolazov, and F. M. Peeters Phys. Rev. B 69, 094512 (2004). V. V. Baranov, A. G. Balanov, and V. V. Kabanov Phys. Rev. B 84, 094527 (2011). K. Harrabi, A. F. Salem, K. Ziq, A. I. Mansour, S. Kunwar, J. P. Maneval, G. Berdiyorov, Appl. Phys. A [117]{}, 2033 (2014). G. R. Berdiyorov, M. V. Milošević and F. M. Peeters, Phys. Rev. B [81]{}, 144511 (2010); V. L. Gurtovoi and A. V. Nikulov Phys. Rev. B [90]{}, 056501 (2014); G. R. Berdiyorov, M. V. Milošević and F. M. Peeters, Phys. Rev. B [90]{}, 056502 (2014). G. Berdiyorov, K. Harrabi, J. P. Maneval and F. M. Peeters, Supercond. Sci. Technol. [28]{}, 025004 (2015). R. D. Averitt, G. Rodriguez, J. L. W. Siders, S. A. Trugman and A. J. Taylor, J. Opt. Soc. Am. B [17]{}, 327 (2000). C. Larsen, D. G. Cooke and P. U. Jepsen, J. Opt. Soc. Am. B [28]{}, 1308 (2011). R. Matsunaga and R. Shimano Phys. Rev. Lett. [109*]{}, 187002 (2012).
Why are @illumina flowcell names so similar (but only occasionally rude) Anyone who’s run Illumina instruments over the years is likely to have noticed how flowcells can have remarkably similar (and occasionally amusing) names. This can create a real headache when looking for a specific run as a single mismatch can cause you to spend some time looking at one run when you thought you were supposed to be looking at something else. Even the BaseSpace search appears to allow mismatches in this key identifier. This has been an obvious issue their HiSeq platforms for many years but has remained unchanged. It’s only a problem for labs running lots of flowcells because these are generally shipped in a similar order to their manufacturing date. As such it is not uncommon to have two flwocells being run on the same day with different sets of samples on paper and in the LIMs – a recipe for flwocell mixups if ever there was one! And one my team is very careful to avoid!!! This is what HiSeq flowcells look like (feel free to fill in the gaps): NovaSeq looks like it’ll have the same issue – but with many fewer flowcells being run per week due to the vast volumes of data obtainable on Illumina’s newest sequencer: NovaSeq: H27FHDSXX The problem is worst on MiSeq. Of over 1500 MiSeq runs performed in my lab almost one third of the 5 character flowcell IDs differed by only a single character e.g. A9YV6, A9YVD, A9YVK, A9YVL, A9YVM, A9YVR, A9YVT & A9YVU (a run of 8) or 64D50, 64D53, 64D54, 64D55, 64D5A, 64D5B, 64D5C, 64D5F, 64D5G & 64D5L (a run of 10). It’d be great if Illumina increased the number of characters, or used these few characters more sensibly, or randomly assigned flowcells IDs rather than simply increment (which is what it looks like they do). Sometimes small things make all the difference. Rude flowcells: One of the interesting, but unsubstantiated, things I’ve learnt about Illumina over the years is that they employ a rude word filter to screen flowcell IDs. If you’ve got any interesting ones to share please do (I’ll start a Twitter thread on this). Fortunately for me they did not seem to catch these little w*****s: C6J0WANXX, C5MCWANXX, C5U6WANXX, C4NYWANXX, C5ECWANXX, C40JWANXX, C4EKWANXX ! 2 Comments Hi James, The GAI used four or five numbers (without letters) in 2007 The GAII used a combination of five numbers and letters, starting with two or three numbers in 2008 (FC3….) The GAIIx used a combination of five numbers and letters, starting with two or three numbers in 2010 (FC6…) So it has always been a combination of five numbers and letters, where the flow cells for HiSeq seem to have more letters than numbers, and an additional four letter code specific for the sequencing platform. About Enseqlopedia The new home of the Core Genomics blog, and a site for NGS users to tell people who they are and what they do (on the map), and share knowledge (on the Enseqlopedia NGS methods wiki). This site is aimed at the whole NGS community - users, core labs & services, technology providers. Thanks for looking - James. Contribute to Enseqlopedia Enseqlopedia encompasses three elements: The NGS methods wiki "Enseqlopdia", the Googlemap of sequencers "NGS Mapped" and the Core Genomics blog. Please do sign-up and contribute to the Map or the Wiki, or to receive future blog posts - you can register for any or all.
Saturday, February 03, 2007 I spent most of the Sharks-Chicago game up near the rafters chatting with Lew Shapiro, PR director for the NHL's Oakland/California Seals (1967-76), and the PHL San Francisco Shamrocks (1977-79). It was interesting talking to him about the media coverage back in the day, the opening of the Oakland Coliseum, and a few other hockey related topics. I wandered down to the top of the aisle in the lower bowl in the second period to take a few photos. After the above Chicago goal by Martin Havlat over a sprawled Vesa Toskala, one fan in a soccer jersey let out a gooooo-ooo-oooaaa-ooooaaal that would have made Andres Cantor proud. Patrick Marleau answered with a goal of his own a few minutes later. Marleau wristed the puck around Khabibulin before he could reset after a scramble. This time soccer fan stumbled, barely getting out a gaa ol-ol. The section had a good laugh. There was a massive collision between Mark Bell and a player who is not on my score sheet, #89 Troy Brouwer. After the game, Vesa Toskala said he could not remember ever scoring 2 assists in a game before. It was 1 point shy of an NHL single game record, and half of the total for current NHL goalie points leader (Turco). When someone jiibed him about Evgeni Nabokov's power play goal a few years back, he said he picked one up in Europe so he was fine. Toskala had an open net late in the third, but he cleared the puck off the boards instead of trying to loft a shot up ice. Given the way the bounces have gone the last few games, smart move. More on the Sharks-Blackhawks here. Sharks play Anaheim at HP Pavilion in beautiful San Jose on Tuesday, before heading to Anaheim on Wednesday to play in the smog. Let the Battle of California begin!
Transection of the base of the tongue caused by penetrating injury. Traumatic transection of the base of the tongue can be a life-threatening injury because of blood loss and airway obstruction. Airway control, hemostasis, and meticulous anatomic repair are necessary to prevent speech and airway dysfunction. Laryngeal injuries, when present, require these same principles.
Importance of thymidine kinase activity for normal growth of lumpy skin disease virus (SA-Neethling). In order to study the importance of an intact thymidine kinase (TK) gene for the vaccine strain of a southern African capripoxvirus, namely, lumpy skin disease virus (LSDV) (type SA-Neethling), a TK disruption recombinant was generated expressing the Escherichia coli beta-galactosidase (lacZ) reporter gene. A comparative growth study of the recombinant and wild-type (wt) LSDV in TK-positive primary and secondary cells and TK-negative secondary cells was performed. It was found that although recombinant and wt virus both grew in TK-positive cells without selection, the recombinant was unable to grow in TK-negative cells (with or without selection), indicating that TK activity is important, if not essential, for normal growth of LSDV.
Coming up they were confused Dec 05, 2008 Danny Boyle’s “Slumdog Millionaire” is an emotionally uplifting tale about an orphaned boy struggling through life in Mumbai that just might usher in Bollywood to the masses. Though the ending is predictable within its first few minutes, Boyle brings a gripping energy to the film, offering a balanced dose of harsh reality and thoughtful escapism. One question away from winning 20 million rupees on India’s version of “Who Wants to be a Millionaire,” Jamal Malik (Dev Patal) is dragged from backstage and mildly tortured by authorities who suspect this uneducated “tea boy” is cheating. In order to continue playing in the next week’s episode, Jamal must explain how he arrived at each answer. Thus the film jolts backwards and forwards through a series of flashbacks, as Jamal shares the poignant moments in his story that led him to this point. Jamal’s coming of age is a story of competition and survival, like modern India itself. While the elite classes roll around in luxury cars and live in skyscrapers, slum-dwellers struggle to get by. Crime fills Mumbai’s dirty streets and entire villages go up in flames in one night. Jamal’s craftiness was born in the gutters — he manipulates, steals and cheats to stay alive. The driving force of this film is young Jamal’s devotion to another “slumdog,” the enchanting Latika (Freida Pinto). The tension between Jamal’s idealized love and the devastation that surrounds him provides the film with an energy that keeps the audience involved. Though the film’s ending is like a modern fairy tale, the inventive structure of the film avoids any clichés. It’s not the ending point that we are rushing to get to; rather, every step of Jamal’s young life is significant in his future. Cheesy Bollywood dancing accompanies the closing credits, as if Boyle couldn’t resist playing on the stereotype. That aside, “Slumdog” is a much more accessible Indian film for American audiences that don’t favor the grandiose style of many Bollywood musicals. Mark Herman’s “The Boy in the Striped Pajamas” presents a far different coming-of-age story. The son of a highly ranked Nazi soldier, Bruno is part of the German privileged class. Unlike Jamal, Bruno has never witnessed the atrocities in his homeland, and has parents who knowingly hide the truth from their young son. It is only when Bruno encounters the oppressed that he questions what he has been told, though he never shares Jamal’s grasp of reality. Jamal rises out of the slums by any means possible, but Bruno remains tragically innocent at the film’s conclusion. At its outset, Bruno’s family moves to the country, only steps away from the concentration camp his father commands. Though his tutor spews propaganda daily to Bruno and his sister about the evil ways of the Jewish race, Bruno ultimately befriends another eight-year-old boy, Shmuel (Jack Scanlon), a Jewish prisoner in the camp. This friendship grows, despite the electric barbed wire that separates them, and Bruno begins to struggle with the Nazi ideology and the child before his eyes. The most interesting facet of the film is its unique point of view through the eyes of a Nazi child. For Bruno, concentration camps are farms, worker uniforms are striped pajamas, and their numbers are all part of some game. It’s easy to sympathize with the naïve view of this child, who stands in sharp contrast to his older sister, who buys into the Third Reich’s rhetoric — posters of Hitler and Nazi Youth blanket every inch of her walls. Though it is assuredly not Herman’s intent to trivialize the plight of the Jews, the narrow scope of the film hinders a strong emotional response to the atrocities of the Holocaust. Rather, we are repeatedly and not so subtlely confronted with innocence versus Nazism. Shmuel, the most innocent victim in the film, speaks no more than 10 sentences throughout the film, and the Jews themselves are practically used as extras. What’s worst, the final shocking moments render the film’s message meaningless, essentially demeaning the Holocaust. In the final shots of the film the iron doors of a gas chamber are shut tight with Bruno inside, and his family screaming out in anguish — transforming this into a family tragedy, when it shouldn’t be. We are shocked and nauseous, but for a young German boy and his grotesque father. The hundred dead Jewish bodies that lie inside seem like an afterthought. In one instant, 120 minutes worth of a heartfelt story loses all its purpose.
72 B.R. 181 (1986) In re NERLICH, N.V., A Netherlands Antilles Corporation, d/b/a Cherokee Plantation, Debtor. In re NERLICH CORPORATION d/b/a Cherokee Plantation, Debtor. Bankruptcy Nos. 85-01199, 85-01200. United States Bankruptcy Court, D. South Carolina. June 9, 1986. Frank B. Wilensky, Macey, Wilensky, Cohen & Wittner, Atlanta, Ga., for debtor. Stanley H. McGuffin, Asst. Gen. Counsel, Columbia, S.C., Mark S. Sharpe, Sinkler and Boyd, Charleston, S.C., for S.C. Nat. Bank. MEMORANDUM AND ORDER J. BRATTON DAVIS, Bankruptcy Judge. Before the court is the approval, vel non, of the disclosure statement relating to the plan of reorganization, both of which were filed by South Carolina National Bank (SCN) on February 20, 1986. The debtors and Hans Joachim Nerlich (Nerlich) object to the disclosure statement on the ground that a disclosure statement should not be approved if the plan of reorganization cannot be confirmed. The debtors contend that SCN's plan of reorganization proposes to liquidate the assets of farmers, which, debtors allege, is prohibited by the Bankruptcy Code (11 U.S.C. § 101 et seq.). Nerlich objects to the disclosure statement on the ground that his claim impermissably was classified separately in the plan of reorganization. 182 FACTS On June 24, 1985, the debtors filed a petition for relief under chapter 11 of the Bankruptcy Code. The debtors have not filed a plan of reorganization. More than 120 days have passed since the filing of the petition. Thus, the debtors' exclusive period for filing a plan has expired.[1] SCN's plan of reorganization calls for the sale of the debtors' assets through a chapter 11 liquidation. ISSUES I Whether a disclosure statement for a plan of reorganization which calls for the liquidation of a farmer's assets should be approved over the farmer's objection. II Whether SCN's disclosure statement should be approved even though SCN's plan of reorganization places Nerlich's claim in a separate class. DISCUSSION AND CONCLUSION I Although the Bankruptcy Code includes provisions which afford special protection to farmers 11 U.S.C. § 303(a) excepts farmers from involuntary cases; 11 U.S.C. § 1112(c) prohibits the court from converting a farmer's chapter 11 case to a case under chapter 7 unless the debtor requests such conversion there is a split of authority as to whether a creditor's chapter 11 plan of reorganization, which proposes the liquidation of the assets of a farmer, should be confirmed over the farmer's objection. (A plan of reorganization which calls for the liquidation of a farmer's assets over his objection may be approved. In re Jasik, 727 F.2d 1379 (5th Cir.1984), In re Button Hook Cattle Co., Inc., 747 F.2d 483 (8th Cir.1984) and Toner v. Staunton P.C.A. (In re Toner), 40 B.R. 461 (Bankr. W.D.Va.1984), aff'd Case No. 84-2389 (4th Cir.1985) 767 F.2d 912 (table). In other courts a plan of reorganization which called for the liquidation of a farmer's assets was not approved over the farmer's objection. In re Lange, 39 B.R. 483 (Bankr.D.Kan. 1984), and In re Blanton Smith Corp., 7 B.R. 410 (Bankr.M.D.Tenn.1980)). Once the farmer has entered Chapter 11 voluntarily, there should be no complaint that the provisions protecting creditors' rights are applied on an equal footing with those provisions that provide relief to debtors. Thus, creditors should be allowed to submit their own reorganization plans once the farmer has exhausted 11 U.S.C. § 1121's exclusive filing period. If a creditor's plan satisfies the requirements set forth in 11 U.S.C. § 1129, it should be confirmed over the farmer's objections notwithstanding the fact that it may propose the liquidation of the farmer's assets. The Code recognizes that liquidation is an appropriate form of reorganization, see 11 U.S.C. §§ 1123(a)(5)(d), (b)(4), 1129(a)(11), and, absent an indication of congressional intent to the contrary, we decline to imply a farmer's exemption from chapter 11 liquidation plans. Toner, Case No. 84-2389 (4th Cir.1985), at 6. With this guidance from the Court of Appeals of the Fourth Circuit, this court concludes that at this point in the case when the debtor's exclusive filing period (11 U.S.C. § 1121) has expired SCN's "rights apply on an equal footing with those provisions that provide relief to the [debtor, thus SCN] should be allowed to submit [its] own reorganization [plan] . . . notwithstanding the fact that it may propose the liquidation of the farmer's assets." See, Toner. SCN's disclosure statement contains "adequate information", as defined in 11 U.S.C. § 1125, and it should be approved. A hearing on the confirmation of SCN's plan will be scheduled for a later day. 183 II Nerlich, contending that the plan of reorganization should not be approved in that it classifies his claim separately, would have this court deny approval of SCN's disclosure statement. As authority for his position he relies on 11 U.S.C. § 1122, which states: (a) Except as provided in subsection (b) of this section, a plan may place a claim or an interest in a particular class only if such claim or interest is substantially similar to the other claims or interests of such class. (b) A plan may designate a separate class of claims consisting only of every unsecured claim that is less than or reduced to an amount that the court approves as reasonable and necessary for administrative convenience. Nerlich's reliance on 11 U.S.C. § 1122 is misplaced. Section 1122 requires that all claims in a class be substantially similar to the other claims in that class but does not require that all similar claims be placed in the same class. Section 1122 permits classification of claims and interests subject to the restriction that a claim or interest may be included in a particular class only if it is `substantially similar' to other claims and interests of such class. Note that the Code does not requires that all claims that are substantially similar be placed in the same class. Collier on Bankruptcy, ¶ 1122.03, p. 1122-7 (15th ed. 1979) (emphasis added). This court agrees that 11 U.S.C. § 1122 does not require that all claims, which are substantially similar, be in the same class; therefore, the objection of Nerlich to SCN's disclosure statement should be overruled even though SCN's plan of reorganization places Nerlich's claim in a separate class. ORDER The disclosure statement, as amended,[2] should be approved and the objections thereto overruled. AND IT IS SO ORDERED. NOTES [1] See 11 U.S.C. § 1121(b). [2] Subsequent to the court's taking this matter under advisement, SCN filed an amendment to the disclosure statement which states: "Proponent has filed an objection to the claim of Nerlich and asserts in the objection that the claim is actually a contribution to capital rather than a valid debt of Debtor. In the event the Court determines the claim is actually a contribution to capital, Nerlich would remain a Class IV Creditor. In the event the Court determines the Nerlich claim is a valid debt of Debtor, the Plan would be amended to delete the Class IV classification and Nerlich would share in the distribution scheme as a Class III Creditor. This issue must be ruled upon prior to confirmation of any plan. An amendment to the plan deleting Class IV would be a material amendment and would require notification to creditors and a new vote on the amended plan."
# About emptyExample ![Screenshot of emptyExample](emptyExample.png) ### Learning Objectives This example is the simplest possible openFrameworks app! It does nothing. ...Well, almost nothing. Although it may not be apparent, the emptyExample activates all of the default system states. (For example, it sets the default fill color to white; it just doesn't happen to draw anything with it.) The emptyExample is great for making sure that your openFrameworks development environment is compiling properly. It can also be useful as a "starter template" for making simple programs. The emptyExample will help you understand what are the bare necessities of an openFrameworks program. In this regard, you can think of it as a "Hello World" for OF. ### Expected Behavior When launching this app, you should see a light-gray screen. * There's no interaction. * There's nothing to see. * That's it. Instructions for using the app: * There's nothing to do. Move along. ### Other classes used in this file This example uses no other classes.
Julius Borcea Julius Bogdan Borcea (8 June 1968 – 8 April 2009) was a Romanian Swedish mathematician. His scientific work included vertex operator algebra and zero distribution of polynomials and entire functions, via correlation inequalities and statistical mechanics. Biography Born in Bacău, Romania, by a math teacher who instilled in her son's intellect the beauty of mathematics, he studied in 1982-1984 at the Lycée Descartes in Rabat, Morocco, and he completed his Baccalaureat at the Lycée Français Prins Henrik of Copenhagen. In 1987–1989 he attended the Lycée Louis-le-Grand in Paris. He obtained his PhD in Mathematics in 1998, at Lund University, under the direction of Arne Meurman. After defending his PhD thesis in 1998, he embarked in postdoctoral studies at the Mittag-Leffler Institute for six months and at the University of Strasbourg for two years. He was appointed Associate Professor in 2001, and Lecturer in 2005 at Stockholm University. A year later he was granted the Swedish Mathematical Society's Wallenberg Prize. Promoted to Full Professor in 2008, he was awarded a Royal Swedish Academy of Sciences Fellowship, in 2009, and the Crafoord prize research grant diploma. Professional profile Borcea's scientific work ranged from vertex operator theory to zero distribution of polynomials and entire functions, via correlation inequalities and statistical mechanics. His thesis consists of two seemingly independent parts: one in vertex operator theory and the other devoted to the geometry of zeros of complex polynomials in one variable. In vertex operator theory, Julius generalized results of Mirko Primc and Arne Meurman and gave a classification of annihilated fields. As concerns complex polynomials, he tackled Sendov’s conjecture on zeros and critical points of complex polynomials in one variable. Using novel techniques, he proved the conjecture for polynomials of degree not exceeding 7. Earlier (1969) the conjecture had been proven for polynomials of degree not exceeding 5. At Stockholm University, Julius had a steady collaboration with Rikard Bøgvad and Boris Shapiro. They worked on rational approximations of algebraic equations, piecewise harmonic functions and positive Cauchy transforms, and the geometry of zeros of polynomials in one variable. Borcea and Petter Brändén collaborated on a project on the geometry of zeros of polynomials and entire functions. They characterized all linear operators on polynomials preserving the property of having only real zeros, a problem that goes back to Edmond Laguerre and to George Pólya and Issai Schur. These results were subsequently extended to several variables, and a connection to the Lee–Yang theorem on phase-transitions in statistical physics was made. Together with Tom Liggett (UCLA) they applied their methods to problems in probability theory and were able to prove an important conjecture about the preservation of negative dependence properties in the symmetric exclusion process. Borcea had a comprehensive project on the distribution of positive charges and the Hausdorff geometry of complex polynomials. One of the motivations for the project was to bring Sendov’s conjecture into a larger and more natural context. He formulated several interesting conjectures, and in the summer of 2008 he was the driving force of two meetings, one at the American Institute of Mathematics in San Jose, California and the other at the Banff International Research Station together with Dmitry Khavinson, Rajesh Pereira, Mihai Putinar, Edward B. Saff, and Serguei Shimorin. These two encounters were focused on structuring and expanding Julius’ program. His continuous and vivid interest in the Hausdorff geometry of polynomials was triggered by an École normale supérieure (Paris) exam he took in 1989. Publications Borcea, Julius; Brändén, Petter, Hyperbolicity preservers and majorization. C. R. Math. Acad. Sci. Paris 348 (2010), no. 15-16, 843–846. Borcea, Julius; Brändén, Petter, The Lee-Yang and Pólya-Schur programs. II. Theory of stable polynomials and applications. Comm. Pure Appl. Math. 62 (2009), no. 12, 1595–1631. Borcea, Julius; Brändén, Petter, The Lee-Yang and Pólya-Schur programs. I. Linear operators preserving stability. Inventiones Mathematicae 177 (2009), no. 3, 541–569. Borcea, Julius; Brändén, Petter, Pólya-Schur master theorems for circular domains and their boundaries. Annals of Mathematics (2) 170 (2009), no. 1, 465–492. Borcea, Julius; Bøgvad, Rikard; Shapiro, Boris, Homogenized spectral problems for exactly solvable operators: asymptotics of polynomial eigenfunctions. Publ. Res. Inst. Math. Sci. 45 (2009), no. 2, 525–568. Borcea, Julius; Bøgvad, Rikard, Piecewise harmonic subharmonic functions and positive Cauchy transforms. Pacific J. Math. 240 (2009), no. 2, 231–265. Borcea, Julius; Brändén, Petter; Liggett, Thomas M., Negative dependence and the geometry of polynomials. J. Amer. Math. Soc. 22 (2009), no. 2, 521–567. Borcea, Julius; Brändén, Petter, Lee-Yang problems and the geometry of multivariate polynomials. Lett. Math. Phys. 86 (2008), no. 1, 53–61. Borcea, Julius; Shapiro, Boris, Root asymptotics of spectral polynomials for the Lamé operator. Comm. Math. Phys. 282 (2008), no. 2, 323–337. Borcea, Julius, Convexity properties of twisted root maps. Rocky Mountain J. Math. 38 (2008), no. 3, 809–833. Borcea, Julius; Brändén, Petter, Applications of stable polynomials to mixed determinants: Johnson's conjectures, unimodality, and symmetrized Fischer products. Duke Math. J. 143 (2008), no. 2, 205–223. Borcea, Julius, Choquet order for spectra of higher Lamé operators and orthogonal polynomials. J. Approx. Theory 151 (2008), no. 2, 164–180. Borcea, Julius, Equilibrium points of logarithmic potentials induced by positive charge distributions. I. Generalized de Bruijn-Springer relations. Trans. Amer. Math. Soc. 359 (2007), no. 7, 3209–3237 (electronic). Borcea, Julius, Spectral order and isotonic differential operators of Laguerre-Pólya type. Ark. Mat. 44 (2006), no. 2, 211–240. Borcea, Julius, Maximal and linearly inextensible polynomials. Math. Scand. 99 (2006), no. 1, 53–75. Borcea, Julius; Bøgvad, Rikard; Shapiro, Boris, On rational approximation of algebraic functions. Adv. Math. 204 (2006), no. 2, 448–480. Borcea, Julius; Shapiro, Boris, Classifying real polynomial pencils. Int. Math. Res. Not. 2004, no. 69, 3689–3708. Borcea, Julius; Shapiro, Boris, Hyperbolic polynomials and spectral order. C. R. Math. Acad. Sci. Paris 337 (2003), no. 11, 693–698. Borcea, Julius, Dualities and vertex operator algebras of affine type. J. Algebra 258 (2002), no. 2, 389–441. Borcea, Julius, Annihilating fields of standard modules for affine Lie algebras. Math. Z. 237 (2001), no. 2, 301–319. Borcea, Julius, Two approaches to Sendov's conjecture. Arch. Math. (Basel) 71 (1998), no. 1, 46–54. Borcea, Iulius, The Sendov conjecture for polynomials with at most seven distinct zeros. Analysis 16 (1996), no. 2, 137–159. Borcea, Iulius, On the Sendov conjecture for polynomials with at most six distinct roots. J. Math. Anal. Appl. 200 (1996), no. 1, 182–206. References Category:20th-century Romanian mathematicians Category:Lund University alumni Category:Stockholm University faculty Category:Members of the Royal Swedish Academy of Sciences Category:1968 births Category:2009 deaths Category:Romanian emigrants to Sweden Category:People from Bacău Category:21st-century Romanian mathematicians
Vickers 1103 VC10 ex G-ASIX/A4O-AB (1964) This aircraft operated in the Sultan of Oman’s Royal Flight, based at Muscat. It was built at Brooklands and initially delivered to British United Airways in 1964. It was eventually sold to the Omani Government in 1974. The first VC10 flew from Brooklands on the 29th June 1962, and was the largest all-British production airliner ever built. With four Rolls-Royce Conway engines grouped in pairs at the back it is very loud by modern standards, although for its time it was regarded by passengers as quiet and comfortable, something the original operator, BOAC, was keen to trumpet, describing it as “triumphantly swift, silent, serene”. A further 53 examples (32 ‘standard’ and 22 Super VC10s) left the factory here over the next eight years. The largest VC10 customer was the British Overseas Airways Corporation, other operators including British United Airways, Ghana Airways and the Royal Air Force. A4O-AB’s final flight was from Muscat to Brooklands via Heathrow on 6th July 1987. The RAF operated VC10s until September 2013 having added 14 ex-airline examples to its fleet during the 1980s/90s in an air-to-air refuelling role. Vickers 1101 VC10 G-ARVM (1964) This was the last of the 12 Standard VC10s built at Brooklands for BOAC, making its maiden flight in July 1964. It operated both as a passenger carrier as well as a crew trainer with BOAC and British Airways. In 1974 the British Airways Standard VC10 fleet was retired, apart from Victor Mike, which remained in service as a training aircraft and also as a standby aircraft for the airline’s Super VC10 and Concorde fleets. In 1977 it performed a very low flypast for the Queen’s Silver Jubilee Air Display. Finally being retired in October 1979, it made its final flight to the RAF Museum at Cosford and became the first VC10 to be preserved. In 2006 British Airways offered the fuselage of G-ARVM to Brooklands Museum and it arrived at the Museum in October of that year in two pieces. It has since been rejoined and is now the only surviving VC10 1101 in Britain. The interior was refurbished in 2012 to commemorate the 50th anniversary of the first flight of the VC10. Vickers VC10 ZA150 (1969)For news of ZA 150’s arrival at Dunsfold in September 2013, click more
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Introduction {#Sec1} ============ The wild progenitors of the main domestic animals in the Old World are endemic to regions with Mediterranean climate and are adapted to withstand prolonged hot summer droughts and mild but wet winters^[@CR1],\ [@CR2]^. Since domestication, farmers have brought sheep, goats, pigs and cattle to an enormous variety of environments, from semi-deserts to sub-arctic regions. Their present-day distribution, pushed out to the boundaries of the world inhabitable by humans, was mediated through human protection and breeding of animals that thrive under conditions often not tolerated by their wild ancestors. The first steps in this process can be traced back to the farming pioneers of the Balkans who penetrated beyond the borders of the sub-Mediterranean zone of Europe in the early centuries of the sixth millennium BC. How the first Balkan herders succeeded in extending the habitat of their livestock is an intriguing question with pivotal importance for the early history of human-animal relationships. During the later seventh and early sixth millennia BC permanent farming settlements, similar to contemporary sites in the core areas of domestication in southwest Asia, became established in the (sub-)Mediterranean southern Balkans^[@CR3],\ [@CR4]^. The spread of farming economy into the temperate northern parts of the peninsula, however, was accompanied by pronounced changes, including higher (probably seasonal) residential mobility, smaller community sizes and a loss of sophistication in architecture and material culture^[@CR5]--[@CR8]^, a phenomenon which has been designated in the archaeological literature as "the First Temperate Neolithic". Although the adaptation of herding economy to new bioclimatic conditions has been recognised as a major component of this phenomenon^[@CR8]--[@CR14]^, the human strategies which promoted it have remained uncertain. Since early farmers kept domestic animals primarily for food and were dependent on them for survival, we can assume that their use of animal foodstuffs was finely adjusted to the animals' productivity under different ecological conditions. Differences in the use of meat and milk at different latitudes in the Balkans are therefore likely to reflect regional adaptations in the course of the northward expansion of herding. Herein, we combine organic residue analysis of ceramic vessels with faunal data on taxonomic composition to investigate variation in the use of animal products across the different bioclimatic zones of the Balkans. Results {#Sec2} ======= Faunal remains are widely used in archaeology as a proxy for past interactions between people and animals^[@CR15]--[@CR17]^. Datasets with taxonomic frequencies are available from the majority of recently excavated early farming sites in Southeast Europe. These datasets are generally dominated by food species and provide information on the relative proportions of consumed animals, but do not directly reflect differences in the used products (milk, meat, and fat). Investigations of fat residues in archaeological pottery can directly verify the use of particular animal foodstuffs, and differentiate between dairy, ruminant carcass and non-ruminant carcass fats, as well as a range of other commodities, such as aquatic resources or beeswax^[@CR18]--[@CR22]^. Lipid residues and faunal remains are thus complementary strands of evidence for recovering past practices of animal exploitation^[@CR23]^. Regional patterns in lipid residues {#Sec3} ----------------------------------- From the 290 pottery samples analysed in this study, 22% (n = 64) provided identifiable lipid residues with concentrations up to 5679 μg g^−1^ (mean 802 μg g^−1^, for the sherds containing lipids). This preservation rate is comparable with previous studies of prehistoric pottery from the Mediterranean^[@CR24]^, but lower than the proportions of over 50% of sherds with extracted lipids from Central Europe^[@CR25]^. All sites were nearly equally represented with ca. 20% to 35% of the samples containing identifiable lipids of archaeological origin, the only exception being Divostin, where only 7% of sherds contained observable lipids (Table [1](#Tab1){ref-type="table"}). The lipid extracts were dominated by fatty acids derived from animal fat, i.e. palmitic acid (n-hexadecanoic acid; C~16:0~) and stearic acid (n-octadecanoic acid; C~18:0~; Fig. [1](#Fig1){ref-type="fig"}, Supplementary Table [S1](#MOESM1){ref-type="media"}). Biomarkers characteristic of plant material were not detected.Table 1Sample information and summary of organic residue analysis of potterySitesDatingPotsherds analysedResidues DetectedNon-ruminant adipose fatsRuminant adipose fatsRuminant dairy fatsn%n%n%n%C. Hungarian plainAlsonyek5800-5730 BC431432------536964Ecsegfalva 235800-5650 BC41820112225563B. Northern BalkansBlagotin6200-6000 BC43921------222778Grivac6200-6000 BC33618------350350Divostin6000-5700 BC433726700133A. Southern BalkansYabalkovo6000-5700 BC421535320960420Nova Nadezhda6000-5600 BC45920111889------Total29064227---30---28---(descriptions of sites, radiocarbon dates, stratigraphic contexts, and sample descriptions are given in the Supplementary Information). Figure 1Gas chromatograms of TLEs from pottery from the three regions of study showing high concentration of palmitic acid (C~16:0~) and stearic acid (C~18:0~): (a) Ecsegfalva 23, sample 16, (b) Grivac, sample 17, and (c) Yabalkovo, sample 38. IS -- internal standard: C~34~ n-tetratriacontane. The identification of the various commodities was based on comparison of the carbon isotope compositions of archaeological fatty acids to those of modern reference animal fats. To eliminate differences in diets between the modern reference and the prehistoric animals caused by environmental and dietary factors, the Δ^13^C values (δ^13^C~18:0~ − δ^13^C~16:0~) of the archaeological samples were calculated and compared to that of modern reference fats^[@CR25]--[@CR29]^. All archaeological lipids derived from ruminant or non-ruminant animals. Potential contributors of non-ruminant fats include domestic pig, wild boar, fowl and domestic dog. No biomarkers of aquatic resources, such as ω-(o-alkylphenyl)alkanoic acids, were detected. The difference between the southern and northern part of the Balkans in respect to the distribution of commodities among the lipid residues is highly significant (p = .002, Fisher's exact test). Over 70% (n = 17) of all animal fat residues detected in pottery from the southern part of the Balkans in the present study plot within the range of ruminant adipose fats (Fig. [2b](#Fig2){ref-type="fig"}). At Yabalkovo, all three sources of animal fat were identified, although non-ruminant and dairy residues were represented only in low proportions (20% each). The pattern is even more pronounced in the distribution of residues from Nova Nadezhda, where dairy fats were not detected and the proportion of ruminant adipose fats reached 89%. These findings agree well with previously published data from early farming sites in other areas with Mediterranean climate, e.g. the Levant, Syria, Anatolia, Greece and Italy^[@CR24],\ [@CR27],\ [@CR30],\ [@CR31]^. We can denote this type of early livestock use, reflected in strong predominance of ruminant carcass fat and low incidence or absence of dairy fat among the residues in ceramic vessels, the "Mediterranean type".Figure 2Regional differences in Δ^13^C values ( = δ^13^C~18:0~ − δ^13^C~16:0~) of archaeological lipid residues in pottery. (a) proportions of lipid residues according to commodity type; (b) Δ^13^C values of archaeological lipid residues from sites in (b) the southern Balkans, (c) northern Balkans (d) the Carpathian basin (including published data for Ecsegfalva^[@CR32]^). Each data point represents an individual vessel. The lipid residues from sites in the northern part of the Balkans and in the Hungarian Plain, characterized by transitional and sub-continental climate, demonstrate a different pattern (Fig. [2c,d](#Fig2){ref-type="fig"}). Notable similarities exist between distant sites in present-day Serbia and Hungary (with the only exception of Divostin, which is not representative because of the very small number of sherds with residues, n = 3). Residues classified as non-ruminant fats are nearly absent, which agrees with the very low percentages of pigs in the faunal assemblages. With 60% (n = 24), dairy fats are by far the most abundant class of animal fat residues. The results obtained in the current study represent the first substantial dataset from the earliest farming sites in the temperate zone. They are comparable to the results of a previous study of pottery from Ecsegfalva 23 with n = 7 sherds with residues^[@CR32]^. The type of animal product exploitation reflected in a residue record with a strong emphasis on dairy fats and nearly absent non-ruminant residues can be provisionally assigned as the "Temperate type". Faunal data on species preferences {#Sec4} ---------------------------------- The taxonomic compositions of the faunal assemblages from early farming sites in the interior of the southern Balkans are similar to these from the Mediterranean littoral of the peninsula, with a somewhat lower proportion of caprines and more cattle compared to the Aegean (Fig. [3](#Fig3){ref-type="fig"}). The faunal data from the northern Balkans, in contrast, suggests a clearly different strategy of animal foodstuff supply. The proportion of caprines decreased compared to the south and cattle assumed a major role among livestock in the northern Balkans, clearly predominating as a supplier of meat when their body mass is considered. Together with the increasing importance of large game, this change in taxonomic frequencies highlights a shift to ''local'' food species (animals which are native to or have close endemic relatives in temperate Europe). Surprising is the nearly complete absence of domestic pigs (represented by only a few percent of NISP), since pigs must have thrived in the temperate forests and marshlands. One possible explanation for the scarcity of pigs in the northern Balkans is seasonal mobility of herds: although pig transhumance is known from the ethnographic record^[@CR33]^, pigs are in general untypical for the seasonally relocated herds. It has been previously argued that the preference for mobile fauna in the northern Balkans relates to other mobility indicators, such as smaller community size, lower settlement permanence, less substantial or semi-subterranean dwellings, and possibly decreasing reliance on plant cultivation^[@CR34]^. Seasonal mobility is also tentatively suggested by the age distribution of caprines and by the absence of migratory species among birds in the faunal assemblage from Blagotin, indicating cold season (late autumn to late spring) presence at this location^[@CR35]^. However, other causes for the decline in pig husbandry also need to be considered.Figure 3General trends in the exploitation of the most abundant mammalian taxa. Faunal data from early farming sites in the Aegean, the Balkans and the Carpathian basin, symbol size corresponds to relative body size of species, each symbol represents 10% of NISP. See Supplementary Table [S2](#MOESM1){ref-type="media"} for the complete dataset. Similar taxonomic abundances are characteristic of the faunal distributions from the Hungarian Plain. The small ruminants seem more numerous here compared to the northern Balkans, though this picture is biased by several sites in the northern periphery of the region which focused intensively on caprines (70 to 80% of NISP; Fig. [4](#Fig4){ref-type="fig"}). Since the swampy wetland environments of the Danube and Tisza plains are adverse to sheep husbandry, these assemblages have often been described as puzzling^[@CR36],\ [@CR37]^ and the preference for caprines has been attributed to emotional motives of the early farmers, who adhered to the pastoral traditions of their Mediterranean ancestors against all odds^[@CR38]^. However, a large area between the Aegean and the Carpathian basin where ''local'' species (cattle and large game) prevailed in the faunal remains indicates that continuity of herding practices is not a completely satisfactory explanation for the sites with high proportions of caprines in eastern Hungary (Fig. [4](#Fig4){ref-type="fig"}). Rather, the latter can be considered more anomalous than typical for the temperate zone. A likely pragmatic reason for the prevalence of caprines at some sites in Hungary, despite the unfavourable environment, are problems with livestock overwintering due to snow cover and shorter plant growing season. "Caprine" sites are situated in grassland areas, where large game hunting was not as rewarding as on the forest margins^[@CR39]^. In view of their higher reproductive rate, opting for caprines (rather than cattle) may be an advantage when herders are forced to slaughter many of their animals before or during winter because of limited fodder, since the annual growth rate in number of heads in sheep herds and goat herds is higher than that of cattle^[@CR40]^. Moreover, in competition with pigs, caprines possess an advantage which becomes crucial under conditions of decreasing animal productivity -- milk exploitation yields up to four times higher yield of food energy compared to hunting or growing animals for meat^[@CR41]^.Figure 4Summary of climatic conditions in Southeast Europe. Dots indicate the location of faunal assemblages included in this study (see Supplementary Table [S2](#MOESM1){ref-type="media"}); black dots -- sites where caprines were represented with \>60% of NISP of the large- and middle-sized domestic and wild mammalian taxa, white dots -- caprines \<60%. The dotted lines indicate regional boundaries between the Aegean/Adriatic littoral, southern Balkans, northern Balkans and Carpathian Basin. Numbers show location of sites where organic residue analyses were performed 1. Yabalkovo, 2. Nova Nadezhda, 3. Blagotin, 4. Divostin, 5. Grivac, 6. Alsónyék, 7. Ecsegfalva 23. (Climate data from: Hijmans, R. J., S. E. Cameron, J. L. Parra, P. G. Jones and A. Jarvis. 2005. Very high resolution interpolated climate surfaces for global land areas. International Journal of Climatology 25(15): 1965-1978; <http://worldclim.org/>, Layer BIO6 = Min Temperature of Coldest Month, interpolations of observed data, representative of 1960--1990). The map was created using QGIS Version 2.8.9-Wien (<http://qgis.org/de/site/>). Discussion {#Sec5} ========== The interior of the Balkan Peninsula and the adjacent Hungarian Plain occupy an intermediate position between the Mediterranean and the Central European bioclimatic regions. The present-day distribution of thermophilous mixed deciduous broadleaved forests indicates fluid transitions of temperature and precipitation, from mild winter temperatures in the south and occasional winter frosts in the northern parts of the peninsula to regular periods of winter frost and snow in the Hungarian plain^[@CR42]^. Reconstructions of warmest month, coldest month and mean annual surface air temperatures, based on fossil pollen data, suggest that winter temperatures in southeast Europe have generally remained at the same level from 6000 calBC through to the present (Fig. [4](#Fig4){ref-type="fig"})^[@CR43]^. Farmers and their domestic animals spread fast, in c. 10 human generations, across these biogeographic zones from sub-Mediterranean Macedonia to the northern limits of the temperate Carpathian Basin^[@CR10],\ [@CR44]--[@CR46]^. The increasingly unfavourable climate, and particularly the long frosty winters, had certainly an impact on Mediterranean livestock. Climate affects animals in a direct way through thermoregulation, and indirectly, through trophic links (e.g. pasture quality and biomass)^[@CR47]^. Climate-driven selective pressure brings forward changes in the genome, such as the adaptation to feed scarcity through accumulation of fat as energy reserve, or through a seasonal decline in appetite and the ability to reduce metabolism in winter^[@CR48],\ [@CR49]^. Genetically-determined improvements of feed efficiency, pigmentation, coat and body size are further common adaptations to harsh environments. However, since genetic changes do not occur immediately, farmers spreading into higher latitudes in the Balkans are likely to have initially experienced difficulties in maintaining the productivity of all domesticates, and in particular of sheep, which do not have native wild relatives in Europe and, being grazers, are not adapted to feed in the forested environments of the Balkan interior. The most serious hurdle to overcome was the provision of feed under conditions of a shorter period of plant growth and deep snow impeding access to grass for weeks in winter. Spring temperatures have also been recognized for their effect on animal productivity. For example, 1 °C decrease in mean spring temperature has been estimated to reduce lamb autumn body mass by nearly 0.4 kg^[@CR50]^. One further climate-related parameter, directly associated with animal productivity, is the seasonality of mating and birth, which is determined by day-length through a genetically controlled mechanism for sheep and through feed availability for cattle^[@CR51],\ [@CR52]^. Before genetically adapted breeds became established, these obstacles must have been overcome by techniques of herd management, such as control of mating, strategic culling, adjustments in the species composition, interbreeding with wild populations, and labour-intensive feeding practices (stalling, foddering, change of pastures). Equally important must have been, however, adjustments in the use of animal foodstuffs and in the techniques of food processing. For example dairying, a practice familiar to the early farmers of southwest Asia and the Mediterranean^[@CR24],\ [@CR27],\ [@CR53]^, is highly efficient in increasing the yields of animal husbandry. Milk pastoralism can provide up to four times higher yields of food energy in comparison to growing animals for meat^[@CR41]^. T. Ingold lucidly explains the higher productivity of milking in comparison to meat exploitation by the respective position of the herders in the food chain. Pastoralist who milk their animals intercept the chain of conversions from grass to milk, and from milk to meat, at an earlier point, thus avoiding the net loss of energy that takes place at the latter stage of this conversion^[@CR54]^. Our investigation of animal lipids preserved in pottery and of taxonomic frequencies of large- and medium-sized mammalian species shows differences in the use of animal products between the Aegean and the southern Balkans, on the one hand, and the northern Balkans and the Hungarian Plain on the other hand. We observe a significant increase of dairy fats in the biochemical record coupled with a decline in caprines at most sites north of the Balkan mountain range. Our study indicates that dairying, being a highly efficient way to counterbalance reduced productivity of animal husbandry, was instrumental to the spread of the Mediterranean livestock system into the temperate areas of the Balkans, and from there across the entire European continent. The general distinction of a "Mediterranean" and a "Temperate" type of early animal husbandry outlined in the present study does not rule out the existence of small-scale regional variation. Previous studies of lipids in early ceramics in the Mediterranean, for example, suggest that a high proportion of dairy residues might be characteristic for early farmers' habitations in caves and rock-shelters^[@CR24],\ [@CR55],\ [@CR56]^, possibly pointing at the presence of specialized seasonal herding sites. Finally, dairying represents not only an efficient economic strategy, but also provides an important dietary component. Milk was one of the main potential sources of dietary fat for the first Balkan farmers, together with lard, oily fish and probably waterfowl. Having in mind that pigs were barely represented in the faunal assemblages from the northern Balkans and the Carpathian Basin, and that non-ruminant lipids were very rare among the residues in pottery, we can regard dairying as a key strategy of obtaining fat in this geographic region. Fresh milk in small-scale non-industrial animal husbandry is a seasonal product. Peak lactation in temperate climates generally coincides with the warm season, when pastures can support the high nutritional requirements of lactating stock^[@CR51]^. Being a perfect medium for pathogenic microbial growth, in the hot months milk spoils to an ill-smelling liquid within hours, if not consumed or heated and processed in a controlled manner (for example through controlled souring by lactic bacteria). The low frequency or absence of the −13,910\T allele, associated with continued production of lactase into adulthood (and thus with the ability to digest fresh milk), in hunter-gatherer and early farming populations in Europe^[@CR57]--[@CR61]^, suggests that high-lactose fresh milk could not have been consumed in large quantities by the first farmers. Hence, most of the milk must have been processed without delay both to reduce its lactose content and to convert it into a storable year-round staple food. The increase in dairying observed in this study thus represents a remarkable example of complex cultural behavior employed to circumvent the limitations of environment and of human and animal biology. Methods {#Sec6} ======= Organic residue analysis {#Sec7} ------------------------ ### Sampling {#Sec8} In this study, we analysed a total of 290 potsherds from seven pottery assemblages dating to c. 6100--5700 calBC (Table [1](#Tab1){ref-type="table"}). The sherds derive from well-documented and published excavations in Bulgaria (Yabalkovo and Nova Nadezhda), Serbia (Blagotin, Divostin and Grivac), and Hungary (Alsónyék and Ecsegfalva 23), which have provided the earliest Neolithic assemblages in their respective geographic area^[@CR35],\ [@CR62]--[@CR67]^ (Supplementary materials). Sherds were selected following two main criteria -- an undisturbed stratigraphic context and a representative spectrum of wares and shapes (including diverse types of plates, bowls and jars); they were mostly diagnostic rim fragments (73%). ### Lipid extraction and derivatisation {#Sec9} Lipid extractions were performed using direct acidified methanol extraction, according to the protocol of Correa-Ascencio and Evershed^[@CR68]^. Using a modelling drill, a small area of each fragment was cleaned to remove modern contaminants (from soil burial, excavation and post-excavation handling) and a sample of ca. 2 g was taken. The sherd fragment was crushed into a fine powder, weighed and an internal standard of n-tetratriacontane (20 μl, 1.0 mg ml^−1^ solution) was added. Lipids were extracted from the powder by adding 5 ml of a H~2~SO~4~-MeOH (4% sulphuric acid/methanol) solution (δ^13^C known), heated for 1 h at 70 °C, whirl mixed every 10 min to ensure contact between solvent and powdered sherd. In order to help observe the solvent layers, the H~2~SO~4~-MeOH was transferred to a clean culture tube, where 2 ml of DCM extracted-double-distilled water was added. To ensure the recovery of lipids not fully solubilized by the methanol solution, hexane (2 ml portions) washing was performed 2x for the powdered sherd and 3x for the diluted methanol extract. All hexane extracts were combined and evaporated to dryness under a gentle stream of nitrogen. Prior to instrumental analysis one fourth aliquots of total lipid extracts (TLEs) diluted in hexane were blown down to dryness with nitrogen and derivatised with 20 μl of N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA containing 1% trimethylsilyl chloride) for 1 h at 70 °C to trimethylsilylate free alcohols. ### Gas chromatography (GC), GC/mass spectrometry (GC/MS) and GC-combustion-isotope ratio MS (GC-C-IRMS) {#Sec10} Derivatised TLEs were blown to dryness then diluted with hexane and screened by GC to make preliminary identifications of components and quantify lipid concentrations in potsherds by reference to the n-tetratriacontane internal standard. Two different GC systems were used, employing either manual or autosampling injections: (1) Agilent Technologies 7820 series 2 with a silica capillary column (50 m × 0.32 mm) coated with a dimethyl polysiloxane stationary phase (J&W Scientific; CP-Sil 5 CB, 0.12 μm film thickness) or (2) Agilent 7890a with a capillary column (15 m × 0.32 mm) coated with a dimethyl polysiloxane stationary phase (J&W Scientific; DB1-HT, 0.1 μm film thickness). On both systems, the carrier gas was helium and a flame ionization detector (FID) was used to monitor the column effluent. The temperature programs began with an initial hold at 50 °C for 2 min followed by temperature programming at 10 °C min^−1^ and a final hold for 10 min at 350 °C (Agilent 7890a) or 300 °C (Agilent 7820). Collection of the data and quantification were performed using a Agilent Chemstation software. Where structures of components were not identifiable based on GC alone, GC/MS analyses were performed on a ThermoFinnigan Trace MS quadrupole mass spectrometer coupled to a Trace GC. Using either manual or auto-injections samples were injected via the splitless mode onto a fused-silica capillary column (60 m × 0.32 mm) coated with a polymethylpolysiloxane stationary phase (Phenomenex; ZB1, 0.1 μm film thickness). The temperature programs for the GC began with an initial temperature held at 50 °C for 2 min and followed by a constant increase at a rate of 10 °C min^−1^ to 300 °C then held for 10 min. The MS was operated in electron ionisation (EI) mode (70 eV) with a GC interface temperature of 300 °C and a source temperature of 200 °C. The emission current was 150 μA and the data collection was between m/z* 50--650 at 1.3 scans s^−1^. Xcalibur v3.0 software and a NIST spectra library were used to acquire, analyse and identify separated compounds. The same samples were screened for ω-(o- alkylphenyl)alkanoic acids using GC/MS selected ion monitoring (SIM; m/z 105, 262, 290, 318 and 346). The extracts were injected in the same GC as above equipped with a fused-silica capillary column (60 m × 0.32 mm) coated with a 50% cyanopropyl-methylpolysiloxane stationary phase (Varian, Factor Four; VF-23 ms, 0.15 μm film thickness). The GC oven temperature was programmed from 50 °C, following an isothermal hold for 2 min, to 100 °C at 10 °C min^−1^, and then to 240 °C at 4 °C min^−1^, following by an isothermal hold at 240 °C for 15 min. The extracts dominated by C~16:0~ and C~18:0~ fatty acids and free from plant lipids (e.g. long-chain n-alkanols and long-chain n-alkanoic acids), were analysed in duplicate by GC-C-IRMS to obtain their individual δ^13^C values. GC-C-IRMS analyses used an Agilent 6890 GC coupled to a Finnegan MAT Delta^plus^ XL mass spectrometer via a Finnigan MAT GCCIII interface. Samples were injected using a CTC A200S autosampler in splitless mode onto a Varian silica capillary column (CP-Sil 5 CB, 100% dimethylpolysiloxane with 0.12 μm film thickness, 50 m × 0.32 mm). The temperature program for the GC began with an initial temperature held at 50 °C for 2 min, followed by a constant increase in oven temperature at10 °C min^−1^ to 250 °C, followed by a 15 min hold. Faunal analyses {#Sec11} =============== Taxonomic abundances in 39 early farming faunal assemblages from the Aegean, the Balkans and the Carpathian Basin were calculated based on NISP (number of identifiable specimens, identified to species level, with the exception of indistinguishable sheep/goat remains that represent the caprine subfamily; Supplementary Table [S2](#MOESM1){ref-type="media"}). To limit bias through taphonomic history, recovery techniques and laboratory procedures, only the most ubiquitous large- and medium-sized mammalian taxa were considered. Because small assemblages of less than 500 NISP tend not to represent reliably the relative importance of animals^[@CR38],\ [@CR39]^, the assemblages included in this study exceed 890 NISP (with the exceptions of Nea Nikomedia n = 450 and Alsónyék n = 428). Animal bones from excavations represent butchering and cooking remains and are thus directly related to the consumption of animal products. However, straightforward estimates of dietary contribution from taxonomic abundances based on NISP are not possible, since NISP neither corresponds to meat quantity, nor to the use of animals for meat and milk products. Other proxies, such as age-at-death (AtD) data, are available only for a handful of sites (Prodromos, Blagotin, Ecsegfalva 23, Miercurea Sibiului-Petriş, Foeni Salaș and Foeni Gaz)^[@CR37],\ [@CR69]--[@CR71]^. The AtD data were considered in the interpretation of the organic residues in pottery; they are, however, insufficient for inter-regional comparisons. Although no calculation of dietary contributions was attempted in this study, we take into consideration the relative contributions of large- and medium-sized livestock and large game in the discussion of their importance in diet. We adopted a modified version of Clason's "live-weight factor" approach to express the live weight of taxa in terms of sheep equivalents (sheep = 1, cattle = 28, pig = 1.2)^[@CR72],\ [@CR73]^. For large game, we use a factor of 22, based on the average of the aurochs (36), equid (24) and cervid (7) factors. These factors are only rough approximations of the relative meat contribution of taxa and do not represent actual body sizes or meat yields. Electronic supplementary material ================================= {#Sec12} Supplementary Information Electronic supplementary material Supplementary information accompanies this paper at doi:10.1038/s41598-017-07427-x Publisher\'s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The organic residue analysis of pottery was conducted as part of the collaborative project ''Food cultures: Interdisciplinary studies of early farming, food technology and palaeodiet in Southeastern Europe'', funded by an award of the German Research Council, DFG-IV101/5-1 (to M.I.). Branka Zorbic (Kragujevac), Tibor Marton and Krisztián Oross (Budapest), Nadezhda Todorova and Vanya Petrova (Sofia) are thanked for their support in selecting the pottery samples from Divostin, Grivac, Alsónyék, Ecsegfalva 23, Nova Nadezhda and Yabalkovo. We are grateful to Haskel Greenfield, Laszlo Bartosiewicz and Marie Balasse for their comments on this work. We also thank Elena Marinova-Wolff for advice on Fig. [4](#Fig4){ref-type="fig"}. J.E., M.I. and R.P.E. conceived and designed the study. M.I. and J.E. wrote the paper. J.E. collected the faunal data. J.E. and M.R.-S. performed analytical work on pottery and data analysis. M.I., E.B., J.V., K.L. and K.B. either conducted sampling of pottery for lipid residue analyses or directed excavations. All authors reviewed and approved the paper. Competing Interests {#FPar1} =================== The authors declare that they have no competing interests.
#Ad Hoc Liaisons. Appointed at the request of NMRT or another ALA Unit to work on a specific program or project or for a specific purpose. These positions are appointed upon request; length of appointment is the completion of the program, project, etc. Not excluded is the possibility of a Regular Liaison working on a specific program or project or seeking co-sponsors for NMRT programs when appropriate. #Ad Hoc Liaisons. Appointed at the request of NMRT or another ALA Unit to work on a specific program or project or for a specific purpose. These positions are appointed upon request; length of appointment is the completion of the program, project, etc. Not excluded is the possibility of a Regular Liaison working on a specific program or project or seeking co-sponsors for NMRT programs when appropriate. − ===Relationship to ALA Unit appointed Liaisons=== + ====Relationship to ALA Unit appointed Liaisons==== Another model of Liaisons is where an ALA Unit appoints a liaison to NMRT. That ALA Unit appointed liaison will serve as our NMRT liaison "mentor" or guide to the Unit; the Unit liaison will help the NMRT member get to know the Unit liaised and will help to identify appropriate issues, activities, information and ideas of mutual interest. Another model of Liaisons is where an ALA Unit appoints a liaison to NMRT. That ALA Unit appointed liaison will serve as our NMRT liaison "mentor" or guide to the Unit; the Unit liaison will help the NMRT member get to know the Unit liaised and will help to identify appropriate issues, activities, information and ideas of mutual interest. Liaisons Program Goal The Liaison Program will be used as a method of outreach from the New Members Round Table (NMRT) to other American Library Association (ALA) units. It will promote attendance and participation in programs, discussion programs, discussion forms, events and committees. Becoming a liaison will enable the NMRT member to take an active role in the activities of NMRT and other Units within ALA, and will provide the liaison an opportunity to provide others in NMRT and ALA Units with knowledge of activities that may be of interest to them. Further, in accordance with Article II of the NMRT Constitution and Bylaws, becoming a liaison will enable "leadership training and opportunities to help those approaching the end of their NMRT eligibility make the transition to future positions in the association and the profession." Definition A liaison from NMRT to another ALA unit is appointed to communicate NMRT interests held in common with the other group and to advise NMRT regarding activities and issues of the other Unit that may have implications for NMRT. The working relationship between NMRT appointed liaisons and the Unit is defined by the interest NMRT has with the ALA Unit where: The Unit addresses issues and concerns relevant to new members. Programs and other activities can be jointly administered or planned, and not duplicated. Polices and actions of either group can be served by the relationship. The relationship will improve attendance to programs and participation in either group. Specifically, the resulting relationship will allow the two groups: To provide two-way communication between NMRT and other ALA Units such as round tables, assemblies, committees, or sections. The liaison serves as a channel for communicating concerns and interests shared by the two Units. The liaison keeps NMRT members informed of the activities, programs and operations of the Unit to which he/she is liaison. To give senior NMRT members the opportunity to keep members of another ALA Unit informed of the activities, programs, and operations of NMRT where appropriate, to make valuable contributions to that Unit, become oriented in another ALA Unit, and to make contacts outside NMRT. To give NMRT members the chance to participate and gain experience in program planning outside NMRT by way of co-sponsorships of programs with other ALA units. The communication between NMRT and the ALA Unit will help to avoid duplicate programming activities and will enable sharing, if appropriate, of programming and publication efforts in areas of mutual interest through co-sponsorship. History of the Committee The Liaisons were a loosely organized group, reporting to and coordinated by the Networking Director. Also, in the past, the NMRT groups of state ALA chapters sent representatives to NMRT, called the Affiliates Council. To revitalize these groups, a Liaison Coordination and Support Ad Hoc Committee was appointed in 2002-2003 to investigate the possibility of creating a standing committee for liaisons and to propose a plan to establish the NMRT Liaison Program. The Executive Board decided during Midwinter 2003 that a separate committee should reevaluate the Affiliates Program. Liaison Types The Basic Categories for NMRT Liaisons include: Regular Liaisons. Appointed at the request of NMRT or another ALA Unit to provide two-way communication between NMRT and that Unit. These positions are appointed every year; length of appointment is one year unless the Executive Board approves reappointment. Ad Hoc Liaisons. Appointed at the request of NMRT or another ALA Unit to work on a specific program or project or for a specific purpose. These positions are appointed upon request; length of appointment is the completion of the program, project, etc. Not excluded is the possibility of a Regular Liaison working on a specific program or project or seeking co-sponsors for NMRT programs when appropriate. Relationship to ALA Unit appointed Liaisons Another model of Liaisons is where an ALA Unit appoints a liaison to NMRT. That ALA Unit appointed liaison will serve as our NMRT liaison "mentor" or guide to the Unit; the Unit liaison will help the NMRT member get to know the Unit liaised and will help to identify appropriate issues, activities, information and ideas of mutual interest. If NMRT does not already have an NMRT appointed liaison to the Unit, NMRT will vet members and appoint a liaison to work with the ALA appointed liaison. The NMRT Liaison will invite the Unit counterpart to appropriate activities of mutual interest, such as Orientation, President’s Program, Alumni and Student receptions. Liaisons also might create an informal mentorship relationship with alumni who can advise the new liaison on issues of a particular ALA Unit that are beneficial for NMRT. Selection and Appointment of Liaisons Criteria Liaisons should be NMRT members in good standing. Liaisons will either be designated by NMRT to liaise with a group or will be requested by the ALA Unit to be included in NMRT activities. Liaisons therefore should have an established interest in the ALA Unit with which they will liaise. Because the main responsibility of the liaisons is to transmit information between NMRT and the ALA Unit, they should already be involved in the ALA Unit to be represented. Recruitment NMRT members will be informed of the opportunity to serve as a liaison to an ALA Unit via the Committee Volunteer Interest form on the NMRT homepage, and via brochures and other advertisements distributed on listservs, website, Footnotes, and other publications, and at Conferences. Examples are listed as Attachment A, Recruitment Devices. Separate emails sent to the NMRT listserv is another method to recruit for volunteers. The Committee will modify the form on the NMRT website to capture appointments automatically. Volunteers can select up to three ALA Unit preferences to serve as liaisons. The Liaisons Handbook that includes criteria and expectations information will be accessible from the Committee Volunteer Form so that NMRT members can determine their appropriateness to serve as a liaison. Appointment Process The appointment process each year consists of: Members complete the Committee Volunteer Interest form including preferences in committees. Liaison Committee will email members to confirm interest to serve and will send the NMRT President a list of interested members. NMRT President will appoint liaisons based on the recommendations of Liaison Coordination and Support Committee Chair at Annual. Liaison Coordination and Support Committee Chair will confirm appointments via email and will invite appointed liaisons to next conference meeting (e.g. Midwinter) to give briefing of responsibilities. Members already serving as a liaison who wish to continue their service will contact the Liaison Coordination and Support Committee Chair to express their continued interest to serve as liaison for Unit. When NMRT sends a liaison to another Unit, the Liaison Coordination and Support Committee Chair should announce the appointment in a written communication to that group which: Asks the ALA Unit to accept the liaison, States NMRT’s purpose in establishing the liaison, Requests the ALA Unit include the liaison in the distribution of agenda and minutes, and Informs the ALA Unit that the liaison will observe and submit relevant information to NMRT. Term and Number of Appointments Liaisons are not appointed as full Committee members within NMRT and are considered to be volunteers. Liaisons are appointed to one-year terms and can be reappointed for two consecutive terms with the recommendation of the Liaisons Coordination and Support Committee Chair. Liaisons may be appointed to no more than two ALA Units at a time. Service as a liaison does not count against the three direct committee appointment rule governing ALA. Major Responsibilities The liaisons take a key role in increasing awareness of information and ideas of mutual interest to NMRT and ALA Unit members. The responsibilities of the liaisons are to: Meet at Midwinter and Annual NMRT meetings and events, and attend meetings of their respective ALA Units. Submit committee meeting dates and program information for their ALA Unit. Request inclusion in the distribution of agenda and minutes for the Unit. Publicize information concerning the ALA Unit including relevant program invitations, announcements and other information. Keep their ALA Units informed of NMRT activities that would be of interest, such as the programs sponsored by the Student and Student Chapter Outreach Committee, the Student Reception, Mentoring, etc. Invite Unit representatives to attend functions like Orientation and the Student Reception. Report on discussions, policies, and action of their ALA Units that are relevant to NMRT. Obtain minutes, if possible, and summarize relevant sections. Report on discussions, policies, and action of NMRT that are relevant to their ALA Unit. Identify and alert NMRT of Unit programs which NMRT may wish to co-sponsor, either from Unit breakout sessions, listservs or other means. Submit a written report of meetings attended to the Executive Board at the Midwinter Meeting, at the Annual Conference, and at other times upon requestif necessary. If necessary, provide an oral report to the Board, under the supervision of the Chair. Reports will be considered, and highlights will be provided to NMRT members via Footnotes, NMRT-L and other forum. Find an alternate (e.g. ALA Unit counterpart) to attend and report on meetings of NMRT or ALA Unit if attendance to meetings is not possible. This alternate will submit the report to the liaison. If an alternate cannot be found, secure the minutes or other information from the meeting by making a request to the Secretary or another officer. Basic Checklist to Meet Roles/Responsibilities Make contact with NMRT Liaison Coordination and Support Committee Chair, the assigned ALA Unit, ALA Unit counterpart, and past NMRT Liaison to the Unit. Join appropriate listservs. Check ALA Unit and NMRT websites for current and upcoming activities and opportunities and disseminate relevant information to members. Submit NMRT liaison report form on NMRT website. Maintain contact with NMRT officers and members and stay abreast of NMRT activities and discussions so that a proper picture of NMRT concerns can be made to the ALA Unit. To this end, liaisons are encouraged to attend NMRT Executive Board meetings. Leadership and Support Structure The Liaison Coordination and Support Committee is responsible for the Liaison Program. The Committee ensures the proper administration of the overall program, including updating the necessary web forms, collection of liaison volunteers and advertisement of the program. The NMRT President appoints liaisons at the recommendation of the Liaison Coordination and Support Committee Chair. Liaison Coordination and Support Committee Charge To provide a method of outreach from New Members Round Table (NMRT) to other American Library Association (ALA) members in order to promote attendance and participation in programs, discussion forums, events and committees. Chair’s Major Responsibilities Serve as a resource/contact for internal and external inquiries about the liaison program or about involving the liaisons in a committee project or other venue Recommend liaison appointments to President each year. Advise new liaisons. Oversee recruitment efforts by the Committee. Establish new liaison positions with other ALA Units. Organize and chair a liaison meeting at Midwinter and Annual conferences via email. Identify and suggest list of breakout or other meetings of interest for liaisons to attend. Collect reports/checklists from liaisons after conference. Vet reports submitted by NMRT Liaisons by selecting the most relevant and timely items that might be of interest to the NMRT membership, including potential co-sponsorship opportunities. Report on liaison activities and items of importance to NMRT Executive Board and create webpage to disseminate that information. Maintain the liaison roster. Follow up with and thank liaisons for their service. Maintain files on liaison activities and committees. Help to establish relationship with other NMRT committees/groups including those associated with NMRT Alumni. Liaison Reporting Process Dissemination of Information Liaisons attend meetings at Conferences and monitor appropriate listservs in order to introduce NMRT members to other ALA Units and help NMRT members get involved. Therefore, liaisons transmit important information to NMRT before and after conferences which NMRT members might have otherwise missed. To alert members to relevant activities at the conferences, liaisons should use the NMRT listserv or the Liaison website. Liaisons should subscribe to NMRT-L, not only to keep abreast of NMRT activities but also to disseminate information. Liaisons also submit information to Footnotes and to the NMRT Publicity Committee Chair when applicable. Liaisons involved in planning conference programs work with the publicity chairs of the appropriate program-planning subcommittees when submitting publicity notices to Footnotes. Standard information for particular activities includes date, time, Unit, liaison contact, and minutes/major goals or discussion. Documents to Create/Records Generation and Archiving Liaisons will submit meeting minutes and other information of interest to NMRT. Formal reports will be submitted via the NMRT Liaison Report Form. This includes requests made for NMRT support for projects with the ALA Unit. Reports including Conference and other meeting minutes that are submitted to the Liaison Coordination and Support Committee should generally fall along the timeframe of the conferences. The Liaison Chair will compile and filter the Liaison reports by selecting the most relevant and timely items that might be of interest to the NMRT membership. The final report will be sent to the NMRT Executive Board and then disseminated to NMRT via an email, the website, Footnotes and via other formats to ensure NMRT members are not inundated with email through NMRT-L. Standard information included in the report includes the type of report, date submitted, ALA Unit, major goals and objectives of ALA Unit and or/meeting notes, action items/issues to be resolved. The NMRT Liaison’s name and contact information are also submitted. Record Keeping Liaisons maintain a file of correspondence, reports, and other information concerning their activities. Correspondence and Carbon Correspondence NMRT President NMRT Vice-President/President-Elect NMRT Liaison Coordination and Support Committee Chair NMRT Staff Liaison Appropriate officers, committee members, and representatives of the non-NMRT Unit Units Served The Committee Volunteer Form will enable interested members to select up to three ALA Unit preferences. Below is the list of liaison positions. NMRT members may find that there is no established liaison position serving a particular ALA Unit in which they are interested. In this case, NMRT members are encouraged to contact the Liaison Coordination and Support Committee Chair, who will begin the process of establishing the new liaisonship. General Timetable July/August Receive orientation materials, including contact information for the predecessor liaison, ALA Unit appointed liaison, etc. from Chair of Liaison Coordination and Support Committee. Receive files from predecessor if applicable. Contact the committee chair, round table chair or president, or other appropriate officer of the ALA Unit to introduce yourself and remind them of your appointment. Ask to be placed on the Unit's publications mailing list if possible. Prepare a Liaison Planning Report and send it to the NMRT Liaison Coordination and Support Committee Chair, copying the NMRT President and Vice-President/President/Elect. September/November Join appropriate listservs and monitor the ALA Unit's publications and communications. Communicate with your contact person as you have ideas for furthering the purpose of your liaisonship. Communicate informally with the NMRT Liaison Coordination and Support Committee Chair to keep him/her informed of your activities. December/January Attend meetings and activities of your ALA Unit. Ask your contact person to alert you to scheduled Midwinter meetings of the Unit you are liaison to. Prepare and present a report of your activities and ideas for activities at the NMRT Executive Board meeting. If you have a request for NMRT support for projects with the ALA Unit, include them in your report. Attend the NMRT Liaisons' Meeting. In addition to the NMRT Executive Board meeting at which you present your report, if appropriate, you are encouraged to attend other meetings of the Board as your schedule allows. This provides a fuller view of current NMRT activities, which may be useful to your work as a liaison. February Inform your ALA counterpart of the outcome of any request for support you may have made to the NMRT Executive Board at Midwinter. Submit a Liaison Report for important information that should be distributed to NMRT members. March-June Participate in project planning with your ALA Unit as requested. Continue to monitor publications and to communicate with your contact person and the NMRT Liaison Coordination and Support Committee Chair. Annual Attend meetings and programs of your ALA Unit. Carry out your responsibilities to your ALA Unit. Prepare and present a report of your activities to the NMRT Executive Board. Attend the NMRT Liaisons' meeting. If you are continuing in your position, participate in planning activities for next year's projects. July If you are finishing your two-year appointment, weed your files and transfer them to the new liaison. Please include a letter of suggestions and advice to your successor if you believe your experience may benefit him/her. If you have suggestions for revisions or additions to the official description of your liaison position, please send them to the NMRT Liaison Coordination and Support Committee Chair, who will see that needed changes are made.
Kellyanne Conway would like to thank Kellyanne Conway for starting the sexual harassment discussion. The White House counselor appeared on “Fox & Friends” on Thursday morning to discuss Alabama Republican Senate nominee Roy Moore and the recent accusations from eight women who allege sexual misconduct on his part when they were minors and he was an adult. When asked why President Donald Trump has yet to weigh in on the Moore accusations, Conway responded that he’s been “very busy” with his recent trip to Asia. Conway then added that she should be credited for breaking open the conversation around sexual harassment. She said that she tried to make this topic an issue last October, a day after the “Access Hollywood” tape leaked showing Trump bragging about being able to grab women “by the pussy” with impunity. “I would like to say that I was the first person in the administration last Thursday when this news broke, I happened to be interviewed on a different network at the time, to come out against conduct as it was described, and I went a step further,” she said. “I tried to make this an issue over a year ago on Oct. 9, 2016, when I talked about maybe when I was younger and prettier, folks on Capitol Hill behaving in such a way that we should take a look at fresh.” “And I’m so glad that women on the left, particularly on Capitol Hill, are now coming forward and want to have hearings and are swearing under oath and getting people to come forward,” she continued. “That’s great. I tried to do it 13 months ago; nobody wanted to listen to me because of the campaign I was managing. This is an important topic but in terms of this particular issue and this particular Senate race, I will not get ahead of the president and anything he wishes to add.” Skip ahead to minute 4:30 to hear Conway discuss Moore. .@KellyannePolls: "@POTUS will make a statement when he wants to make a statement" on Roy Moore. pic.twitter.com/vWXU6IfxOv — Fox News (@FoxNews) November 16, 2017 At least 16 women have accused Trump of sexual assault dating back to the 1980s. During a talk at the University of Virginia last November, an audience member asked Conway how she rationalized being Trump’s campaign manager in the wake of the assault allegations. “For you to use sexual assault to try to make news here I think is unfortunate,” Conway responded.
Introduction {#Sec1} ============ Several studies have evaluated sex-related differences in functional outcomes among patients with intracerebral hemorrhage (ICH)^[@CR1]--[@CR3]^; however, mortality rates and outcomes following ICH remain controversial. For example, some studies have reported a higher mortality rate among women^[@CR4]--[@CR6]^, while others have reported a higher mortality rate among men^[@CR7],\ [@CR8]^. Other studies have reported no sex-related differences in mortality after ICH^[@CR3],\ [@CR9],\ [@CR10]^. Moreover, there are limited data regarding sex-related differences in long-term outcomes (particularly outcomes at \>1 year), including recurrence and dependency rates after ICH. Therefore, the present study aimed to evaluate sex-related differences in functional outcomes (mortality, dependency, and recurrence rates) in the short-term (3 months), medium-term (12 months), and long-term (36 months) after ICH. Results {#Sec2} ======= During the study period, 1,533 consecutive patients diagnosed with first-ever hemorrhagic stroke were registered in our database. Among these patients, 1,330 patients fulfilled our inclusion criteria, and we analyzed the records of 1,325 patients with complete data. The patient selection flow chart is shown in Fig. [1](#Fig1){ref-type="fig"}. Of the 1,325 patients who had experienced at least 3 months after stroke onset, 1,287 patients (97.1%) completed the 3-month follow-up; among 1,170 patients who had experienced at least 12 months after stroke onset, 1,092 patients (93.3%) completed the 12-month follow-up; and among 893 patients who had experienced at least 36 months after stroke onset, 770 patients (86.2%) completed the 36-month follow-up.Figure 1Response rates were 97.1% at 3 months after ICH, 92.9% at 12 months after ICH, and 86.2% at 36 months after ICH, respectively. ICH, intracerebral hemorrhage. The present study included 897 men (67.7%) and 428 women (32.3%). The mean age at ICH onset was younger in men than in women (59.14 years vs. 63.12 years, respectively), and men were more likely to be \<45 years of age at ICH onset (11.5% vs. 3.0%; P \< 0.001 for all). Men were also more likely to have a basal ganglia hematoma (47.4% vs. 36.2%; P \< 0.001), although women were more likely to have a thalamus hematoma (21.7% vs. 12.4%; P \< 0.001). Moreover, the frequency of number for multi-hematoma was similar between men and women (8.7% vs. 11.7%, P = 0.085). Regarding in-hospital complications, urinary tract infections were more prevalent in women than in men (3.7% vs. 1.6%; P = 0.013), although there were no other statistically significant sex-related differences in complication rates. Women had significantly greater neurological function deficits, with lower Barthel indices (BIs) and higher modified Rankin scale (mRS) scores at admission; men and women had similar National Institutes of Health Stroke Scale (NIHSS) scores. There were higher prevalence rates of diabetes mellitus (DM) (22.9% vs. 17.7%; P \< 0.001), cardiovascular disease (26.6% vs. 17.7%; P \< 0.001), and obesity (15.7% vs. 10.8%; P = 0.012) in women than in men; however, there were no other significant sex-related differences in medical history factors (P \> 0.05 for all). The rates of current smoking status (47.2% vs. 11.9%; P \< 0.001) and alcohol consumption (30.5% vs. 1.6%; P \< 0.001) were higher in men than in women. Women had significantly higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting glucose (FG), and glycosylated hemoglobin (HbA1c) (P \< 0.05 for all), and men had significantly higher diastolic blood pressure (DBP). We did not observe any significant sex-related differences in levels of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), or systolic blood pressure (SBP) (Table [1](#Tab1){ref-type="table"}).Table 1Sex differences in demographical and clinical characteristics.CharacteristicsMenWomenPNumbers, n(%)897 (67.7)428 (32.3)Age, year, mean(SD)59.14 (12.74)63.12 (11.62)\<0.001Age group, n(%)\<0.001 \<45 years103 (11.5)13 (3.0) 45--59 years393 (43.8)163 (38.1) ≥60 years401 (44.7)252 (58.9)Hematoma location, n(%)\<0.001 Basal ganglia425 (47.4)155 (36.2) Lobar98 (10.9)47 (11.0) Thalamus111 (12.4)93 (21.7) Brainstem142 (15.8)62 (14.5) Cerebellum43 (4.8)21 (4.9) ≥2 locations78 (8.7)50 (11.7)Number of the hematoma, n(%)0.085 Single hematoma819 (91.3)378 (88.3) Multi- hematoma78 (8.7)50 (11.7)Stroke severity, n(%)0.219 Mild401 (44.7)176 (41.1) Moderate/Severe496 (55.3)252 (58.9)Neurological function deficit NIHSS9.00 (0--42)9.00 (0--40)0.265 BI40.00 (0--100)30.00 (0--100)0.001 mRS4.00 (0--6)4.00 (1--6)0.009Complication in hospital, n(%)188 (21.0)94 (22.0)0.676 Pulmonary infection131 (14.6)61 (14.3)0.865 Urinary Infection14 (1.6)16 (3.7)0.013 GI hemorrhage65 (7.2)29 (6.8)0.755 Seizure4 (0.4)2 (0.5)0.957 Electrolyte disturbance30 (3.3)15 (3.5)0.880 Liver/renal toxicity16 (1.8)3 (0.7)0.121Medical history, n(%) Hypertension766 (85.4)370 (86.4)0.608 Diabetes159 (17.7)98 (22.9)0.026 Atrial fibrillation23 (2.6)16 (3.7)0.237 Cardiovascular disease159 (17.7)114 (26.6)\<0.001 Obesity97 (10.8)67 (15.7)0.012 Current smoking423 (47.2)51 (11.9)\<0.001 Alcohol consumption274 (30.5)7 (1.6)\<0.001Blood pressure, mmHg, mean(SD) SBP165.27 (27.08)165.49 (26.69)0.926 DBP93.75 (15.05)87.89 (13.24)\<0.001Laboratory, mmol/l, mean(SD) Total cholesterol4.94 (1.04)5.37 (1.07)\<0.001 Triglyceride1.60 (1.20)1.47 (1.02)0.068 High density lipoprotein cholesterol1.22 (0.36)1.35 (0.36)\<0.001 Low density lipoprotein cholesterol2.93 (0.85)3.15 (0.86)\<0.001 Fasting glucose6.37 (2.39)6.94 (2.90)0.002 Glycosylated hemoglobin6.10 (1.17)6.41 (1.32)0.017 In the univariate analysis, we observed significant sex-related differences in mortality rates at each follow-up period. The mortality rates at 3 (13.5% vs. 9.0%, P = 0.021), 12 (17.2% vs. 13.4%, P = 0.111), and 36 months (25.3% vs. 21.9%, P = 0.307) were higher for men than for women. The unadjusted OR (95%CI) was 1.58 (1.07--2.33) at 3 months after ICH. However, there were no significant sex-related differences in recurrence or dependency rates (Table [2](#Tab2){ref-type="table"}).Table 2Sex differences in outcomes at 3, 12, 36 months after ICH.OutcomesMenWomenUnadjusted OR (95% CI)P3 months (n = 1287) Mortality118 (13.5)37 (9.0)1.58 (1.07, 2.33)0.021 \<45 years11 (10.9)2 (15.4)0.67 (0.13, 3.44)0.631 45--59 years41 (10.6)8 (5.0)2.27 (1.04, 4.96)0.036 ≥60 years66 (17.0)27 (11.3)1.60 (0.99, 2.59)0.053 Recurrence27 (2.1)7 (1.7)1.84 (0.97, 4.27)0.147 \<45 years00------ 45--59 years16 (4.1)1 (0.6)6.88 (0.90, 52.29)0.063 ≥60 years11 (2.9)6 (2.5)1.14 (0.42, 3.12)0.801 Dependency271 (35.7)150 (40.0)0.83 (0.65, 1.07)0.159 \<45 years20 (22.2)6 (54.5)0.24 (0.06, 0.88)0.021 45--59 years121 (35.0)41 (26.8)1.47 (0.97, 2.24)0.072 ≥60 years130 (40.2)103 (48.8)0.71 (0.50, 1.00)0.05112 months (n = 1092) Mortality129 (17.2)46 (13.4)1.34 (0.93, 1.93)0.111 \<45 years11 (13.4)2 (15.4)0.70 (0.13, 3.66)0.669 45--59 years41 (12.5)11 (8.8)1.49 (0.74, 2.99)0.265 ≥60 years77 (22.6)33 (15.9)1.54 (0.92, 2.42)0.058 Recurrence74 (9.9)27 (7.9)1.28 (0.81, 2.03)0.288 \<45 years2 (2.4)1 (9.1)0.25 (0.02, 3.01)0.241 45--59 years33 (10.1)10 (8.0)1.29 (0.62, 2.70)0.498 ≥60 years39 (11.5)16 (7.7)1.55 (0.84, 2.85)0.158 Dependency172 (27.7)84 (28.0)0.98 (0.72, 1.34)0.923 \<45 years6 (8.5)5 (55.6)0.07 (0.02, 0.35)\<0.001 45--59 years78 (27.3)25 (21.6)1.37 (0.82, 2.28)0.234 ≥60 years88 (33.3)54 (30.9)1.12 (0.74, 1.69)0.58736 months (n = 770) Mortality136 (25.3)51 (21.9)1.21 (0.84, 1.75)0.307 \<45 years11 (18.6)2 (28.6)1.50 (0.15, 2.99)0.532 45--59 years44 (19.3)12 (13.8)0.57 (0.10, 3.35)0.253 ≥60 years81 (32.4)37 (26.6)1.32 (0.83, 2.09)0.235 Recurrence159 (29.6)62 (26.6)1.16 (0.82, 1.64)0.398 \<45 years7 (11.9)2 (28.6)0.34 (0.06, 2.08)0.223 45--59 years61 (26.8)19 (21.8)1.31 (0.73, 2.35)0.370 ≥60 years91 (36.4)41 (29.5)1.37 (0.88, 2.14)0.168 Dependency205 (50.9)87 (47.5)1.14 (0.81, 1.62)0.455 \<45 years19 (39.6)3 (60.0)0.44 (0.07, 2.86)0.378 45--59 years87 (47.0)31 (41.3)1.26 (0.73, 2.17)0.403 ≥60 years99 (58.2)53 (51.5)1.32 (0.80, 2.15)0.274 Furthermore, the results stratified by age groups showed that mortality at 3 months after ICH was significantly higher in men than in women among those aged 45--59 years, and the dependency rate was greater in men than in women at 3 and 12 months among patients aged \<45 years (Table [2](#Tab2){ref-type="table"}). Table [3](#Tab3){ref-type="table"} presents the adjusted ORs for men at the 3-, 12-, and 36-month follow-ups. Men had a higher risk of death at 3 months after ICH (OR, 2.32; 95% confidence interval \[CI\], 1.45--3.72; P \< 0.001) than did women after adjustment for those covariates found to be significant in the univariate analysis, including age, stroke severity, hematoma number, hypertension, atrial fibrillation (AF), dyslipidemia, complications, current smoking, and alcohol consumption. Moreover, severe stroke, AF, and complications were independent risk factors for mortality at 3 months after ICH. However, there were no significant sex differences for recurrence and dependency rates at 3, 12, and 36 months after ICH. Severity, AF, complications, and multiple hematomas were associated with high risk of mortality at 12 months after ICH; severity, complications, and multiple hematomas were associated with a high risk of mortality at 36 months after ICH. Furthermore, older age, greater severity, and complications were determinants of dependency at 3 and 12 months after ICH, but severity and AF were determinants of dependency at 36 months after ICH.Table 3Adjusted OR (95% CI) for associated factors of outcomes at 3, 12, and 36 months after stroke.Risk FactorsReferencesMortalityRecurrenceDependency3 monthsMenWomen2.32 (1.45, 3.72)---Age group\<45 years 45--59 years0.84 (0.39, 1.78)1.15 (0.90, 3.67) ≥60 years1.33 (0.63, 2.78)2.67 (1.54, 4.62)SeverityMild Moderate3.12 (1.51, 6.48)7.57 (5.50, 10.42) Severe35.12 (17.85, 69.09)18.71 (11.84, 29.56)HypertensionNo1.34 (0.80, 1.60)1.22 (0.78, 1.90)AFNo2.64 (1.01, 6.89)---DyslipidemiaNo---0.82 (0.57, 1.18)ComplicationNo2.19 (1.44, 3.35)1.70 (1.17, 2.48)Multi-hematomaSingle1.36 (0.76, 2.45)1.44 (0.88, 2.36)Alcohol consumptionNever---0.88 (0.63, 1.25)12 monthsAge group\<45 years 45--59 years0.76 (035, 1.65)2.36 (1.18, 4.74) ≥60 years1.26 (0.59, 2.68)3.18 (1.59, 6.35)SeverityMild Moderate2.69 (1.43, 5.03)3.61 (2.57, 5.09) Severe25.95 (14.37, 46.89)5.26 (3.32, 8.34)HypertensionNo0.39 (0.22, 0.67)---AFNo3.03 (1.11, 8.23)---DyslipidemiaNo------ComplicationNo2.47 (1.63, 3.76)1.50 (1.02, 2.20)Multi-hematomaSingle1.89 (1.04, 3.44)0.97 (0.55, 1.73)Current smokingNever0.96 (0.59, 1.56)---Alcohol consumptionNever0.80 (0.43, 1.50)---36 monthsAge group\<45 years 45--59 years0.87 (0.40, 1.92)2.16 (1.00, 4.55)1.21 (0.66, 2.22) ≥60 years1.89 (0.87, 4.08)3.25 (1.56, 6.78)1.76 (0.96, 3.23)SeverityMild Moderate1.81 (1.06, 3.10)1.45 (1.01, 2.09) Severe14.10 (8.41, 23.64)1.93 (1.13, 3.28)AFNo2.34 (0.83, 6.56)9.90 (1.25, 18.46)ComplicationNo2.07 (1.36, 3.15)1.08 (0.70, 1.65)Multi-hematomaSingle2.61 (1.45, 4.71)---Alcohol consumptionNever0.86 (0.49, 1.51)--- Discussion {#Sec3} ========== To our knowledge, this is the first study to examine sex-related differences in long-term outcomes after ICH. Using a large hospital-based registry, we evaluated mortality, recurrence, and dependency rates at 3, 12, and 36 months after ICH. Our findings revealed various sex-related differences in patients' demographic and clinical characteristics. Women were more likely than men to be older; have a greater frequency of urinary tract infections, DM, cardiovascular disease, obesity; and have higher levels of TC, HDL-C, LDL-C, FG, and HbA1c. However, men were more likely than women to be younger and have higher DBP. Men aged 45--59 years had significantly higher mortality at 3 months after ICH; male sex was an independent risk factor for mortality after adjusting for covariates. Moreover, severity and complications were determinants of mortality and dependency after ICH. Recurrence was associated with older age only at 36 months after ICH. Over the past few decades, the incidence of ICH in developed countries has remained unchanged or decreased^[@CR2],\ [@CR11]--[@CR14]^. However, the trends in China are inconsistent, as the incidence of ICH has decreased in urban areas but increased in rural areas (for both sexes)^[@CR15],\ [@CR16]^. Interestingly, studies have also found that men are more likely to experience their first stroke at a younger age than women are. A study with exclusion criteria similar to those utilized in the present study reported that women were on average 8 years older than men at ICH onset^[@CR11]^. Another study found that women were on average 6 years older than men at the time of stroke^[@CR17]^. Similarly, we found that men were approximately 4 years younger at ICH onset than women were. However, conflicting trends have been reported in other studies; an American study reported that women in North Carolina experienced ICH 4 years before men did^[@CR18]^, and other studies have reported no significant differences between sexes in the age of onset^[@CR19],\ [@CR20]^. In the present study, men aged 45--59 years had a significantly higher mortality at 3 months after ICH. It is possible that the neuroprotective effects of female gonadal hormones delay the onset of ICH among women, as these hormones play roles in decreasing lipid levels and altering rapid vasomotor responses in vessel walls^[@CR21]--[@CR23]^. There is a lower rate of hormone replacement therapies in Chinese women; the rate of regularly using hormone replacement therapies (1 year and over) was 1.1% in mainland China^[@CR24]^ and 13.5% in Taiwan^[@CR25]^ among postmenopausal women. In this study, none of the women were taking hormone replacement therapies; therefore, the neuroprotective effects of estrogen may play an important role in delaying the presence of ICH among women. Previous studies have demonstrated that stroke burden is higher among women than among men due to higher rates of pre- and post-stroke disability^[@CR17],\ [@CR18],\ [@CR26],\ [@CR27]^. However, sex-related differences in stroke outcomes may be due to the study design, which include setting (population-based or hospital-based), population (Asian or Western), inclusion criteria, analytical methods, and duration of follow-up^[@CR19]^. For example, some studies have reported higher mortality rates among women after ICH^[@CR4]--[@CR6]^, some have reported similar mortality rates between men and women after ICH^[@CR3],\ [@CR9],\ [@CR10]^, and others have reported higher mortality rates among men after ICH^[@CR7],\ [@CR8]^. In the present study, we observed higher mortality rates among men at 3 months after ICH. This higher mortality rate may be explained by the higher prevalence of smoking and alcohol consumption and the higher DBP levels among men; in addition, lower levels of TC and HDL-C, which have been reported to be associated with a higher risk of death after ICH, may contribute to the higher mortality rate in men after ICH^[@CR28],\ [@CR29]^. Several studies have reported that hypercholesterolemia is a protective factor for ICH. For example, the Ludwigshafen Stroke Study in Germany found that the absence of hypercholesterolemia before ICH was associated with a 22% higher mortality rate after ICH^[@CR30]^. Another study identified an association between a history of hypercholesterolemia and a decreased risk of ICH^[@CR31]^, and TC has been reported to be negatively associated with hemorrhagic and total stroke mortality^[@CR32]^. Recently, two studies reported the long-term mortality rates and functional outcomes among stroke patients^[@CR31],\ [@CR32]^. A study from the Swedish Stroke Register indicated there were higher mortality rates among women than among men at 3 and 12 months after stroke, and elderly women (aged 75 years and over) were most susceptible to deterioration, with dependency rates increasing from 23.2% to 45.5%^[@CR33]^. Another Collaborative Evaluation of Rehabilitation in Stroke Across Europe Study showed that functional and motor outcomes at 5 years were equal to those 2 months after stroke. Increasing age and increasing stroke severity negatively affected outcomes^[@CR34]^. However, only a few studies have reported sex-related differences in long-term (\>1 year) functional outcomes after ICH. For example, one Chinese study found that women had a higher risk of dependency at 3 and 6 months after ICH^[@CR19]^. In contrast, we found no sex-related differences in recurrence and dependency rates at 3, 12, and 36 months after ICH. Although this study included a large sample of patients diagnosed with ICH and evaluated long-term outcomes, there are also several limitations. First, all patients were from a single hospital in northern China, and it cannot be assumed that our findings are representative of the general Chinese population. However, given the high incidence of ICH in northern China, our large sample provides reliable information regarding local sex-related differences in ICH outcomes. Second, we did not collect information regarding pre-stroke medications. This omission may have confounded our analysis of sex-related differences for various factors. Third, our registry did not contain information regarding hematoma volume, which could affect outcomes after ICH. However, we replaced hematoma volume with the number of hematomas, which could roughly estimate the hematoma volume. Finally, information regarding rehabilitation therapy after the acute phase was not provided in this study, but it might have an effect on the evaluation of prognosis after ICH. Finally, a follow-up rate of \<90% at 36 months after ICH could impact the evaluation of outcomes at 36 months after ICH. Conclusions {#Sec4} =========== This is the first study to evaluate sex-related differences in the clinical features, risk factors, and short- to long-term outcomes among Chinese patients diagnosed with ICH. Our findings revealed that ICH onset occurred approximately 4 years earlier in men than in women. Women were more likely than men to be older; have a greater frequency of urinary tract infections, DM, cardiovascular disease, obesity; and have higher levels of TC, HDL-C, LDL-C, FG, and HbA1c. However, men were more likely than women to be younger and have higher DBP. Men aged 45--59 years had significantly higher mortality at 3 months after ICH; male sex was an independent risk factor for mortality after adjusting for covariates. Moreover, severity and complications were determinants of mortality and dependency after ICH. Recurrence was associated with older age only at 36 months after ICH. These findings suggest that it is crucial to strengthen the management of AF and complications in patients with ICH, especially the management of blood pressure in men, to reduce mortality rates and the burden of ICH in China. Materials and Methods {#Sec5} ===================== This study evaluated data from a prospectively maintained database of patients diagnosed with ICH who were admitted to the stroke unit of Tianjin Huanhu Hospital, China, between January 2005 and September 2014. We assessed the outcomes at 3, 12 and 36 months after ICH in December 31, 2014. Of these, those patients who registered before September 30, 2014 were qualified to assess the outcomes at 3 months after ICH; those patients who registered before December 31, 2013 were qualified to assess the outcomes at 12 months after ICH; and those patients who registered before December 31, 2011 were qualified to assess the outcomes at 36 months after ICH. A diagnosis of ICH was made according to the World Health Organization\'s criteria, and all diagnoses were confirmed using brain computed tomography findings^[@CR35]^. All patients with ICH were admitted to the hospital within 72 h of stroke onset and were ≥18 years of age at the time of database inclusion. We excluded patients diagnosed with subarachnoid hemorrhage, traumatic hemorrhage, and brain hemorrhage caused by vascular malformations, as well as cases of coagulopathy, aneurysmal rupture, and recurrent ICH. Furthermore, patients with premorbid dependency (defined as mRS score \>2) and those who died after completing the neuroimaging diagnosis but before admission to the stroke unit were excluded from this study. For the included patients, we collected data regarding their baseline characteristics (including demographic information), clinical features, medical history, risk factors, routine laboratory test results, and outcomes 3, 12, and 36 months after ICH. Patients with ICH were treated with medications that included diuretics (mannitol, glycerol fructose, furosemide, torsemide, and albumin), antihypertensives, and medications to treat complications occurring during hospitalization. All investigative protocols were approved by the ethics committee of Tianjin Huanhu Hospital. The procedures were performed according to approved guidelines, and a written informed consent was obtained from each patient. The clinical features of ICH included in this analysis were hematoma location, neurological function deficits, severity, and in-hospital complications. Hematoma location was categorized as: basal ganglia, lobar, thalamus, brain stem, cerebellum, or ≥2 locations, as determined using brain computed tomography findings. Neurological function deficits were evaluated using the NIHSS score, BI, and mRS score at admission. Stroke severity was categorized into 3 groups using the NIHSS score: mild (NIHSS score ≤ 7), moderate (NIHSS score 8--16), or severe (NIHSS score ≥ 17)^[@CR36]^. We also identified cases that experienced pulmonary infection, urinary tract infection, gastrointestinal hemorrhage, seizure, electrolyte disturbance, and liver/renal toxicity in the hospital. Furthermore, we collected data on patients' levels of TC, TG, HDL-C, LDL-C, FG, and HbA1c at admission. Regarding patient medical history, we collected data on the presence of hypertension (defined as a history of hypertension or antihypertensive drug use), DM (defined as a history of DM or hypoglycemic drug use), atrial fibrillation (AF, defined as a history of AF confirmed by at least one electrocardiogram, or the presence of arrhythmia during hospitalization), and cardiovascular disease (including coronary heart disease or myocardial infarction). We also evaluated patients' modifiable lifestyle factors, which included current smoking status (≥1 cigarette per day for ≥1 year), alcohol consumption (≥1 drink per week for 1 year), and obesity (body mass index ≥ 30 kg/m^2^). Patient outcomes included mortality, recurrence, and dependency rates at 3, 12, and 36 months after ICH. All outcome data were collected via in-person examinations or telephone follow-ups. Death was defined as all-cause mortality during the corresponding periods after ICH. Recurrence was defined as a new-onset vascular event, which included ICH, ischemic stroke, myocardial infarction, and venous thrombosis within 30 days after stroke. We included patients who died as a result of these vascular events, although we excluded patients with a confirmed non-vascular cause of death. Dependency was defined as an mRS score ≥3 at the time of follow-up; patients who died were excluded from the analysis of dependency rates^[@CR37]^. Follow-ups were performed according to a predetermined procedure, with trained neurologists re-examining the patients in the outpatient department at 3, 12, and 36 months after ICH. All patients completed follow-up with face-to-face interviews or with telephone interviews for patients who could not attend an in-person follow-up. Descriptive statistics were used to evaluate sex-related differences. Age and levels of TG, TC, HDL-C, LDL-C, FG, and HbA1c are reported as means ± standard deviations, while NIHSS scores, BI, and mRS scores are reported as medians (ranges). Continuous variables were compared using the Student t-test or Mann-Whitney U test as appropriate. Dichotomous variables, including stroke subtypes, stroke severity, medical history, stroke risk factors, and outcomes at 3, 12, and 36 months after ICH, are reported as numbers (percentages). The chi-squared test was used to compare dichotomous variables. All patients missing from each follow-up period were excluded from calculations of mortality, dependency, and recurrence rates. We also excluded patients from the dependency rate calculation who completed follow-up via telephone. Sex-related differences in outcomes were assessed using logistic regression models, and the risk is reported as unadjusted ORs with 95% CIs. A multivariate analysis of sex differences in outcomes was performed with a logistic regression model that was adjusted by those variables found to be significantly associated with outcomes at 3, 12, and 36 months after stroke in the univariate analysis, such as age, stroke severity, hematoma location, medical history, risk factors, and in-hospital complications (i.e., pulmonary infection and gastrointestinal hemorrhage). The results of the multivariate analysis are presented as adjusted ORs and 95% CIs. All statistical analyses were performed using SPSS software (version 15.0; SPSS Inc., Chicago, IL), and all tests were two-tailed. Statistical significance was defined as a P-value of \<0.05. Publisher\'s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We thank all participants in this study and the local physicians for their enthusiasm, tireless work, and sustained support, Mr. yueqian Ning for advice on revision of the manuscript. This study was funded by the Tianjin Health Bureau of Science and Technology Fund Key Projects (contract: KY12, and 2013KG120). Y.X. was involved in data interpretation and drafting this manuscript. Y.X., Z.A., X.N., and J.W. were involved in conception and design, data collection, data interpretation, and critical review. Y.X., X.Z., N.Y., and W.Z. were involved in data collection, case diagnosis, and confirmation. J.W. and X.N. were involved in data analysis. Competing Interests {#FPar1} =================== The authors declare that they have no competing interests.
Q: Get images in mysql table to appear in javascript slideshow I have some images in the table images, the fields are id, name and photo. Where the image exists in photo. At the minute, the code below not getting any images, although there should be about 4 images that match the query. The images that meet the query should go into the slideshowimages("") variable. <?php // Connect to the database require('mysqli.php'); // Query for a list of all existing files $sql = "SELECT * FROM images WHERE name= '$pagetitle'"; $result = $conn->query($sql); $directory = ''; while( $image = $result->fetch_assoc() ) $directory .= ($directory != '' ? "," : '') . ('"/images/'.$image["photo"] . '"'); // Check if it was successfull if($image) { // if there are images for this page, run the javascript ?><script> //configure the paths of the images, plus corresponding target links //NEED TO GET ALL RELEVANT IMAGE LOCATIONS INTO LINE BELOW slideshowimages("<?php echo $directory ?>") //configure the speed of the slideshow, in miliseconds var slideshowspeed=2000 var whichlink=0 var whichimage=0 function slideit(){ if (!document.images) return document.images.slide.src=slideimages[whichimage].src whichlink=whichimage if (whichimage<slideimages.length-1) whichimage++ else whichimage=0 setTimeout("slideit()",slideshowspeed) } slideit() </script> <?php } else { // If there are not any images for this page, leave the space blank echo ""; } // Close the mysql connection $conn->close(); ?> The JavaScript that is in the head <script language="JavaScript1.1"> var slideimages=new Array() var slidelinks=new Array() function slideshowimages(){ for (i=0;i<slideshowimages.arguments.length;i++){ slideimages[i]=new Image() slideimages[i].src=slideshowimages.arguments[i] } } </script> A: The nice and simply way, is to use an AJAX call, to get your image urls in a JSON array, which you can parse to a javascript array, and iterate and so on. In that case, the added bonus is that you can separate your code to different files by language, and it makes a way nicer code. But in your current code, you have to iterate your mysqli results with a simple loop. For example: //... // Query for a list of all existing files $sql = "SELECT * FROM images WHERE name= '$pagetitle'"; $result = $conn->query($sql); $directory = ''; while( $image = $result->fetch_assoc() ) $directory .= ($directory != '' ? ',' : '') . ("'/images/".$image['photo'] . "'"); //... In this case, your $directory variable be like something like this: '/images/image1.jpg','/images/image2.jpg','/images/image3.jpg' And you hopefully can pass it to the javascript function as an argument list. I hope I could help.
Archive for December 21st, 2012 (PR) Trenton, NJ)- The Trenton Thunder, the Double-A affiliate of the New York Yankees, announced on Friday that 2012 Eastern League Manager of the Year Tony Franklin will be return to Trenton for the seventh consecutive season. Franklin will be joined in the dugout once again by pitching coach and former Major Leaguer Tommy Phelps who returns for a fifth season, as well as Coach Luis Dorante and Athletic Trainer Scott DiFrancesco, each returning for year two in Trenton. The coaching staff will include new additions Hitting Coach Justin Turner and Strength and Conditioning Coach Orlando Crance. “Tony Franklin is a true professional and a great asset to the Thunder and our community,” said Thunder General Manager Will Smith. “We’re happy to welcome Tony back to guide the team during our 20th season celebration.” Franklin guided the Thunder to back-to-back Eastern League Championships in 2007 and 2008 as well as Eastern League Championship Series appearances in 2010 and 2012. He has led Trenton to the post-season in four of his six seasons and owns a career managerial record of 1080-973 including a record of 488-390 with Trenton (records include post-season). The skipper recorded his 1,000 career managerial win and was named Eastern League Manager of the Year in 2012. The 2008 Eastern League Championship was Franklin’s third title as manager. In 1993, he led South Bend (Single-A affiliate of the Chicago White Sox) to the Midwest League Championship. Prior to his time in Trenton, Franklin spent most of the last 11 years as the Minor League Infield Instructor for the San Diego Padres. His managerial career began with the White Sox organization as the manager for Geneva (NY) of the New York-Penn League in 1982. Franklin spent four seasons in Geneva, making the playoffs in 1985. After one season with Wytheville (Appalachian League), he guided the White Sox affiliate in the Florida State League, the Sarasota White Sox, to a playoff appearance in 1989. Franklin spent two years as the skipper of the Birmingham Barons of the Southern League, including 81 wins in 1991 and a berth in the Championship Series. Tommy Phelps will return for his fifth season as the pitching coach for the Thunder. Phelps pitched for the Florida Marlins in 2003 and 2004 including a 2003 season in which he went 3-2 with a 4.00 ERA in 27 games (seven starts). He was part of a Marlins team that won the World Series over the Yankees. Phelps pitched in 29 games for Milwaukee in 2005 and went 7-4 with a 4.45 ERA in 2006 with Columbus (Triple-A affiliate of the New York Yankees). Phelps was originally an eighth round pick by Montreal in the 1992 draft. Hitting Coach Justin Turner has spent the last two seasons as the Tampa Yankees hitting coach after spending one year with the Charleston RiverDogs. Turner was originally selected by the Angels in the eigth round of the 2001 draft. He played four seasons of affiliated baseball in the Angels (2001-04) and Red Sox (2004) organizations. Coach Luis Dorante spent last season as Coach for the Trenton Thunder and the prior four years in the Pirates organization, serving as the Latin American Field Coordinator in 2011. From 2008-2010, he was the Pirates Bullpen Coach, having joined the Major League staff on November 20, 2007. He served the Florida Marlins in the same capacity during the 2005 campaign. Dorante’s managerial career began with the Montreal Expos in the Gulf Coast League in 1995. The former Harrisburg Senators skipper returns to the Eastern League for the first time since the 2001 season. In 11 seasons as a minor league manager, Dorante led his team to the playoffs four times and compiled a record of 671-696. Primarily a catcher during his playing days, Luis also made appearances at first base, third base and in the outfield during his six-year minor league career. Athletic Trainer Scott DiFrancesco has been in the Yankees organization for six years after spending last year with Trenton. Prior to that he was with Tampa for 2011 and the previous three with Charleston. He also completed an internship at the Yankees complex in Tampa, FL in 2006. He has a Bachelor of Science in Athletic Training from Ball State University. The 2013 Trenton Thunder season will begin on Thursday, April 4 at Portland with the home opener slated for Thursday, April 11 vs. Richmond. Fun Legal Stuff Thunder Thoughts is in no way associated with the Trenton Thunder, Eastern League, New York Yankees, or its employees or players. All information is subject to change. All views and comments made from outside parties, other than Thunder Thoughts personnel, are subject to their own permission. They are not the views of Thunder Thoughts or any of the aforementioned parties. If you have any questions regarding this policy, or for more information, please contact Thunder Thoughts.
Saudi Arabia’s Ministry of Education has made a series of modifications to its history textbooks altering the legacy of the Ottoman Empire and its former rule over parts of the Arabian Peninsula. While the former curriculum taught the topic referencing the Ottoman Caliphate, the new curriculum will now cover the Empire’s “occupation”, crimes and subsequent collapse to pupils in the lower years of high school. Among the crimes the Saudi text books will level against the Ottoman rule are “Fighting with the first and second Saudi states; supporting some local leaders against King Abdul Aziz; destroying Diriyah and surrounding towns; as well as many parts of Zahran and Asir, besides torturing Imam Abdullah Bin Saud, the last imam of the first Saudi state, and assassinating him after taking him to Istanbul.” The curriculum also accuses the Ottoman government of having divided the Arabs of the Peninsula, stating: “The Arab land that came under the subjugation of the Ottoman administrative regime were divided into at least 15 states and each state was administered by a governor. The regime also sought to impose many taxes on the population and agricultural crops as well as on land, goods and services with collecting money to serve the Ottoman state and its sultans without leaving any significant revenues for these states.”The Ottomans, as the new narrative puts it, governed primarily by a policy of divide and rule, enforcing “political domination and sowing discord in order to prevent the Arabian Peninsula from being united, transferring skilled craftsmen and builders from Egypt and the Levant to Istanbul, building fortresses and forts to protect the state soldiers and their states, and prevalence of instability and insecurity within these countries and along the pilgrimage routes.” READ: Saudi-Turkey dispute affects economy Saudi Arabia’s official defamation of the Empire – or Caliphate, as it is widely known – signals a heightened sense of nationalism, as well as a strong anti-Turkish sentiment which has dominated the kingdom’s narrative in recent years. Critics of the move by the Saudi ministry have likened it to the similarity of deposed Iraqi dictator Saddam Hussein’s popular narrative of the Ottoman Empire, exploiting a rising sense of Arab nationalism while countering the perceived increasing influence of Turkey in the region by attacking and defaming its imperial history. Over the past few years, relations between Saudi and Turkey have been increasingly strained by diplomatic differences and by each other’s involvement in the Syrian civil war, and especially by Turkey’s support of Qatar following the ongoing blockade imposed on it by the kingdom, the United Arab Emirates (UAE), Bahrain and Egypt in 2017. Relations reached breaking point with the murder of US-based Saudi journalist Jamal Khashoggi in the Saudi consulate in Istanbul in October last year. Following months of investigations into the murder and a UN report concluding that Saudi agents killed Khashoggi under the direct command of Crown Prince Mohammed Bin Salman, Turkey has repeatedly called for those responsible to be brought to justice. Consequently, the Kingdom has been pushing a campaign to encourage its tourists to boycott Turkey through all possible means, including the purchase of products, consumption of foods, sale of properties, dealings with Turkish companies, and especially tourism to the country. The campaign has garnered support amongst Saudi royals and figures, a famous case being when Riyadh’s influential governor Faisal bin Bandar declined an offer of Turkish coffee, triggering a call for a boycott of Turkish products. READ: In effort to discourage tourism, Saudi warns of passport thefts in Turkey
Radiation therapy is widely performed on patients with breast tissue affected, for example, with cancerous cells and following breast conserving surgery. The acute toxicity, long-term side effects, and cosmetic outcome of such treatment are attributable to a number of factors including technical aspects of surgery, pre-existing systemic medical conditions, the use of specific chemotherapeutic agents and administration of such relative to delivery of radiation therapy, radiation therapy treatment technique, and patient morphology. Patient morphology is generally the most difficult factor to compensate for in seeking optimum delivery of radiation therapy and a factor which most directly affects cosmetic outcome. Optimal radiotherapy technique is described as 4500-5000 cGy to the whole breast over a period of 4.5-5 weeks, followed by a boost to the excisional biopsy site with an additional 1000-1500 cGy. The technical aspects of delivering radiation therapy as a part of breast conserving therapy are less well defined and have evolved as a function of technical innovation and studies examining the patterns of failure. Improvements in methods for field matching, the abandonment of routine regional nodal irradiation, controversies concerning the necessity and method for boost treatment, sequencing of chemotherapy, and indications for radiation therapy, have distracted the radiation oncologist from attempting technical improvements in the delivery of radiation therapy. Treatment simulation and set-up are carried out primarily with the patient in the supine position, although certain cancer centers continue to use the decubitus position as their standard treatment position. When patients with large breasts are encountered, the decubitus position is sometimes used as an alternative to the supine position. While the supine position is considered more reproducible, it irradiates more lung and requires the use of wedge filters, high energy radiation beams, and bolus to overcome non-homogeneous dose distributions and skin overdose. The decubitus technique is performed with the breast tissue compressed to an even thickness of 6-8 cm and results in a more homogeneous dose distribution. The decubitus technique requires meticulous positioning and protection of the contralateral breast; it is therefore considered less reproducible and lacks the flexibility of supine position treatment, especially when nodal irradiation is considered. For these reasons, the decubitus technique is seldom used and has dropped from favor. Women with large and/or pendulous breasts, or women with small to medium size breasts and unusual chest wall contours, have relatively large medial to lateral separations. The separation is defined as the measure transverse distance across the base of the breast which will require radiation therapy. Such patients require modifications and alterations to traditional treatment techniques. When treatment is carried out in the supine position, the transverse displacement of breast tissue over the anterior chest wall creates a large separation. This separation, combined with potential folding of the breast at its most caudal extent, are two of the aspects of breast radiation therapy that contribute to non-uniformity of dose distributions and irradiation of large volumes of lung and heart tissue. A number of technical modifications have been proposed to improve the dose distribution in women with large separations. These modifications include the use of wedge filters, high-energy photon beams, beam-spoilers and bolus but which do not entirely or satisfactorily overcome the above described disadvantages and dangers. As mentioned, an alternative method of administering such therapy is to have the patient fully reclined in the decubitus position upon a horizontal surface and to position the radiation energy source adjacent the surface of tissue to be treated. Because this method does not physically isolate the part to be treated by radiation, it has the serious disadvantage of irradiation of tissue other than the affected portion of the breast and further including heart, lung and skin tissue proximate to the breast, all resulting from the patient being in the decubitus position. These and other associated problems are especially acute in patients with large breasts and/or pulmonary or cardiac conditions to whom scattered and excessive radiation creates significant risks.
/* * This file is part of a module with proprietary Enterprise Features. * * Licensed to Crate.io Inc. ("Crate.io") under one or more contributor * license agreements. See the NOTICE file distributed with this work for * additional information regarding copyright ownership. * * Unauthorized copying of this file, via any medium is strictly prohibited. * * To use this file, Crate.io must have given you permission to enable and * use such Enterprise Features and you must have a valid Enterprise or * Subscription Agreement with Crate.io. If you enable or use the Enterprise * Features, you represent and warrant that you have a valid Enterprise or * Subscription Agreement with Crate.io. Your use of the Enterprise Features * if governed by the terms and conditions of your Enterprise or Subscription * Agreement with Crate.io. */ package io.crate.auth.user; import com.google.common.collect.Lists; import org.elasticsearch.test.ESTestCase; import org.elasticsearch.common.io.stream.BytesStreamOutput; import org.junit.Test; import java.util.List; import static org.hamcrest.Matchers.is; public class PrivilegesResponseTest extends ESTestCase { @Test public void testStreaming() throws Exception { List<String> unknownUsers = Lists.newArrayList("ford", "arthur"); long affectedRows = 1L; PrivilegesResponse r1 = new PrivilegesResponse(true, affectedRows, unknownUsers); BytesStreamOutput out = new BytesStreamOutput(); r1.writeTo(out); PrivilegesResponse r2 = new PrivilegesResponse(out.bytes().streamInput()); assertThat(r2.isAcknowledged(), is(true)); assertThat(r2.affectedRows(), is(1L)); assertThat(r2.unknownUserNames(), is(unknownUsers)); } }
[Leaving the Self and meeting the Other: some reflections on psychiatric education]. This manuscript has served for an oral presentation in honour of Professor Pierre Bovet who retired from his position as head physician at the Department of Psychiatry of the Lausanne University Hospital, Switzerland. Pierre Bovet has focused his clinical and scientific interest and his teaching activities on the schizophrenic spectrum disorders. The author tries to describe the essential elements of a clinical attitude which allows to really encounter the patient.
>> creating virtual people, to pay for something that was never paid back. andrew thomas, al jazeera, sydney. >> a quick reminder, you can keep up with all the latest at aljazeera.com. aljazeera.com. both sides now mistrust america's leadership. the middle east is consumed by violence and president obama's foreign policy is coming undone in iraq, yemen and syria. but the palestinians and the the 1:31 am israelis, clashes in the wawrinka have killed at least 39 palestinians and eight israelis and counting. despite a five decade process, all we've seen is another emergency meeting of the united nations council. everyone flos what th knows whas supposed to look like. shepherding based on a two state solution, israel and palestine living side by side in peace, that's supposed to end with israel withdrawing from territories it seized in 1967. instead the palestinians have limited self rule in parts of the west bank and gaza and israel has confiscated more than half the land of the west bank and built settlements housing more than half a million israelis. 1:32 am to say there is a lack of trust between israel and palestine leaders is to say the least. israeli prime minister benjamin netanyahu has lashed out against president obama's deal with iran on its nuclear program callings him naive about the danger facing the region today. mahmoud abbas doesn't think israel is a rming environment environment that can foster peace. amid this mistrust peace in the holy land is no close to reality and the dangers are only growing amid all the violence consuming the middle east. karl penhall is on the ground with the latest. >> rain on the streets of bethlehem. a new generation rising up determined to solve an age-old 1:33 am complaint. israeli occupation. >> it's no life here. there's a life without freedom and you can't do anything here. >> reporter: protesters wield sling shots against one of the best-armed militaries in the world. some palestinians wounded by israeli live fire, others downed by rubber bullets. this started as a grass roots revolt after years of on-off peace talks, protesters accused their own palestinian leaders of failing to win an independent home land. >> we are here as a palestinian we are lead ourselves just as our revolution we will lead it by ourselves. we don't need any leader for this revolution. >> reporter: friday marked just the latest round of clashes. i'd been here two days earlier. the scenario was much the same. 1:34 am from the outside this may all look really chaotic but once you're in the thick of it, there is a certain level of coordination. there is this first line of defense their role is to stop israeli troops pushing deeper into the neighborhood and when it gets too hot they will simply fall away and let others take up the defense. 20 minutes drive away at the gates of jerusalem's old city, this is one of the core issues, fueling the current violence. israeli security forces banned muslim men under 40 from attending friday prayers in the al-aqsa mosque compound. so they pray on the streets . this is a religious war they want to steal our right to the prophet's holy place. they want to steal al-aqsa mosque compound he says. the israeli government denies it 1:35 am wants to alter the long standing agreement on what it calls temple mount. the distrust is almost genetic. even prayer time brings little peace. as soon as prayer is ended israeli police started to move in, they went into the crowd and detained one young palestinian man and now they brought in the police forces trying oensure thato ensurethat the crowd disperses. tactics learned from their fathers and grandfathers before them. they all resisted and we're continuing to do so. our children will resist as well. who knows until when, perhaps until we die he says. words of defiance, but little sense of hope. karl penhall, al jazeera, 1:36 am bethlehem. >> karl joins us from west jerusalem. karl, what has triggered today's violence and how widespread have these protests been on both sides today? >> well ali there have been lots of moving parts today. we have seen in the occupied west bank three deaths there of palestinians. two came during clashes with israeli security forces but the third death a somewhat worrying development a palestinian man disguised as a journalist approached an israeli soldier, and was shot dead. the first attempt that the palestinians have used this kind of reduce t ruse to attack their enemies. an incident from israeli authorities we hear that gaza militants may have opened fire on an israeli patrol. israelis then returning fire and 1:37 am killing two gazans, opening up a second front in this current wave of protest. here in jerusalem things have been somewhat calmer. here hasn't been any repeat of these incidents, but beefe beefed up security to stem this campaign, but young muslim men were forced to pray on the pavement at the gate of the old city and that is once again enflaming religious and political sensibilities, ali, that is why it's very difficult to talk about any sense of conciliation here. we only seem to be set for more confrontation. >> and you mentioned the fact that men under the age of 40 are not being allowed to the al-aqsa mosque. are there other security measures being implemented as we head into the weekend or do we think things have called down a 1:38 am little bit? >> no, absolutely, during the week in fact the israeli government approved a beefed up package of security measures and we're seeing those come into force right now. for example additional border police units have been brought into jerusalem to work alongside the regular police and we expect also to see some of the first israeli soldiers out on the streets in jerusalem as well over the course of the weekend. another development as well as part of these beefed up security measures is that now israeli security forces are putting up concrete cordons around some of the palestinian neighborhoods in occupied east jerusalem and that is an attempt, the israeli government says to try and stop potential palestinian attackers crossing over into other parts of jerusalem about what we are seeing even now as night falls more of these concrete blocks simply being tossed out onto city streets trying to block 1:39 am people, trying to block vehicles coming through. as i say, these look like battle lines are being drawn. >> karl penhaul fo penhall for 0 number. jerusalem. >> launching a big initiative is going to fail. >> "inside story" takes you beyond the headlines, beyond the quick cuts, beyond the sound bites. we're giving you a deeper dive into the stories that are making our world what it is. >> ray suarez hosts "inside story". only on al jazeera america. 1:40 am 1:41 am >> every saturday night. >> i lived that character. >> go one on one with america's movers and shakers. >> we will be able to see change. >> gripping... inspiring... entertaining. "talk to al jazeera". saturday, 6:00 eastern. only on al jazeera america. 1:42 am >> the surge in violence between israelis and palestinians is just the latest sign that the american led peace process has had any ing policy under the clinton, bush and obama administrations. and his new book, deeme doomed to succeed, here's what he told me when i asked him about the title of his book. >> americans look at israel and see israel as the only real democracy in the region. the region itself today is characterized by unbelievable turmoil, conflict over basic identity. terrible conflict. syria 300,000 dead, 12 million displaced. you see a threat and a breakdown to the state system and israel seems the stem the tide, even 1:43 am though there are problems still it has institutions a rule of law a separation of powers. and it's more capable of dealing with its problems and i think when the united states looks at israel it looks at israel and contrasts it to the region and even the trajectory, even those there's tension between the president and the prime minister, the relations will stay as they have been. >> the tensions between barack obama and benjamin netanyahu are serious, real tensions. >> they are but the only real leader that he didn't like was yitzak shamir. planes were parked next to each other at l.a.x. 1:44 am so it is not that we've always seen u.s. presidents and israeli prime ministers get along case. this is not unprecedented. i do think it's a difficult situation to say the least, but they will try to mend fences partly because of everything else going on in the region and the aftermath of the differences over iran and in the congress most of the democrats stayed with the president. they will be saying with the president look, having stood with you, we need you also to make life a little easier for us when it comes to israel. >> the danger that the president atakes a bit left on iran and, standing as a bullwark against iran in the middle east. >> that's right. >> and you think they can both overcome that? >> i think they can. if you look at prime minister netanyahu right now, number one, he has an interest in showing 1:45 am he's not partisan in the united states. it's not been a republican or democratic issue, it's an american thing. >> it changed this year. >> it has the feeling of changing this year. he has an interest of counteracting that, number one, and because you have real troubles right now in israel, i think this is a time when he wants the united states being seen as being with israel and also mending fences and not compounding things. >> most people, yourself says, a two state solution is not entirely likely with abbas and netanyahu. >> i don't have a high expectation of going from where we are to resolving the conflict, a big initiative that's bound to fail. i think for me, one of the things that's concerned me for the last three or four years has been the growing level of disbelief between both the israeli and the palestinian 1:46 am publi publicize. pliks. publics. when the anger and fear right now is at a high pitch the idea that can you go from that and solve the conflict strikes me as simply being illusory. the worst thing we can do when there's great disbelief is launch a big initiative that can fail. the reason why we are where we are is failed attempts before. one, figure out a how can you calm the situation? b, how can you change the reality on the ground and that means in a sense for both sides but certainly for palestinians, on the one hand you have palestinians aged 15 to 25 who don't feel they have a lot to lose, who feel that no one is paying attention, who have anger at their own leadership as long as the israelis. you have to address that. >> the fear that the stuff 1:47 am that's going on now in jerusalem may be born of that unlike intifadas, this doesn't have the same feeling of organization behind it. >> absolutely. i think that -- you can say it doesn't have organization behind it and you can say that's the good news but it is also the bad news. because without organization it means you don't have the same means to address it. it means there's a psychology here that also is going to have to be addressed. you are going to have to find a way to create a context where those that are doing this decide it doesn't make sense to do it but they also have a sense of possibility. they have to have a sense of what you lose but they also have to have a sense of what can be gained. >> let me ask you this though, when you look at a situation and all the years you have been involved in the negotiations, and you have mahmoud abbas very weakened, he has not held elections in palestine for a 1:48 am while, we know why, his party may not win, hamas may win, and then the negotiations get much trickier, don't they? >> though do. you can conduct negotiations in a context where you have people that lack legitimacy, you fear making big decisions so there's a lot of work that we have to do first things first, find a way to create calm. i think smarter way to proceed is to focus on how you can create what i would call coordinated unilateralism. steps that would be noted by palestinians that would be meaningful. >> wouldn't that be mostly about settlements? >> one of the things would i like to see, the israelis take an initiative that would show the settlement policy is consistent to a two state solution. >> what does that mean for the viewers who don't understand? >> i've said this in the book. what i mean is we have been 1:49 am talking since the year of 2000, those of us who are negotiators, in mutually agreed swaps. territorial negotiation for the settlement blocks. 80% of the settlers found in the settlement blocks that take up about 5% of the west bank. so you have territorial compensation for that. >> so rather than doing what happened in gaza where you dismantle the settlements and everyone goes back behind the line, you trade off area. >> that's right. when i say make your settlement consistent with the two state aspect, don't build outside the blocks. i would like the israelis to say we will no longer build in what we consider to be the palestinian state. it may not be the same, but for us to come to a common disagreement, until we can negotiate that border, we will not build in what we believe will be a palestinian state. as a way of saying we mean what 1:50 am we say about two states. even if that's not something palestinians will suddenly cheer about, it sends a message, that they're acting in a way that's consistent with that. >> you can see more of my interview with denni den ross on dennis ross on third rail. >> puerto rico's debt crisis. >> they're gonna demonstrate right outside where the governor lives. >> are hedge funds offering a fix? >> those investments will spark the economic recovery. >> or just fixing the odds? >> they're trying to force us into one course of action. >> "faultlines". >> what do we want? >> al jazeera america's hard-hitting... >> today the will be arrested. >> ground-breaking... >> they're firing canisters of gas at us. >> emmy award-winning, investigative series. 1:51 am 1:52 am >> i've been asked to keep my 1:53 am >> despite two decades of engagement, the united states has made little progress. we just heard from dennis ross. now diana bottu, she served as negotiator now is an international lawyer and works for the international institute, joins me from haifa in northern israel. thank you for joining us. i don't know if you got to hear dennis ross saying that what he would like, and i think he was expressing american desire is that the israelis treat 1:54 am settlements as if they were working towards a two state solution, in other words, agree that they will not build settlements on land that they think will end up as part of a two state solution. he doesn't think palestinians would cheer about it but would show commitment on the israeli side. do you agree with that? >> absolutely not. i think the united states should be treating them as they are which is illegal and what the united states should be doing is doing two things. one, puchg for their complete dismantle much and number 2, that the united states doesn't give israel any more money unless and until it ends the apartheid regime and settlement activity. >> you feel financial assistance military equipment what about this conversation that dennis ross had about what he calls coordinated unilateralism, that the u.s. is the third party that oversees whatever happened, is that still a likelihood, is the united states still a legitimate player in peace talks or any 1:55 am peace process between israel and palestine? >> the only role that the united states has played over the course of the past several decades is to be israel's enabler. it has provided israel with unbridled military and financial 74tsupport and military support whether it is in the united nations or otherwise. the role that the united states has been playing is being israel's lawyer, israel's advocate. this is the role that the rest of the world has recognized, and the role the u.s. should be playing is to step back, throw rest of th allowthe rest of the world to ie order and let that be the order of the day. i think what needs to happen is that we need to treat israel the 1:56 am same way as south africa apartheid was treated. dennis ross speak going the special relationship between israel and the united states, this is the same special relationship and the same book that could have been written back in the 1980s when somebody was talking about the special relationship between apartheid south africa and the united states. i think rather than allowing or enabling apartheid i think we should be looking for measures to end israeli apartheid whether pushing for boycotts, sanctions, divestment, pushing to isolate israel, making sure israel is held accountable under international law, same way they were done under apartheid south africa. >> so when i pose they'd to dennis ross to say that many palestinians don't see the u.s. as an honest broker, he, i paratrays, do you want an honest broker or an effective broker as israel's biggest friend in the world? the u.s. he suggested has the 1:57 am influence and the power to try and get israel to do something else. if we have a lull in the possibility. do you agree with that? >> ali, it's laughable. we've tried the united states being the honest broker, the effective broker in the last 22 years and all that the palestinians saw was a tripling of settlers on their territories. we have seen more demolitions of homes in the past years than in the last 20 years. >> let me discuss issues that we were talking to karl penhall about, young palestinians age 15 to 25 are angry at their leaders as well as israel, this doesn't have the mark of an organized protest in the west bank and jerusalem. do you share that view that it's not argued? >> no, it's not at all organized. i'm somebody who lives here and 1:58 am i've seen what's going on with these protests and these are a group of people who have spent their whole lives ali living under israeli military occupation. the false promises of oslo and the united states false promises. this is a generation that has only seen home demolitions, that they have to obtain a israeli permit to do something as simple as go to the sea and they know it is long. there is no end to the denial of freedom and this is a generation that has only seen the palestinian authority that has served as security subcontractor. this is a generation that has expressed their frustration as other palestinians to express their frustration. it is now time for the world to stand up and listen. i think it's time for us to really step back and say, is 48 years of occupation enough? or do we want this to continue for another 48 years and i think the answer is it's enough and 1:59 am these young people are saying that. >> you say something interesting, you see the palestinian authority acting as israel's subcontractor. mawmedz abbas was talking about the oslo accords and saying that nobody is living up to them. what does that mean? >> it's not entirely clear ali awhat that means and he has not means. what is clear is there's still some palestinian authority presence in the west bank areas but it's not all clear to me. what was lacking in his speech is he didn't at all state what it is and how it is he intends to take palestinians to the next level. he didn't articulate that he supports the boycott, vie vestment and sanction he proposal that the vast majority of palestinians have signed on to, a division of leadership, 2:00 am all that being said, we don't needs to rely on mahmoud abbas, this is a generation that's saying very clearly it's about obtaining our freedom and we want it now. >> diana, it's good to see you. she was previously an advisor to abbas. that is our show for today. i'm ali velshi. thank you for joining us. getting afghanistan often its feet and getting the u.s. out of the country. but reality has intruded. the taliban has hung on and even looked up with i.s.i.l. kunduz last briefly fell, and now there's a change in plans. the longest war, it's the "inside story."
"What a goddess." "A pity." "What's wrong?" "She's insane." "How so?" "I've lived here over a year." "I've never seen her talk or smile." "Isn't she insane?" "Come buy this new toy." "Excuse me." "What's so funny?" "Can't you pull a rickshaw properly?" "Are you blind?" "Get off." "Don't be nosey." "You're all arrested." "Why?" "Why?" "This is obscene." "Hurry." "You'll catch a cold." "We will have a lucky year." "Sure." "You're arrested." "Come along." "Well?" "I'll bet you" "$10 for making her smile." "You're on." "You mustn't talk too much to her." "Not even one word?" "Not more than one word" "I'll make her smile." "Then I'll make her angry" "I'll put another $10 on that." "It's a deal." "What if she doesn't smile?" "I'll lose $10 to you." "Fine." "Dad" "mother." "Are you crazy?" "Pay me" "I'm crazy now." "Pay me" "I'll pay you at home." "Can we buy toys, mum?" "Let's go." "Anything new." "It'd best be practical." "Yes." "What do you wants?" "Let's play a new game." "Right, let's match words." "Good" "I'll give you words to match." "By." "With." "And." "Or." "Good." "Large." "Small." "With or small for "By and Large"." "You're dumb." "It sounds poor." "You must die." "Listen." "This is not my best." "Don't be mad." "Do what you like." "Good." "How smart." "Not at all." "Very shrewd." "Not really" "I'll buy vegetables." "Like father, like son." "The son is more cunning." "Write 'Good Health'" "Well?" "What's the matter?" "How is it?" "Why put your money here?" "Why did you touch my safe?" "Madam." "That's..." "Whom was 'Madam' for?" "You, of course" "I'm not married yet." "This kid stole my things" "I'll kill you." "Why are you beating up my kid?" "Where can you run?" "Your kid stole my things." "They're all here." "Doesn't he deserve a beating?" "I'll sue you for this" "I'm single, and you call me Mrs" "I'll sue you." "You said my kid stole your things." "A court case?" "An unmarried girl with a kid?" "I have kids whenever I like." "You have the guts." "I belong to the year of the pig." "Let's get a policeman." "You're unreasonable." "Yet she's lucky." "What luck?" "The luck to give birth." "So what." "Well, we've married for 10 years." "We have no children." "We can't afford to." "We barely have enough." "Don't misjudge me." "Can't I get rich?" "I've foretold your fortunes." "What?" "You can't get rich." "Even if you do." "You're so mean." "You can't teach your kids well." "What?" "I've given you 3 sons." "And one daughter." "Spring is flowers fluttering in town." "Flowers flutter in town in Spring." "Spring is flowers fluttering in town." "Flowers flutter to the Hu's." "Are there some stocks around?" "Deeds and outstanding bills." "Is there gold in that house?" "Is it your will?" "Say it out." "Your savings passbook." "Jewellery box?" "Is it a jewellery box?" "Say it out, dad." "What's the light for in that empty house?" "Remember the energy crisis." "Turn it off." "What extravagance" "I've told you so many times already." "Frugality is a virtue." "That's how my fortune was made." "Ask mum how it was with us." "When we had rice for our meals." "We made sure it was plain." "We just looked at salted vegetables." "Don't look so long it's salty." "Remember frugality." "We couldn't afford your extravagance." "What do you plan when I've died?" "You're the eldest tell me first." "You've worked hard all your Life." "All your years are well deserved." "If you should die." "We must have a grand funeral for you." "We will go through all the formalities." "And get you a luxurious coffin." "To be carried by forty nine men." "We will even get people from afar." "Forget it." "It's beyond what I can afford." "My fortunes will be ruined in your hands." "Tell me your plans, my second." "Brother is obsessed with extravagance." "That's his folly." "Tell me your plans." "Say it out" "I'm for half measures." "It doesn't pay to stretch too far." "Take half of what brother suggested." "Spend only 21 days for the funeral." "Do away with religious rites." "Right." "Monks will make a mess of things." "The coffin needn't be luxurious." "It will rot in the earth anyway." "Have fewer people involved." "Let 21 men carry the coffin." "I don't want that." "You both are big spenders" "I've led a thrifty Life." "Why be so wasteful on my death?" "How can you be so squandering?" "Tell me what your plans are now." "Come on." "My brothers don't know how to save." "Right." "If you should die." "We mustn't spend any money." "We should try to make money instead." "You're my worthy son." "Listen to this." "See what a thrifty man he is." "What a difference." "Make the funeral as short as possible." "Right, wonderful." "Forget the coffin altogether." "Great." "Your body must not be wasted." "It's to be salted." "The meat can then be sold." "Superb." "Come, all of you." "Say it out." "Say it out, dad." "Come." "Say it quickly, dad." "You must remember." "Don't sell my flesh at east Town." "Credits are poor there." "You can't go to heaven." "Do you know how to reproduce?" "Forget it, As long as you're rich." "Everyone will call you daddy." "If not..." "Children provide for your old age." "They will plot." "To divide your riches." "If you're poor, they will desert you." "Stop grumbling." "Where are you going?" "For a shave." "Two cakes and two fried couplets." "Two cakes and two fried couplets." "Delicious." "Barber." "Barber." "How much does a shave cost?" "Fifty cents." "Give me a shave." "Sit please." "Take care." "Damn it." "Don't take me for blind" "I'll shove you up." "Let's have peace." "Why be so mad?" "Be tolerant." "You bastard" "I'm shaved by a bastard." "What are you going?" "My knife is broken." "What sort of a shave is this?" "It's all your fault." "Why?" "You keep cursing me." "How did I curse you?" "If you should die." "The kids will split your riches" "I will have rough days." "How so?" "I'll have no cash to back me up." "Eat while it's hot, mum." "It's specially made for you." "Eat it, mum." "I want another dumpling." "The kids need better food." "Have some hard beans, mum." "Have a rest, mum." "What's the matter, mum?" "If you like brother's place." "Why don't you stay a few days more." "He is a disappointment" "I've had poor food for 10 days." "The hard beans are terrible." "Well, we..." "We know that's what you like." "We've got it ready for you too." "Have you got hard beans too?" "Of course we must have hard beans." "Sit down for a while, mum" "YU didn't even make the bed well." "Are you all right, mum?" "I'm fine." "How was it with my two brothers?" "Those days have been terrible." "How could they serve you so badly?" "They have no variety of offer?" "That's right" "I've prepared fish for you." "Fish?" "Have some fish, mum." "Chi Sheng." "Mother." "The ingots are ready." "That's heavy." "Not as heavy as armour." "Talk politely to mum." "That was a good joke." "Where is the real gold one?" "It's here." "Let me help you, mum." "Take care." "This one is borrowed." "Put it in your pocket." "When brothers are around." "Drop it and let them see it." "Then they won't know how much you have" "I'll go home now." "Let me pass the word to them first." "They will give you VIP reception." "Really?" "Don't let the others know." "We will keep it a secret" "I always said filial piety is a virtue." "How can we share mother." "Right." "Hurry to the phone." "Get a cab for mum." "Right" "54188?" "Get me a car right away." "What?" "You're a funeral house?" "Sorry." "You can't even make a phone call." "Get me 54188 please." "I always said mum needs good food." "Yet you never agreed." "You're pushing money out the door." "A cab to 25 Cotton Drive please." "Excuse me, you're our fortune bringer." "Forget it." "What are you bringing this for?" "Don't you know mum likes this?" "You're right." "Of course." "Why are you here?" "I've come to get mum back." "How about you?" "I've come to get mum too." "Have you checked the calendar?" "Mum should stay with us." "Forget it." "Mum is fed up with you." "You should be ashamed." "You have no food for mum" "You drew a fish to mock her." "How beastly." "How about you?" "You've not any better." "Did you give mum any of your good food?" "What are you trying to do?" "You're trying to cheat me." "Mum will stay with me, the eldest son." "Are you trying to start a fight?" "Well?" "Do you want to fight?" "Arrest them all." "No, we weren't fighting." "We've come to get mum." "Mum?" "Yes, our mother." "Right, our mother." "What good sons you are." "Good sons and good citizens." "Disperse now." "It's all young brother's fault." "Stay with me from now on." "Yes." "Stay with us, our house is lucky." "Don't listen to them, stay with us." "The youngest in always nice and gentle." "Besides, I know you like dumplings" "I've sent my wife to buy shrimps." "To make dumplings for you." "Come with me, mother." "Board my cab, mum." "Why all this pushing and pulling?" "I'm picking it up for mum" "I'll help you keep it away." "I can do it myself." "My daughter." "Mum." "This is for you." "Why don't you keep it, mum?" "It's nothing." "Take care on the way." "Eat while it's hot, mum." "Have some vinegar too." "Help yourself too." "After you, mum." "Take the sweater off, mum." "No, the weather is bad these days." "Don't touch my sweater." "Ingots." "Dumplings are shaped like ingots." "You told me years ago." "Dumplings are like ingots." "I thought you mean ingots in my sweater." "Are there ingots in your sweater?" "That must be very heavy." "What so heavy?" "I mean the ingot-shaped collars." "You have ingots everywhere, mum." "Don't touch it." "My waist is not feeling well." "You should have told me" "I'll get you a doctor for x-ray." "Right, an x-ray radiograph." "Exposes everything." "Exposing?" "What are you taking me for?" "You talk so stupidly." "Never mind." "Take care." "I know what to do." "She talks well." "She can sell anything she says." "What is this?" "You like cakes, mum." "My wife has baked you some cakes." "Now, let's make it clear." "With your knowledge of law." "Your know what rights and duties are." "Let's settle it as brother." "It's my duty to serve mum, not you." "Everyone has the right to serve mum." "You're my darling sons." "Eat while it's hot, mum." "Here are a few nice dishes." "That's too much." "What wrong have I done you?" "Why should you make fun of me?" "Take care." "This is your favourite soup, mum." "Here are some hot buns." "Your teeth can't stand hard baked cakes." "Who says my teeth are not good?" "Eating hard beans have made them strong." "Whose idea was it!" "To feed mum with hard beans." "Open it." "Have a puff, mum." "Have some soup and prosper, mum." "Take some dumplings and keep fit, mum." "Thanks for your good wishes." "This is a special dish for you, mum." "It symbolizes longevity." "You all talk well." "Collect your pay for the show." "Hold yourself." "Let's be happy for mum's sake." "Right, we should respect the old." "Especially our mother." "Let mum eat in silence." "Stop talking." "Eat while it's hot, mum." "As the proverb goes." "You are vain and hollow." "I like proverbs." "You like hearing them?" "Good." "Ok, as the proverb goes." "You can't sell to everyone." "You're not a genius either." "As the proverb goes." "You are all not there." "As the proverb goes." "You are the wife of the cuckolded." "And it's a pygmy dance for you." "What does this mean?" "Holding on to somebody taller, that's it." "As the proverb goes." "You're reaching beyond yourself." "As the proverb goes." "It's time you'll tumble." "Isn't that right?" "As the proverb goes." "You're driving it home the wrong way." "And a pigheaded one, too." "You are overstrained." "And you are finished." "Your rib will be ripped." "Your limbs will be limp." "You're a bastard." "You're the bastard of bastards." "You're a bastard's son." "Your son's a bastard." "You are the mother of a bastard." "You're the real bastard." "You're the son a bitch." "You're the son a bitch." "You're the son a bitch." "That's enough." "Now, they are sons of a bitch." "And they are bastards wives." "Then, just who am I?" "They all talk nonsense." "Eat now;" "I will give you money tomorrow." "To take the kids to see a show" "I love that." "Big theatres are expensive." "Small theatres are much cheaper." "Come buy my toys." "Over there." "Things for men and women." "Toys for children;" "All for sale." "Come in please." "Time for the show..." "Come in please." "The best shows in town." "Action packed." "Come inside please." "Sit over there please." "Rhubarb." "Coming." "What are you doing?" "Pay attention to the show." "It's nice to see them throwing towels." "We are here." "You're early" "I've been waiting for you" "I don't know what the show is about." "Sit over here" "I can't get over." "It's all a mess." "The sky is clear today." "How come it's raining?" "What is the matter?" "What is this drizzle?" "The seeds stink." "It's time to pay." "Thanks." "It's time to pay." "That's a bit too frequent." "We have a heavy overhead." "Madam It's time to pay." "Thanks." "That's robbery." "It's costlier than big theatres." "What's so funny?" "It's a poor show." "They're even coming after me." "They're toy for your kids." "What a shock." "Mother." "It's so hot these days." "It'll be hotter with a fur coat." "People are like elephants now." "Elephants?" "An elephant keeper in the zoo." "Always wears the same outfit." "Elephants messed him up when he changed." "Really?" "People are identified by their clothes." "The fortune teller says if I wear this." "My sons will be nice to me." "Don't believe that." "Where is my son?" "He's gone to buy you an electric fan." "Coming." "It's the newest model from USA." "Is it 110 or 220?" "It only costs $5,80" "I mean the voltage, not the price." "See, you burned the fuse." "Isn't this too much?" "She has passed away." "It's the fan that killed her." "What are you doing?" "Shut up." "Listen, I'm the eldest." "So what?" "She died in our custody" "I want only her sweater." "Why?" "Take it out." "This warrants my right" "I've invested for this sweater." "We've spent $500 already." "Right." "Show them our bills." "See?" "What about you?" "Show them." "Look at mine." "They're all overdue an dead." "So are ours." "Let's talk over it." "Let's have a peaceful talk." "We've all invested to get the sweater Right." "Let's divide the ingots up." "What do you think of that?" "I agree" "I agree too" "I've no objections" "I'm for it." "Let's start." "Let me do it." "Don't fight for it." "Don't fight for it." "Don't fight for it." "Don't fight for it." "Don't fight for it." "Silver ingots." "It's just tin." "Just tin." "Tin." "O Mother." "Mother." "Don't think ill of them." "I can bear children too." "Before I married you" "I had quite a few children." "Ladies and gentlemen." "Come to our famous Spring Inn Our House of Spring is famous too." "Come into out House of Spring." "Crowds of beauties bring you spring." "Come... inside please." "Come meet the guest." "The winner will soon be announced." "The winner will be announced." "Hurry up." "'Reunion' is the winning word." "It's 'Reunion'" "It's 'Reunion', sir." "Reunion?" "Right, sir." "Didn't I say so this morning?" "I dreamed of Tang last night." "He slipped into my bed, stark naked." "What?" "I did nothing of the sort" "I didn't do anything like that." "It's a dream You wouldn't dare." "'Reunion' means in bed together" "I'm in bed with you every day." "We're in bed together." "But you're incapable of any union." "You're old and useless." "No wonder you dreamed about Tang." "He is a terrific lad." "He looks terrific too." "Have you paid yesterday's rent yet?" "I lost my just a number." "Or I would have paid you double." "Tough luck." "Tang, come rap my bones for me." "My neck is feeling uneasy." "Not so hard." "It's difficult to please you, hard or light." "You naughty boy." "It's all fixed" "I won't do it." "See what a daughter you've got." "What's bad about her?" "There's nothing wrong with her." "You can't sell her after selling me." "What has that to do with you?" "Ling Tze is a miserable girl." "She must be lovable too." "How your thought fly." "Let me tell you the truth." "A new whore house is just opened." "A virgin would bring them luck" "I recommended Ling Tze." "She will get $300 for that." "Do you think she can earn the $300?" "How would I know?" "Don't act the innocent boy." "Whether she's a virgin or not." "Is something only you would know." "Stop kidding." "She's not a Lady." "If $300 is there for the taking." "Why wouldn't she sell?" "She may have nothing to sell though." "The owner is so old anyway." "You still stand a very good chance." "Why not let her dad earn $300." "Why associate Ling Tze with me?" "What you've been doing?" "Is known to me." "You've got to do it" "I can't turn down the $300." "Ling Tze." "Rice dumplings." "Selling rice dumpling on new year eve." "Goldfish." "Sugared gourds." "Goldfish." "Dates rice dumplings." "Rice dumplings." "Dates." "Do me a favour buy a dumpling form me?" "Who would sell this on new year's eve?" "I'm a fugitive from Ho Nan." "I used to be very rich too" "I can make only rice dumplings." "Please, I've starved for 3 days." "How stupid you are to starve." "Why can't you eat the dumplings?" "They are made 5 days ago." "They've all gone bad." "They're rotten." "You try to sell me rotten rice?" "Please buy it as a favour." "You look a new hand in doing business." "My family was very rich." "Why would I have to do anything?" "I was ashamed to stay in my home town." "You avoid the crowded spots" "I'm shy." "You're yelling around deserted areas." "Right." "You're a man with insight." "Can you buy six pieces of them?" "How about four?" "Or two?" "That won't do you much good." "What would do me enough good?" "Well, I own a rickshaw factory" "I'll let you pull a rickshaw." "Come, let's have a meal first." "Great." "You're so nice" "I'm so grateful" "I'll thank you for all my Life." "Forget this." "You're so kind." "If you ate the dumpling, you'd be sick." "A kid died after eating it last night." "Pay your rent if you have money." "If not, pay me later." "Thanks." "You'll soon get used to the job." "You must use your strength cleverly." "Just strength would not work." "This is new, I'm used to the rear push." "Why are you laughing?" "Never mind her." "Your words reminds her of our boss." "Do you pull rickshaws too, sir?" "Not in daytime." "You're so hard working." "You're a cunning lad." "Teach Wang the job." "Teach him how to serve customers." "Let me teach you, Mr. Wang." "You're my teacher then." "There isn't really that much to it." "Board the rickshaw." "Give a kick when you start." "Running is smooth after you've started." "Keep quiet while you pull." "Speak nicely to the customer." "What would be nice to say?" "You've arrived, sir." "Don't bother to pay, sir." "What if he really doesn't pay?" "Nobody would be like that." "He would even give you tips." "I wouldn't if it were me." "Only a bastard would not pay." "Why are you cursing me?" "That's because you refuse to pay." "I must pay to avoid the cursing." "Take care not to bump into others." "If you do, release the car, step out." "Say sorry politely." "See, I get bumped in haste." "What I mean is in cases like this." "It isn't a single person's fault." "When he sees you're so polite." "His anger will be calmed down." "I can't see why I must step out." "In case you meet a rough man." "You can escape his attack." "Look." "Are you blind?" "See, if you had stepped out." "It's to your advantage." "Can I tackle him with my handles?" "That would be bad." "Your customer would fall off." "Let's have a competition." "Go up." "Hit me." "I will." "How can you pull like that?" "Can you see it?" "You're making it real." "Sorry." "Charge less, and work harder." "Don't overcharge your customers." "Thanks for the first lesson." "The rest is up to you." "Go ahead." "Rickshaw." "Take my rickshaw" "Shing Huang Miao 40 cents, 50 cents, 30 cents." "Excuse me." "What's the hurry?" "Rickshaw." "Please take mine." "Rickshaw." "How are you?" "I bet 50 cents on 'Fiery'" "I saw a bill in my dream last." "That may be 'ball', 'bull', 'bell'." "Right, I will bet $1 on each of them." "I'll win and have a new year party." "Let's go." "Right, let's go." "Bet 50 cents on 'Quarry' for me" "I just saw Ho in a quarrel with his wife." "Let me jot it down." "Hurry up." "Where is the kid?" "Ling Tze." "Did you see Ling Tze?" "I didn't notice." "Ling Tze..." "I said she isn't around." "Have you settled that deal?" "Everything is set for you." "Let's make it tomorrow evening." "Remember what is expected of her." "Or it will be a disgrace for me." "Don't worry." "You know us well enough." "The trouble is I don't." "Stinking women." "Never mind her." "Your dad would be furious" "I prefer to die with you." "Ling Tze." "Damn, what a moment." "Rickshaw." "Rickshaw." "Rickshaw." "Rickshaw." "Rickshaw Where are you going?" "The stone bridge." "That would be 10 dollars." "Would that take $10?" "It's a firm price." "Don't waste my time if you don't go" "I'll pay 10 dollars." "Board the rickshaw please." "Do you know how to pull?" "Of course." "What?" "I know what I'm doing." "This isn't a cart" "I'm easing my muscles" "I refuse to ride." "You've agreed to the price." "You've got to ride, or I'll starve." "Can you hurry?" "Come out earlier if you're in a hurry." "Why don't you take a plane?" "I'm the one that's pulling." "Pull yourself if you want to be quick." "What a strange world we're in." "This is my nature" "I'll take it easy." "Make way." "Get out of the way." "Make way..." "Make way..." "I'll be bumping into someone." "Here, I've really done it." "Don't do it here" "I'm just bumping in." "It's raw and not edible;" "Let me get it." "He bumped into me." "Are you blind?" "How are you pulling your rickshaw?" "You're lucky" "I broke someone's leg the day before" "I got someone in hospital yesterday." "Yet you're still fine." "It's fate that brings us together." "Of all people, I bump into you." "This is the wonder of fate." "What a show." "Damn it" "I'll beat you up." "Why are you hitting me?" "What are you laughing at?" "Why should you be involved?" "Who are you?" "I'm your passenger." "Passenger." "Why can't you sit still?" "How did you get down anyway?" "You threw me down, that's how." "Bastard." "You're cursing me." "No, I'm cursing myself" "I just can't learn." "It's my bad luck to ride your rickshaw" "YU haven't paid yet, sir How can you ask for payment?" "Pay for the ride." "It's red he is after, right." "Right" "I'll turn him into a red egg." "Red egg?" "Do you know how red eggs become red?" "They're dyed." "Right, I'll have red cotton ready." "Ling Tze." "It's your mother." "Did you see Ling Tze?" "You didn't put her in my custody." "Where can she be?" "Go down;" "Don't let them find you here." "Good." "It's you." "When did you come up?" "While you were dying eggs." "What's your explanation this time?" "I'm not ashamed to admit what I do." "What do you want to do?" "I've got red cotton ready too." "You..." "Cooperate, and we'll be fine." "Things will get rough otherwise." "I sincerely pray." "Let me win some money." "Today's rickshaw fees." "You shattered my bones" "I'll crawl around this table." "Call out what I look like to you." "Start now" "I know, go ahead." "Can you see what I look like?" "You look exactly like a tortoise." "A real tortoise." "Come down." "Tortoise!" "I'll bet on 'Fiery'" "What?" "Tortoise." "Why must you say I look like a tortoise?" "It's what you are Bet on 'Fiery'" "I'll fire at you." "The winner will be announced now." "'Fiery' is the winning word." "We've won." "That's not bad." "I must buy everybody a drink." "I've won over seventy dollars." "Let's drink, it's on me." "It's really strange." "What so strange." "Thank your god for the tip." "I will." "Mr. Ma" "I won too." "I betted 50 cents even before you crawled." "I could see you are a fiery tortoise." "It's tortoises that grow rich and big." "What does it matter if you're rich?" "Tough luck." "Shave off the bad luck." "Take cane." "Never mind" "I won over seventy dollars on ' Fiery'." "If it catches fire, it's 'Fiery'." "Right, I'll bet on 'Fiery' again." "Damn it." "It's disgusting." "What's so good to look at?" "The old man is out, come to me tonight." "Let's go dying eggs too." "Fear not, I'm harmless." "Bones stiffen with age." "But the flesh loses vigour." "It's like mince-meat?" "The parts don't hold together." "Therefore, have no fear" "I'll just kiss you." "To get the red that brings good luck." "My finger will give a gentle thrust." "Red symbolizes the glorious sunrise." "Which carries you upwards." "With bones soft as cotton." "It's a gay and happy time." "Good." "Call me a tortoise." "But I'll bet $100 on 'Fiery'." "Ma..." "Ma..." "Right, bet on 'Fiery'." "Don't block my way, I'll bet on it." "Ma..." "This seems a strange disease." "It's certainly an interesting subject."
/* * Copyright (c) 2015 Christopher M. Baker * * 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 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 THE * AUTHORS OR COPYRIGHT HOLDERS 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. * */ var should = require('should'); var ifconfig = require('../ifconfig'); var IFCONFIG_STATUS_LINUX = [ 'eth0 Link encap:Ethernet HWaddr DE:AD:BE:EF:C0:DE', ' inet addr:192.168.1.2 Bcast:192.168.1.255 Mask:255.255.255.0', ' UP BROADCAST RUNNING MULTICAST MTU:1500 Metric:1', ' RX packets:114919 errors:0 dropped:10 overruns:0 frame:0', ' TX packets:117935 errors:0 dropped:0 overruns:0 carrier:0', ' collisions:0 txqueuelen:1000', ' RX bytes:28178397 (26.8 MiB) TX bytes:23423409 (22.3 MiB)', '', 'lo Link encap:Local Loopbacks', ' inet addr:127.0.0.1 Mask:255.0.0.0', ' UP LOOPBACK RUNNING MTU:65536 Metric:1', ' RX packets:0 errors:0 dropped:0 overruns:0 frame:0', ' TX packets:0 errors:0 dropped:0 overruns:0 carrier:0', ' collisions:0 txqueuelen:0', ' RX bytes:0 (0.0 B) TX bytes:0 (0.0 B)' ].join('\n'); var IFCONFIG_STATUS_INTERFACE_LINUX = [ 'wlan0 HWaddr DE:AD:BE:EF:C0:DE', ' inet6 addr:fe80::21c:c0ff:feae:b5e6/64 Scope:Link', ' MTU:1500 Metric:1', ' RX packets:0 errors:0 dropped:0 overruns:0 frame:0', ' TX packets:0 errors:0 dropped:0 overruns:0 carrier:0', ' collisions:0 txqueuelen:1000', ' RX bytes:0 (0.0 B) TX bytes:0 (0.0 B)' ].join('\n'); describe('ifconfig', function() { describe('ifconfig.status(callback)', function() { it('should get the status for each interface', function(done) { ifconfig.exec = function(command, callback) { should(command).eql('ifconfig -a'); callback(null, IFCONFIG_STATUS_LINUX, ''); }; ifconfig.status(function(err, status) { should(status).eql([ { interface: 'eth0', link: 'ethernet', address: 'de:ad:be:ef:c0:de', ipv4_address: '192.168.1.2', ipv4_broadcast: '192.168.1.255', ipv4_subnet_mask: '255.255.255.0', up: true, broadcast: true, running: true, multicast: true }, { interface: 'lo', link: 'local', ipv4_address: '127.0.0.1', ipv4_subnet_mask: '255.0.0.0', up: true, loopback: true, running: true } ]); done(); }); }) it('should handle errors', function(done) { ifconfig.exec = function(command, callback) { callback('error'); }; ifconfig.status(function(err, status) { should(err).eql('error'); done(); }); }) }) describe('ifconfig.status(interface, callback)', function() { it('should get the status for the specified interface', function(done) { ifconfig.exec = function(command, callback) { should(command).eql('ifconfig wlan0'); callback(null, IFCONFIG_STATUS_INTERFACE_LINUX, ''); }; ifconfig.status('wlan0', function(err, status) { should(status).eql({ interface: 'wlan0', address: 'de:ad:be:ef:c0:de', ipv6_address: 'fe80::21c:c0ff:feae:b5e6/64' }); done(); }); }) it('should handle errors', function(done) { ifconfig.exec = function(command, callback) { callback('error'); }; ifconfig.status('wlan0', function(err, status) { should(err).eql('error'); done(); }); }) }) describe('ifconfig.down(interface, callback)', function() { it('should take down the interface', function(done) { ifconfig.exec = function(command, callback) { should(command).eql('ifconfig wlan0 down'); callback(null, '', ''); }; ifconfig.down('wlan0', function(err) { should(err).not.be.ok; done(); }); }) it('should handle errors', function(done) { ifconfig.exec = function(command, callback) { callback('error'); }; ifconfig.down('wlan0', function(err) { should(err).eql('error'); done(); }); }) }) describe('ifconfig.up(options, callback)', function() { it('should bring up the interface', function(done) { ifconfig.exec = function(command, callback) { should(command).eql('ifconfig wlan0 192.168.10.1' + ' netmask 255.255.255.0 broadcast 192.168.10.255 up'); callback(null, '', ''); }; var options = { interface: 'wlan0', ipv4_address: '192.168.10.1', ipv4_broadcast: '192.168.10.255', ipv4_subnet_mask: '255.255.255.0' }; ifconfig.up(options, function(err) { should(err).not.be.ok; done(); }); }) it('should handle errors', function(done) { ifconfig.exec = function(command, callback) { callback('error'); }; var options = { interface: 'wlan0', ipv4_address: '192.168.10.1', ipv4_broadcast: '192.168.10.255', ipv4_subnet_mask: '255.255.255.0' }; ifconfig.down(options, function(err) { should(err).eql('error'); done(); }); }) }) })
Monday, December 19, 2011 Alkaline Batteries marked as 'Heavy Duty'...a misleading notion As I mentioned in an earlier blog there are several grades of alkaline batteries. The Heavy Duty Alkaline Battery is the lowest grade of Alkaline Battery. When you purchase an item with 'batteries included', check the label on the battery. If it is labeled Heavy Duty...no matter the brand...make sure to have extra higher quality alkaline batteries becasue the Heavy Duty ones don't last very long. So parents out there who want to keep their children happy on Christmas Day...get some good high quality alkalines for their toys!!
Pulmonary arterial hypertension from a pediatric perspective. This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.
Matthew 17:20. He replied, "Because you have so little faith. I tell you the truth, if you have faith as small as a mustard seed, you can say to this mountain, 'Move from here to there' and it will move. Nothing will be impossible for you." (G) No more (A) lives torn ( C) apartThat (Am) wars would never (D) startThat (G) time would heal all ( C) heartsAnd (G) every (A) one would have a ( C) friendAnd (Am) right would always (D) winAnd love (A7) would never ( C) end (G) No more (A) lives torn ( C) apartThat (Am) wars would never (D) startThat (G) time would heal all ( C) heartsAnd (G) every (A) one would have a ( C) friendAnd (Am) right would always (D) winAnd love (A7) would never ( C) end (G) This is my (Am) grown-up Christmas (G) list. (Gm) What is this illusion called (A) the innocence of youthMaybe (G) only in our blind belief can we (A) ever find the truth (G) No more (A) lives torn ( C) apartThat (Am) wars would never (D) startThat (G) time would heal all ( C) heartsAnd (G) every (A) one would have a ( C) friendAnd (Am) right would always (D) winAnd love (A7) would never ( C) end
Q: How to insert child category by specific parent category into table using ado.net? I am trying to insert categories and subcategories from Excel into a database table. I have 1 Excel file which contains some data and from this Excel file I am creating dataset which contains lots of datatables. In this dataset I have 2 datatables in the form of this: Datatable 0 with records:Category ParentCategory Description Electronics jhdkhsd Sports kjshfhs Datatable 1 with records:SubCategory Subcategory ParentCategory Description Mobile Electronics weprwp Tv Electronics sdflskd Balls Sports kjshdfkjh Shoes Sports uytuyt Now my database tables are like this: Category:Id,Name,Description,parentid So far I am successful inserting parent category but now trying to insert child categories but that is where currently i am struggling. This my code so far: var dsFinal = new DataSet(); //Some code to read excel sheets and data from excel and create datatables and records with it. dsControlSheet.Tables[0].Columns.Add("Id"); DataColumn parentId = new DataColumn("ParentId", typeof(int)); parentId.DefaultValue = 0; dsFinal.Tables[0].Columns.Add(parentId); dsFinal.Relations.Add("Abc",dsFinal.Tables[0].Columns["ParentCategory"], dsFinal.Tables[1].Columns["ParentCategory"],false); //creating relation ship between Category datatable // and SubCategory datatable on field ParentCategory using (SqlConnection connection = new SqlConnection("")) { SqlDataAdapter adapter = new SqlDataAdapter(); var insertCommand = new SqlCommand("insert into Category (Name,Description) values (@ParentCategory,@Description) SET @Id = SCOPE_IDENTITY()", connection); var parameter = insertCommand.Parameters.Add("@Id", SqlDbType.Int, 0, "Id"); insertCommand.Parameters.Add("@ParentCategory", SqlDbType.NVarChar, 50, "ParentCategory"); insertCommand.Parameters.Add("@Description", SqlDbType.NVarChar, 50, "Description"); parameter.Direction = ParameterDirection.Output; insertCommand.UpdatedRowSource = UpdateRowSource.OutputParameters; adapter.InsertCommand = insertCommand; adapter.Update(dsFinal.Tables[0]); //successfully inserted parent category and got autoincremented value in Id column of my 0th datatable //trying to insert child category using above insert command foreach (DataRow parentCategory in dsFinal.Tables[0].Rows) { var child = parentCategory.GetChildRows("Abc").CopyToDataTable();//get child category of particular parent adapter.Update(child); } } Here in the last loop to insert child category; I am confused about how to use same insertCommand variable to insert child category? Update:I have used datatable Expression to calculate parentid like this: using (SqlConnection connection = new SqlConnection("")) { SqlDataAdapter adapter = new SqlDataAdapter(); var insertCommand = new SqlCommand("insert into Category (Name,Description) values (@ParentCategory,@Description) SET @Id = SCOPE_IDENTITY()", connection); var parameter = insertCommand.Parameters.Add("@Id", SqlDbType.Int, 0, "Id"); insertCommand.Parameters.Add("@ParentCategory", SqlDbType.NVarChar, 50, "ParentCategory"); insertCommand.Parameters.Add("@Description", SqlDbType.NVarChar, 50, "Description"); parameter.Direction = ParameterDirection.Output; insertCommand.UpdatedRowSource = UpdateRowSource.OutputParameters; adapter.InsertCommand = insertCommand; adapter.Update(dsFinal.Tables[0]); //successfully inserted parent category and got autoincremented value in Id column of my 0th datatable //For inserting child category.. //added column parentid to store child category SqlDataAdapter da = new SqlDataAdapter(); dsFinal.Tables[1].Columns.Add("ParentId", typeof(int), "IIF(Parent.ParentCategory=ParentCategory,parent.Id,0)"); var insertChildCategoryCommand = new SqlCommand("insert into Category (Name,Description,ParentId) values (@Subcategory,@Description,@ParentId) SET @Id = SCOPE_IDENTITY()", connection); var parameter1 = insertChildCategoryCommand.Parameters.Add("@Id", SqlDbType.Int, 0, "Id"); insertChildCategoryCommand.Parameters.Add("@Subcategory", SqlDbType.NVarChar, 50, "Subcategory"); insertChildCategoryCommand.Parameters.Add("@Description", SqlDbType.NVarChar, 50, "Description"); insertChildCategoryCommand.Parameters.Add("@ParentId", SqlDbType.int, 0, "ParentId"); parameter1.Direction = ParameterDirection.Output; insertChildCategoryCommand.UpdatedRowSource = UpdateRowSource.OutputParameters; da.InsertCommand = insertChildCategoryCommand; //Error here that computed column cannot be inserted.Here computed column is parentid da.Update(dsFinal.Tables[1]); } Error:Computed column(parentid) cannot be inserted. A: You are almost there with latest code. The only problem is that the calculated columns are not allowed to be used for inserting/updating the database table. Btw, the error message is not "Computed column(parentid) cannot be inserted.", but: The column mapping from SourceColumn 'ParentId' failed because the DataColumn 'ParentId' is a computed column. I could agree that the message could have been better, and also I didn't find any documentation describing that. Most probably the rationale is that the computed columns are not normally stored. Whatever the reason is, that's the reality. You have no other choice than creating a regular column and populating it with data manually. There are many ways to do that (both efficient and ineffient), but once you already created a relation, you can use the DataRow.GetParentRow method to locate the related category record. With all that being said, replace the line dsFinal.Tables[1].Columns.Add("ParentId", typeof(int), "IIF(Parent.ParentCategory=ParentCategory,parent.Id,0)"); with the following snippet: var dtSubCategory = dsFinal.Tables[1]; dtSubCategory.Columns.Add("ParentId", typeof(int)); foreach (var drSubCategory in dtSubCategory.AsEnumerable()) { var drCategory = drSubCategory.GetParentRow("Abc"); drSubCategory["ParentId"] = drCategory != null ? drCategory["Id"] : 0; } and you are done. EDIT: Let me make it clear. The only time critical operation here is locating the category id by name. Using the relation and GetParentRow is equivalent of the evaluating the expression accessing parent as in your attempt. Data relation internally maintains a lookup structure for supporting such operations. If you want to get the best possible performance, then don't create a relation, but a dictionary. What you need is given a name (string), find the corresponding id (int), so Dictionary<string, int> is a perfect candidate for that: var categoryIds = dsFinal.Tables[0].AsEnumerable().ToDictionary( dr => dr.Field<string>("ParentCategory"), // key dr => dr.Field<int>("Id") // value ); var dtSubCategory = dsFinal.Tables[1]; dtSubCategory.Columns.Add("ParentId", typeof(int)); foreach (var drSubCategory in dtSubCategory.AsEnumerable()) { int categoryId; categoryIds.TryGetValue(drSubCategory.Field<string>("ParentCategory"), out categoryId); drSubCategory["ParentId"] = categoryId; }
Q: Having more than one if statements in one IBAction in the .m file isn't working I am making an iPhone app that will generate something based on quiz answers. I want the button for the answer to change the question text and sometimes the button label text. Background Info: 'a' is a button 'questionNumber' is the question number (duh) and it is why the button will change the texts differently each time it is pressed. Here is the code I am using: -(IBAction) a { questionNumber == 0; if(questionNumber == 0) { question.text = @"How Much Do You Use Suppressed Weapons?"; } questionNumber == 1; if(questionNumber == 1) { question.text = @"Do You Like Sleight of Hand?"; answerA.text = @"Yes"; answerB.text = @"No"; [answerC setHidden:YES]; [answerD setHidden:YES]; [answerButton3 setHidden:YES]; [answerButton4 setHidden:YES]; } } and this repeats for the other buttons (b,c, and d). I thought it should work, but it doesn't do the "do you like sleight of hand" question. It just stays at the how much do you use suppressed weapons question. Please Help! I really want to get into xcoding for the iphone. BTW, I am not sure that the tags for this question are correct. Related Question: How can I have an IBAction that has more than two 'if' statements? A: Try using a switch statement with breaks. switch (questionNumber) { case 0: { question.text = @"How Much Do You Use Suppressed Weapons?"; } break; case 1: { question.text = @"Do You Like Sleight of Hand?"; answerA.text = @"Yes"; answerB.text = @"No"; [answerC setHidden:YES]; [answerD setHidden:YES]; [answerButton3 setHidden:YES]; [answerButton4 setHidden:YES]; } break; }
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Influence of training on the number and complexity of frequent VPBs in healthy athletes. Frequent ventricular premature beats (VPBs) may be discovered during preparticipation screening in asymptomatic apparently healthy athletes. Some authors hypothesize that they may be a manifestation of 'athlete's heart' and suggest a deconditioning period, which should document a regression of arrhythmias, to exclude a concealed disease. To test this hypothesis, we analysed 87 asymptomatic healthy athletes with frequent VPB (>100/24 h). Of these, 44 (group D) underwent at least 3 months' detraining, whereas 43 (group C) continued sporting activity. Athletes underwent 24-h Holter monitoring at the baseline after 5.2 ± 4 (group D) and 7.2 ± 5 (group C) months. Basal characteristics were similar in both groups. Comparison of the basal and follow-up Holter results revealed no significant difference in the mean number of VPB/24 h in either group. In group D, the number of VPB/24 h declined from 8126 ± 8129 to 7998 ± 10 976 (P = 0.48), whereas in group C it rose from 6027 ± 6374 to 6600 ± 8590 (P = 0.51). VPB either disappeared or were markedly reduced (<100 VPB/24 h) in 2/44 (4.5%) group D and 4/43 (9%) group C athletes.In neither group did the number of couplets or nonsustained ventricular tachycardia change significantly. In healthy athletes, frequent VPBs discovered by chance during preparticipation screening may not be a manifestation of 'athlete's heart', but may depend on other causes; in the latter case screening may simply reveal a pre-existing asymptomatic phenomenon; the usefulness of detraining in ascertaining eligibility for sport should be further investigated.
Search form Text Resize You are here First Aid We hope you never, ever have any accidents or mishaps here, but if you do, the first aiders listed below are here to help. In the event an accident does occur this should be recorded in the accident report book and the Departmental Safety Officer (safety-officer@maths.ox.ac.uk) informed. White copies of accident reports are to be passed to the Head of Administration and Finance for review before they are then sent to the university safety office. All accidents should be reported to the department (typically via reception) who will ensure a first aider attends as appropriate, an entry is made in the accident book and any first aid supplies used are replenished. Location of accident report book In the wall mounted holder outside the first aid room S0.31 List of qualified First Aiders If you need a first aider during working hours (8am to 6pm) the recommended approach is to ask at reception (S0.00 73525, 80307, 15100) who will then find a first aider for you. You can of course approach a first aider directly: Elliott Nichol (S0.41 - 73517) Iva Nedyalkova (S0.42 - 15164) David Davies (S0.43 - 15103) Maddie Bond (S0.43 - 15325) Gregg Morris (S0.43 - 15325) Luis Oliveira (S0.43 - 15325) Lucas Savoi (S0.43 - 15325) Tom Rigault (S0.44 - 83880) Petrona Winton (S1.26 - 11500) Aileen Peverell (N0.20 - 15388) Dale White Phillip Whitfeld Locations of First Aid Kits There is at least one first aid kit located on every floor of the buildings. The first aid kits are typically located in the stair cores (cores 2, 3, 5). At the mezzanine level there are also first aid kits within the entry space of the lecture theatres. The kits are regularly checked and restocked by the FM team. If you find a kit that is incomplete or use an item from a kit please report this so it can be replaced immediately. Fully Automated Defibrillators There is a fully automated defibrillator available within the department. Familiarity and some training for such devices has been given to the first aiders. In general though the device is fully automatic and could be used by anyone if the need arose. The device is located in the mail room for ease of access. The device is also available for wider use across the ROQ site should other buildings have a need. Similar devices are also now available within the Blavatnik School of Government and the Primary Health Care buildings.
Nuclear translocation of DJ-1 during oxidative stress-induced neuronal cell death. Loss-of-function mutations in the PARK7/DJ-1 gene cause early onset autosomal-recessive Parkinson disease. DJ-1 has been implicated in protection of neurons from oxidative stress and in regulation of transcriptional activity. However, whether there is a relationship between the subcellular localization of DJ-1 and its function remains unknown. Therefore, we examined the subcellular localization of DJ-1 during dopaminergic neurodegeneration induced by various insults. Immunoblotting and immunocytochemistry showed that the nuclear pool of DJ-1 dramatically increased in both MN9D dopaminergic neuronal cells and primary cultures of mesencephalic dopaminergic neurons after 6-hydroxydopamine (6-OHDA) treatment. This was paralleled by a corresponding decrease in its cytosolic level, indicating drug-induced nuclear translocation of DJ-1. The same phenomenon was detected in other cell death paradigms induced by pro-oxidants including hydrogen peroxide and cupric chloride. Consequently, cotreatment with the antioxidant N-acetyl-l-cysteine blocked the translocation of DJ-1 into the nucleus. However, mutation at cysteine 106 had no effect on the translocation of DJ-1 into the nucleus, suggesting that reactive oxygen species-mediated downstream signaling and/or modifications other than oxidative modification are involved in its nuclear translocation. Ectopic expression of nucleus localization signal (NLS)-tagged DJ-1 prevented cell death from 6-OHDA. We investigated whether nuclear DJ-1 was involved in transcriptional regulation and found that DJ-1 was localized in promyelocytic leukemia bodies, and this localization increased upon 6-OHDA treatment. We also confirmed that binding of DJ-1 and promyelocytic leukemia bodies indeed increased after 6-OHDA treatment. Consequently, expression levels of acetylated p53 and PUMA were downregulated in cells overexpressing DJ-1 or NLS-tagged DJ-1. Taken together, our data suggest that nuclear translocation of DJ-1 may protect neurons from cell death after oxidative stress.
In keeping with what they've done the past couple of seasons, the National Football League will be having former players announced the second-round draft choices of their former teams at the 2015 NFL Draft. The choice for the Minnesota Vikings is a player from their not-too-distant past. Per Chris Tomasson of the St. Paul Pioneer Press, linebacker E.J. Henderson will be announcing the Vikings' selection on Friday night in Chicago. Henderson, of course, was a second-round pick himself, as the Vikings selected him with the 40th overall selection in 2003 out of the University of Maryland. He played for the team for nine seasons, with 2011 being his final year with the team on the field. He was recently hired by the Vikings as the team's youth football director. On the surface, announcing the Vikings' second-round pick may sound like the easiest job of Friday night for anybody. After all, in each of the last three years, the Vikings have traded their second-round selection to move back into the late part of the first round. If Rick Spielman and company should do the same thing this year, Henderson will announce the next selection the team makes.
Q: how can i attach a taxonomy to the users profile? I use drupal 7 and need to attach a certain taxonomy to a user. there is module for drupal 6 but as i see there is no module for that in drupal 7. how can i do that in my module by coding? why do i have this question: i sell some digital files and now i am developing a module for selling my files. i want to sell them this way: each file has a certain taxonomy. when my user buys that file he or she gets that taxonomy. once he clicks on download link i have to check whether that user has that taxonomy already or not! A: Users in Drupal 7 are proper entities and fieldable. Goto Administration » Configuration » People » Account settings » Manage Fields (admin/config/people/accounts/fields) Add a new Field. Choose a label, and choose Term Reference as the field type. Configure as needed. This should identical for how you do it for a Content Type (ie, a node). The click on the Manage Fields tab. Set up the display for how you need it. Edit you users, and add in some field data. It will be in the full loaded $user object, and you can use it in Views over Users.
2015-02-13 2015-02-07 Qt packaging changes in maemo.org extras-devel One of the big changes PR1.2 brought us is official Qt support in the form of Q4.6 in the Nokia SDK and repositories. This change affects all applications depending on Qt currently in extras-devel. We had some talks with Qt/Nokia folks about Qt-related repository changes in Maemo 5 (triggered by aforementioned PR1.2 and potentially again later on by updates to Qt or related components).
Mark Buckland Mark Buckland (born 18 August 1961 in Cheltenham) is an English former footballer, who played in the Football League for Wolverhampton Wanderers. Career Buckland started his football career with his hometown team Cheltenham Town . In November 1983 he played for AP Leamington in their FA Cup tie against Gillingham. He signed for First Division Wolverhampton Wanderers in 1984. He had only one full season at Molineux, 1984-85, during which he made 41 appearances in total. He scored five goals but the club again suffered relegation in what proved his only season in league football. He was still playing on his 50th birthday in 2011 for Bishop's Cleeve 3rd team. References Category:1961 births Category:Living people Category:Sportspeople from Cheltenham Category:English footballers Category:English Football League players Category:National League (English football) players Category:Wolverhampton Wanderers F.C. players Category:Kidderminster Harriers F.C. players Category:Cheltenham Town F.C. players Category:Gloucester City A.F.C. players Category:Leamington F.C. players Category:Association football defenders Category:Association football midfielders
Time of recombination in the Drosophila melanogaster oocyte. II. Electron microscopic and genetic studies of a temperature-sensitive recombination mutant. A test has been carried out to determine if the restrictive temperature (31 degrees) acts to reduce recombination in the temperature-sensitive recombination-deficient genotype rec-l26/rec-l16 by reducing or eliminating the synaptonemal complex. Measurements of the length of synaptonemal complexes in heat-treated and untreated stage 1 oocytes, following termination of the temperature-sensitive period, reveal less than a 5% difference, with the greater length present in the treated oocytes. Alterations are not observed in synaptonemal complex distribution within the nucleus or in its fine structure. Parallel genetic studies confirm earlier observations that the restrictive temperature, whose action is confined to a 36-h sensitive period virtually coextensive with premeiotic-S, drastically reduces recombination to approximately 10% of normal. The results are most simply interpreted to mean that the restrictive temperatures acts directly on the recombination process.
Remodeling: Trends in Kitchen Floors The kitchen is often regarded as the most used space in a home. Whether it’s small and tiny or massive and spacious, a kitchen area should be complemented by adequate flooring. In larger homes, the area comes with a kitchen island, a dining space, and lengthy countertop section. Flooring is often the single largest design element in a room, and your selection of flooring material will dictate the overall style of your kitchen. Here's a rundown of popular flooring materials and how to use them in your kitchen design. Saltillo or terra cotta tile flooring If you want to redecorate your kitchen with a Southwest or Mediterranean flavor, start by laying a Saltillo tile flooring. Incorporating rustic hardware and lively colors into your design will complement the timeless appeal of these terra cotta tiles, which range in color from yellow to deep orange. Durability can vary widely with terra cotta and it must be resealed often, but these disadvantages are often offset by its low price and character. Bamboo flooring Bamboo is much cheaper than hardwood and very chic, due in some part to its reputation as an eco-friendly flooring material. Because it is a grass, it has a much faster growing process than wood and is one of the most renewable materials on Earth. Bamboo flooring works well in modern, minimalist kitchens, and its manufacturers tout its resistance to insects and moisture. Leather floor tiles Leather coffee tables, sofas, and chairs are all conventional uses of leather in the home. However, when people think about leather they don’t usually think of installing it on their floors. The truth is, leather floors are extremely durable. Leather floors are like laminate, so you’ll definitely be able to enjoy the space for extended periods of time. In addition, the material is comfortable and warm, and the unconventional shade will dramatically change the general appeal of your kitchen. Recycled leather floor tiles also have the added appeal of contributing to LEED points. Wood-like or wood-grain tile made of ceramic A lot of people opt for real wood when it comes to their kitchen flooring. However, hardwood has one major disadvantage that makes it unsuitable for use in kitchens and bathrooms: It swells when it gets in contact with water and can be ruined in a matter of minutes. If you want the look of wooden planks in your kitchen floor, you should consider wood-grain or wood-like ceramic tile. It is available in varying widths and lengths, in a wide range of shades and textures, and is hyper-realistic. Most importantly, it won't get scratched, nicked, dented, damaged with water, or eaten by insects. It stays cool in summer, allows for the installation of radiant heating, and is easy to clean and maintain. Hardwood Although hardwood is not that water-resistant, it’s experienced a comeback as a material of choice for homebuilders and remodelers. An open kitchen is highly desirable in today's housing market, and wood can go seamlessly from kitchen to family room or dining room. Additionally, the increasing popularity of the rustic look and people's interest in sustainable and renewable options makes reclaimed wood or salvaged wood an excellent choice for kitchens – the nicks, scratches, and stains associated with foot traffic and cooking will only add to its rough appeal. Having your wood floor sealed with polyurethane will help to combat staining and damage from water spills, as well. Concrete Did you know that concrete is one of the most sanitary types of kitchen flooring? It blends perfectly with a plethora of styles, and it’s associated with the industrial and minimalist looks popular today. Concrete, however, is hard on the feet (you'll need anti-fatigue mats) and prone to cracking. It does allow the installation of a radiant heat system and can be dyed to suit. It will require sealing every one or two years, but it needs little maintenance otherwise. As you can see, flooring options abound, and your choice will make a huge impact on the look and function of your kitchen. Use of this Site constitutes acceptance of our User Agreement and Privacy Policy. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of Buildipedia.com,LLC.
New N,C-Diaryl-1,2,4-triazol-3-ones: Synthesis and Evaluation as Anticancer Agents. A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards their activity in some relevant biological targets related to cancer. This study is focused on the synthesis and the biological evaluation of 2,5-diaryl-1,2,4- triazol-3-ones. In this sense, the effect of the synthetic triazolones on the proliferation of HT-29 and A549 cancer cells and on HEK non-cancer cells has been measured. In addition, the effects of triazolones on the expression of hTERT, c-Myc and PD-L1 genes and on the production of c-Myc and PD-L1 proteins have also been evaluated. A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps. Firstly, N- (aminocarbonyl)-3-methoxybenzamide was prepared by coupling 3-methoxybenzoic acid and cyanamide followed by aqueous HCl hydrolysis. Then, the 2,5-diaryl-1,2,4-triazol-3-ones were obtained upon reaction of N-(aminocarbonyl)-3-methoxybenzamide with arylhydrazines in decaline at 170ºC. The ability of the triazolones to inhibit cell proliferation was measured against two human carcinoma cell lines (colorectal HT-29 and lung A549), and one non-tumor cell line (HEK- 293) by MTT assay. The downregulation of the synthetic triazolones on the expression of the hTERT, c-Myc and PD-L1 genes was measured by an RT-qPCR analysis. Their ability to regulate the expression of the c-Myc and PD-L1 proteins, as well as their direct interaction with c-Myc protein, was determined by the ELISA method. Finally, the direct interaction of triazolones with PD-L1 protein was assessed by the thermal shift assay. Ten 2,5-diaryl-1,2,4-triazol-3-ones were synthesized and characterized by spectroscopic methods. A thorough study by 1H, 13C, 15N and 19F NMR spectroscopy showed that all the synthetic compounds exist as 4H-triazolones and not as hydroxytriazoles or 1H-triazolones. Some triazolones showed relatively high activities together with very poor toxicity in non-tumor cell line HEK-293. 2-(2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4) was particularly active in downregulating c-Myc and PD-L1 gene expression although 2-(4- chloro-2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8) is the one that combines the best downregulatory activities in the three genes studied. Considering protein expression, the most active compounds are 2-(4-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one (5) and 2-(2,4,6-trifluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H- 1,2,4-triazol-3-one (10) (c-Myc expression) and 2-(2,3,5,6-tetrafluorophenyl)-5-(3-methoxyphenyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one (11) and (8) (PD-L1 expression). Some of the triazolones studied have shown relevant activities in the inhibition of the hTERT, c-Myc and PD-L1 genes, and in the inhibition of c-Myc and PD-L1 protein secretion, the 2-(4-chloro-2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8) was found to be a particularly promising lead compound.
I checked the teaser trailer on the 'Tube and according to Jenomorph, the project is on hiatus for some reason so expect it in the fall of 2014. It's a two year delay from the original release date, but it looks like it should definitely come out eventually. It just takes time. I just hope that Hasbro doesn't decide to shut it down at the last minute like they did with Fighting is Magic.
Value based pricing is the way forward for professions seeing their ‘bread and butter’ come under the threat of commoditization. But it’s far from easy in an economy that is struggling out of recession.
Currently, makeup has become an indispensible part of people's daily life. There are many varieties of cosmetics, such as powder, liquid and paste. To facilitate the use of cosmetics, people usually make different cosmetics into different shapes and fill them in suitable containers. Wherein the cosmetics with the shape of powder stick, such as lipstick, lip cream, concealer, skin whitening stick and sun cream stick, are filled in the powder stick tube, collectively known as lipstick tube, to be designed and manufactured. Currently, the lipstick tubes on the market usually include a cover, a mechanism and a base, wherein the mechanism includes an A-shell, an innerbody, a cup and a spiral, and the assembled mechanism is sleeved in the base and then matches with the cover to form the finished product of lipstick tube. At present, the lubricating oil and glue are used to realize a smoothly, flexibly relative movement and fixation among components in most lipstick tubes. Therefore, such defects, such as increased production cost, complex process, and easily causing pollution, may occur. The patent numbered CN201767295U discloses a mechanism of a lipstick tube, including an A-shell, a spiral, an innerbody and a cup, which are coaxially sleeved from outside to inside in sequence, wherein the A-shell is fixedly connected with the spiral; a spiral guide groove is provided on the inner circumference of the spiral, a notch is provided on the wall surface of the innerbody along the axial direction thereof, a bulge which passes through the notch and extends into the guide groove is provided on the outer circumference of the cup, and a plurality of bumps which are fixed on the inner circumference of the spiral or on the outer circumference of the innerbody are provided between the bottom end of the spiral and the innerbody. The plurality of bumps, provided between the bottom end of the spiral and the innerbody, of the mechanism of the abovementioned utility model adjusts the distance between the spiral and the innerbody, so as to control the friction and the torsion during rotation between the spiral and the innerbody. However, the bumps are poor in adjustment of themselves and are easy to jam when the spiral and the innerbody move relative to each other, so that the lubricants are needed, thereby causing the hidden trouble of polluting the beauty cream. The patent numbered CN201533649U discloses a powder stick tube, including an A-shell, a spiral, an innerbody and a cup, wherein the A-shell is sleeved outside the periphery of the spiral and is fixed with the spiral; the spiral is sleeved outside the periphery of the innerbody and is axially fixed with the innerbody; the cup is inside the innerbody and is provided with a bulge; and the innerbody is provided with an axial straight slot. A spiral guide groove is provided on the inner wall of the spiral; the bulge of the cup passes through the straight slot on the innerbody to fall into the guide groove of the spiral; and the spiral and the innerbody are axially fixed in the following way: an outward expanding ring is provided at the top of the innerbody, wherein the outer diameter of the expanding ring is greater than the inner diameter of the spiral, and the top of the spiral is adjacent to the lower side of the expanding ring; and a ring of plate-like bulge is provided on the circumference of the innerbody, wherein the plate-like bulge is between the innerbody and the spiral and is in an arc shape along the axial section of the innerbody and the spiral. In the solution above, because the ring of the plate-like bulge is formed on the circumference of the innerbody, wherein the plate-like bulge is between the innerbody and the spiral and is in an arc shape along the axial section of the innerbody and the spiral, an expanding force may be generated between the innerbody and the spiral so as to ensure the generation of a certain torsion and a lubricant and smooth hand feeling, thereby reducing the use of lubricants. In the structure above, through adding the plate-like bulge, it provides the expanding force generated between the spiral and the innerbody, so as to reduce the use of lubricants, whereas, the A-shell and the spiral are still fixed by glue. During production, it is likely to pollute the beauty cream, so that such hidden trouble such as the deterioration of the beauty cream may exist.
Q: ajax get tha value of input type select option how to get the value of an input select option selected , I have a form with select option. If an option is selected with the value "example_5" I want it to get the value of an selected option var tow; var str; var e = document.getElementById("street"); str= e.value; A: Here's the code you need to use: var e = document.getElementById("street"); var str; for(var i = 0; i <e.children.length; i++){ var opt = e.children[i]; if (opt.selected == true){ str = opt.value; } }
This blog is about struggles for the control of corporations. For the most part, I'll focus on public corporations headquartered in the United States, issuing securities according to the rules stipulated by the SEC in Washington and (typically) governing their affairs by the laws and judicial decisions of the state of Delaware. My own prejudices are ... well, I think I'll let you work them out as we proceed day to day. Wednesday, September 22, 2010 ISS Sides with Burkle in B&N Matter Institutional Shareholder Services (ISS) a major proxy-advisory firm, has recommended that shareholders in Barnes & Noble vote for the dissident slate backed by Yucaipa Cos. in the ongoing proxy fight. B&N holds its annual meeting a week from today. Each of the other three major proxy-advisory firms, Glass Lewis, PROXY Governance, and Egan-Jones, has come down on the management's side. This is in accord with the developing pattern. The folks at ISS are more likely to back insurgents than their colleagues. In this case, ISS says: "Barnes & Noble’s history of poor performance, analysts’ lack of confidence in management’s ability to achieve its targets, corporate governance concerns regarding the company’s employment relationships with Leonard and Stephen Riggio, concerns about the independence of the current board, and questions over the rationale for the 2009 acquisition of Barnes & Noble College Booksellers from Chairman Leonard Riggio." The book selling business is in the midst of a major transformation, and B&N has tried to keep ahead of the curve, bring out its Nook to compete with Amazon's Kindle and the other eReaders on the market for example. B&N has been increasingly aggressive over the last year in using its bricks-and-mortar stores to push the eReader on shoppers. That sounds a bit odd: "Buy this, and you'll never have to come here again!" -- but such is the transition to a digital age. Or to whatever the heck we are all heading for. But some are skeptical of whether they really are out in front. Goldman Sachs, in a late-August report, said: "Results fell short of our forecast and, more importantly, reduced visibility on objectives going forward, given two factors: (1) Additional disclosure revealed surprisingly low gross profit margins for the .com business, reflecting both sharp, structural margin cuts in the traditional (physical) .com realm, and poor underlying profitability of the digital business in aggregate (Nook + ebooks). (2) Soft superstore sales, as results missed guidance issued two thirds of the way through the July quarter."
Brain Injury - Information Brain injuries are generally defined as an injury sustained to the brain tissue and nerves of the brain as a result of trauma to the head or greater cranial region. While there can be many different causes of a brain injury, in most instances serious brain injuries are known to be some of the most traumatic injuries that an individual can suffer. If you or someone you love has suffered an injury to the brain, the victim may be eligible to receive compensation for their injuries - which can include coverage for medical treatment costs, loss of wages, pain and suffering and other related expenses. Here at Greg Coleman Law, we are compassionate to injury victims and our skilled team of attorneys can help to explore the available legal options to those throughout the state of Tennessee. To learn more, simply fill out the "Free Case Review" form located to the right. Causes of Brain Injury Approximately 1.5 million brain injuries occur annually, with about 80,000 of these injuries causing permanent disability to those that receive them. In fact, almost half of all brain injury accidents that occur annually are caused either by an auto collision or a slip and fall accident. Often causing serious and permanent neurological damage, a brain injury can be the result of negligence, recklessness or intentional actions. It's important for any injury victim to seek urgent medical care to ensure that any damage is minimized as quickly as possible. Symptoms of Brain Injury Brain injury symptoms can vary, depending on the severity of the injury and where the point of impact was on the head. However, some common symptoms from a mild brain injury can include: Confusion or unconsciousness for a short period of time (usually less than 30 minutes) Difficulty concentrating Headache Concussion Blurry vision Dizziness Fatigue By comparison, a serious brain injury victim may exhibit symptoms such as: Seizures Emotional irritability Memory loss Loss of coordination and basic motor skills Abnormal speech Vomiting and nausea Unconsciousness for an extended period of time (more than 30 minutes) As with any emergency situation, calling 9-1-1 and alerting them of the injury will generally ensure that a medical practitioner will be quickly dispatched to the scene to assess the extent of the injuries. Types of Brain Injuries There are five primary types of brain injuries that victims are generally classified under. While the severity of each can vary from case to case, these main types help provide medical staff with guide as to the extent of the injuries. This list consists of: Concussion A concussion is defined as temporary unconsciousness after a blow to the head. Concussions are typically the least severe type of brain injury. Contusion A contusion is a bruising of brain tissue. Diffuse Axonal A diffuse axonal injury (or DAI) is a major factor in a brain injury victims state of consciousness. The difference between a DAI and any other form of brain injury is that it is widespread, rather than focal. A DAI can occur in any type of brain injury, regardless of severity. Coup-Contrecoup A coup brain injury occurs where the head came in contact with an object. A contrecoup brain injury occurs on the opposite side of impact. Recurrent Traumatic Brain Injuries Most common in sports-related brain injuries, recurrent traumatic brain injuries refer to when an individual suffers from multiple brain injuries. The severity of a second or third impact is magnified, and both neurological and cognitive functions are often seriously impaired. While some brain injury sufferers are known to recover from their initial injuries - especially sports related injuries - it has been established that in many instances, other brain related illnesses can return at a later stage in the victims life. Contact a Tennessee Brain Injury Lawyer A brain injury is often traumatic for all those involved, regardless of their severity. If you or a loved one has suffered a brain damage injury in Tennessee due to no fault of your own, you are not alone. Contact the Tennessee brain injury lawyers here at Greg Coleman Law today for a free case evaluation. Having won over $250 Million in verdicts and settlements for our clients, the personal injury team at our firm have the knowledge and determination to fight for your MAXIMUM injury compensation. Begin exploring your legal options by contacting us at 1-800-HURT-NOW (1-800-487-8669) and a member from our intake team will quickly connect you an attorney at our firm that is best suited to handle your specific case. To start immediately, simply fill out the "Free Case Review" form at the top of this page. $14 Million – Watts Regulator Co. Settlement Greg Coleman, along with co-counsel, settled two class actions lawsuits against Watts Regulator Co. for a combined $14 million. The settlements resolve claims from homeowners that Water Heater and FloodSafe Connectors designed, manufactured, distributed and/or sold by Watts are defective and caused significant water damage to their homes...Read More $5.3 Million – Nissan Altima Melting Dashboard Settlement Greg Coleman, along with Greg Coleman attorneys Mark Silvey and Adam Edwards, and co-counsel settled a class action lawsuit against Nissan Motor Company on Jan. 6, 2017, less than two weeks before the lawsuit was set to go to trial...Read More $35.5 Million For Product Liability Class Action Greg Coleman along with co-counsel Wexler Wallace LLP and Hansen Reynolds Dickinson Crueger LLC, has obtained a settlement with a minimum settlement value of more than $35.5 million in a nationwide product liability class ... Read More $178.6 Million - AK Steel ERISA Lawsuit Settlement In 2011, Greg Coleman was a part of a team of attorneys who won a $178.6 million class action settlement for retirees of AK Steel’s Butler Works Plant in western Pennsylvania. In 2006, AK Steel negotiated with the United A... Read More Confidential Settlement - Amanda Satterfield Asbestos Case At the age of 25, Amanda Satterfield passed away due to mesothelioma which she had developed after being exposed to asbestos as an infant. Her father worked at Alcoa’s aluminum plant. Her father's clothes were co... Read More $15.8 Million - AK Steel Lawsuit Update Law360, New York (September 19, 2012, 6:23 PM ET) - An Ohio federal judge on Wednesday approved a $15.8 million settlement for AK Steel Corp. and a group of retirees and their families, resolving class action allegations t... Read More Gary West Vehicle Accident Case Gary West was seriously injured in a head-on collision in a northbound lane of US Highway 11W on July 22, 2000. He crashed into Brian Lee Tarver who was driving drunk on the highway in a south-bound direction. Employ... Read More A motorcyclist suffered serious injuries when a trucker waved another vehicle into traffic and the motorcyclist’s path. A 12-member jury in Nashville, Davidson County, Tennessee, awarded a total of $2.5 million in compens... Read More The information on this website is for general information purposes only. Nothing on this site should be taken as legal advice for any individual case or situation. This information is not intended to create, and receipt or viewing does not constitute, an attorney-client relationship. No representation is made that the quality of the legal services to be performed is greater than the quality of legal services performed by other lawyers.
If this is your first visit, be sure to check out the FAQ by clicking the link above. You may have to register before you can post: click the register link above to proceed. To start viewing messages, select the forum that you want to visit from the selection below. Enjoy an ad free experience by logging in. Not a member yet? Register. One popup window for many images to use, no toolbars, please help. Thanks Hi javascript guru's Please help with this one, I've been battling all day trying different scripts but none of them seem to work. I don't want to have to make hundred of htm pages for all the different images, I just want to use ONE pop up window and let all my images use that, all the images are the same size and they all link from seperate thumbnail images. (Small thumbnail, if interested click that to see the larger image). I'd like the pop up window to go centre on the screen if possible and I'd like it to just be a window, no toolbars. I was given a one script that I thought should work but I can't get it to, I don't know what I am doing wrong. ---------- should be, Each no+= has to be on there own line ---------- var no=" addrbar=0,toolbar=0,location=0,directories=0," no+="status=1,menubar=0,scrollbars=0,resizeable=0," no+="width=720,height=576"
3-deazaguanine, a candidate drug for the chemotherapy of breast carcinomas? 3-Deazaguanine (3-DG) is a new purine antagonist that is active against slow- and rapid-growing solid experimental tumors, especially those that are models for human breast carcinomas. These tumors include mammary adenocarcinomas 13762, R3230AC, and C3H/16C. 3-DG also showed positive activity against leukemias L1210 and L1210/araC, adenocarcinoma 755, and EMT-6 mammary adenocarcinoma. On the basis of its activity against these tumors, 3-DG is to undergo clinical trials.
Leviathan Partners Sign Israeli Natgas Supply Deal The partners in Israel’s Leviathan natural gas field said on Sunday they had signed a deal to supply as much as $3 billion worth of gas to a new private power plant in central Israel. Leviathan, one of the largest offshore discoveries of the past decade, was found off Israel’s Mediterranean coast in 2010. It has an estimated 622 cubic meters of natural gas (BCM) of reserves and is expected to become operational in 2019. Under the deal, Leviathan will provide up to 13 billion BCM for 18 years to the IPM plant in Be’er Tuvia once gas starts flowing from Leviathan. The contract comes a week after Israel’s government approved a revised deal aimed at fast-tracking development of the huge field, which has been mostly earmarked for exports. In January Leviathan signed a $1.3 billion gas supply contract with Edeltech, Israel’s largest private power producer. Texas-based Noble Energy, Israeli conglomerate Delek Group and Israel’s Ratio Oil Exploration own the Leviathan site, which will cost more than $5 billion to develop. “This deal is an important milestone, in that it establishes another domestic contract that, together with additional domestic and export contracts, are essential for the quick development of Leviathan,” said Niv Sarne, Noble’s manager of business development. The Leviathan project hit a major obstacle in March when Israel’s Supreme Court blocked a previous agreement between the field’s shareholders and the Israeli state, the terms of which would have stayed unchanged for 10 years. It had been opposed by opposition parties and public advocacy groups on grounds that Noble and Delek – which also own the adjacent Tamar field – would control too much of Israel’s natural gas supply. The ruling will allow the government to change taxes, export quotas or other regulations in connection with the Leviathan field.
Share This Planned Parenthood Action Fund, All* Above All Action Fund, Feminist Majority, NARAL Pro-Choice America, National Organization for Women, and National Women’s Law Center Action Fund issued a letter to the Democratic Platform Drafting Committee Chair, Rep. Elijah Cummings (D-MD 7th District), advocating the inclusion of critical reproductive health and rights policies and principles, including access to safe, legal abortion and the full range of birth control methods, autonomy over decisions around pregnancy, and improving women’s health around the world. Statement from Cecile Richards, President of Planned Parenthood Action Fund “Make no mistake, women’s reproductive rights are on the ballot this year. This is why Planned Parenthood Action Fund and our partners are calling on the Democratic National Committee to acknowledge that reproductive health care is an essential need and human right. We know that access to quality health care is far from a given for millions of marginalized Americans who face obstacles due to their gender, sexuality, race, immigration status, geographic location and income. These issues are deeply interconnected and must be acknowledged by the DNC in the face of Donald Trump’s sexism and dismissal of women, coupled with a Republican Party platform that continues to make invisible millions of Americans and the challenges they face. “While too many Republicans in Congress and in states across the country have moved to ban abortion, block access to care, and roll back the ACA, we have seen the Democratic Party work to break down barriers to make it easier – not harder – for people of all backgrounds to access needed care. We ask them to continue this history and expand their platform to further champion reproductive rights, health equity, and the intersectional nature of these issues – to move us toward truly realizing a more equal country.” The letter addresses many of the intersections of reproductive health and: Opposition to religious liberty or political ideology being used to interfere with access to health care; An emphasis on the intertwined nature of economic security and women's health; A commitment to evidence and fact based policy-making. Planned Parenthood Action Fund is proud to have Action Fund member Joseline Mata, a Planned Parenthood of Arizona Board Member** and incoming junior at the University of Arizona, testifying for the Democratic Platform on Friday, June 17.
Health care companies at this year's J.P. Morgan Healthcare Conference celebrated the Republican tax overhaul and trumpeted optimistic views of their future financial power. But as more Americans become unable to afford drug prices, hospital bills, deductibles and copays — and as they voice their anger — there is sentiment brewing in the industry that a day of reckoning will come. Key quote: "We are in the middle of a bubble in all health care asset classes," said Bijan Salehizadeh, a health care investor at NaviMed Capital. "Everyone knows it, but no one knows how it will end." What we're hearing: The one part of health care that multiple people at the conference said desperately needed to change was pharmaceuticals. Many companies continue to hike list prices on generics and brand-name drugs, game the system by extending old drug patents, and are coming out with relatively fewer breakthroughs compared with a much higher number of "me-too" drugs that provide limited benefits over existing drugs. Firms that are developing innovative treatments are commanding prices that surpass many estimates of what is reasonable. Drug companies looking to get bought out are expecting high takeout prices based on the assumption current pricing tactics will remain the status quo. Yes, but: As many presentations from the J.P. Morgan event confirmed, problems aren't confined to the pharmaceutical industry. Hospital profits and cash reserves are hovering near historic highs. Premium rates reflect the high cost of health care services and drugs, but observers have raised questions about whether insurers are getting the best deals possible, and whether narrow networks have been helpful. Independent Medicare policymakers continue to push for regulatory changes to nursing homes, home health companies and other non-hospital providers that are earning sizable profit margins from the government. "Providers are part of it," Rod Hochman, CEO of Providence St. Joseph Health, a large not-for-profit hospital system based on the West Coast, acknowledged in an interview. "But also pharma has to be part of the solution. Insurers have to be part of the solution." Spencer Perlman, a health care analyst at Veda Partners who wasn't at the J.P. Morgan meeting, has long said companies that obstruct competition or play with regulatory loopholes have been playing with fire. "So much of current health care valuations are based on revenue and earnings projections that are generated by reimbursement arbitrage, legal maneuvering and/or rent-seeking behaviors," Perlman said. Get smart: Health care eats up almost one-fifth of the U.S. economy. The companies that get a slice of that pie don't have incentives to give it up. Even if Congress or federal agencies intervene with new policies, look for many players to point fingers at industries they believe are bigger abusers — like the current fight between drug companies and pharmacy benefit managers.
The NeverEnding Story: Getting The F-35 Right The saga of the F-35 seems to drag out with no real end in sight. Years of delays, gaffes, problems, cost overruns and sometimes just plain bad luck have plagued the project. And trying to get to the truth- at least what can be told publicly, can be very difficult. Through it all, one voice has seemed fairly consistent in their assessment: Dr. J. Michael Gilmore, Director, Operational Test & Evaluation (DOT&E). His job is to keep an eye on projects in the Department of Defense, and to report on a basically simple question: Is this project on track? It’s no minor position. He reports directly to the Secretary of Defense, and is appointed by the President and confirmed by the Senate. The job doesn’t come easily. As the F-35 has developed, I’ve observed that the Air Force seems to view the DOT&E as a bit of a nuisance. While the Air Force insists all is well with the F-35, and Lockheed Martin give a big thumbs up, DOT&E has consistently hammered on some basic points- timelines aren’t being met, and assessments have been far too rosy in light of the reality. The latest news only confirms that the situation seems to have not changed at all. On December 7th, 2016, Bloomberg reported a story detailing how a memo being prepared regarding the progress of the F-35 project did not accurately reflect the reality of the situation. Quoting from the story, “If not changed, the existing responses would at best be considered misleading and at worst, prevarications,” Michael Gilmore, director of operational test and evaluation, wrote in an internal memo criticizing the draft response to questions about F-35 testing from Senate Armed Services Committee Chairman John McCain. That’s no trivial accusation. I’ll admit I had to look up “prevarication”. I understood it in context, but I wanted the precise meaning. Prevarication, according to vocabulary.com, is when someone tells a lie, especially in a sneaky way. And the problems outlined in the story are not small. Not only do they include the timing of major milestones for being declared fully operational, but also smaller- but critical items, like problems with the Navy’s F-35C version not being able to carry Sidewinder missiles on its wingtips, especially crucial for short range engagements. Especially so since the naval version has no gun. Another is “excessive F-35 vertical oscillations” on carrier launches, a phenomenon I’d noticed watching videos of the F-35 doing catapult launches. In one video, the pilots visor actually appeared to flop down on launch the oscillations were so violent. And the past problems are still there. The Block 3F software still isn’t ready for full implementation. That will be the upgrade that brings all of the promised capabilities online. Other problems, ranging from weapons and sensor capabilities to things just catching fire, continue to plague the project. The F-35 program is critical. It’s far, far past the stage to bow to “just cancel it”. It is the farm we’ve bet on. To have an airframe ready for 2030, you have to start in 2010. It’s way to far along to give up on it and find a replacement. It has to work. And though he may seem like a thorn in the side to the Air Force and Navy, the DOT&E seems to be the only voice of truth in the whole sordid affair.
Forensic assertive community treatment: preventing incarceration of adults with severe mental illness. Persons with severe mental illness are overrepresented in jails and prisons in the United States. A national survey was conducted to identify assertive community treatment programs that have been modified to prevent arrest and incarceration of adults with severe mental illness who have been involved with the criminal justice system. Members of the National Association of County Behavioral Health Directors (NACBHD) were surveyed to identify assertive community treatment programs serving persons with criminal justice histories and working closely with criminal justice agencies. Programs were identified that met three study criteria: all enrollees had a history of involvement with the criminal justice system, a criminal justice agency was the primary referral source, and a close partnership existed with a criminal justice agency to perform jail diversion. Senior representatives of each program were subsequently contacted, and a telephone survey was administered to gather information about the design and operation of the programs. A total of 291 of 314 NACBHD members (93 percent) responded to the survey. Sixteen programs that met the study criteria were identified in nine states. The primary referral sources for 13 of these programs (81 percent) were local jails. Eleven programs (69 percent) incorporated probation officers as members of their assertive community treatment teams. Eight programs (50 percent) had a supervised residential component, with five providing residentially based addiction treatment. Eleven of the 16 programs have begun operating since 1999. Only three programs have published outcome data on program effectiveness. Forensic assertive community treatment is an emerging model for preventing arrest and incarceration of adults with severe mental illness who have substantial histories of involvement with the criminal justice system. Further research is needed to establish the structure, function, and effectiveness of this developing model of service delivery.
Q: angular-file-upload update scope onCompleteItem So i have a value in my scope called $scope.selectedComponent Then i have the following uploader: var uploader = $scope.uploader = new FileUploader({ url: 'user_resources/upload.php', formData: [{module_id: $state.params.id, component: $scope.selectedComponent}] }); // FILTERS uploader.filters.push({ name: 'customFilter', fn: function(item /{File\|FileLikeObject}/, options) { return this.queue.length < 10; } }); // CALLBACKS uploader.onWhenAddingFileFailed = function(item /{File\|FileLikeObject}/, filter, options) { console.info('onWhenAddingFileFailed', item, filter, options); }; uploader.onAfterAddingFile = function(fileItem) { console.info('onAfterAddingFile', fileItem); }; uploader.onAfterAddingAll = function(addedFileItems) { console.info('onAfterAddingAll', addedFileItems); }; uploader.onBeforeUploadItem = function(item) { console.info('onBeforeUploadItem', item); }; uploader.onProgressItem = function(fileItem, progress) { console.info('onProgressItem', fileItem, progress); }; uploader.onProgressAll = function(progress) { console.info('onProgressAll', progress); }; uploader.onSuccessItem = function(fileItem, response, status, headers) { console.info('onSuccessItem', fileItem, response, status, headers); }; uploader.onErrorItem = function(fileItem, response, status, headers) { console.info('onErrorItem', fileItem, response, status, headers); }; uploader.onCancelItem = function(fileItem, response, status, headers) { console.info('onCancelItem', fileItem, response, status, headers); }; uploader.onCompleteItem = function(fileItem, response, status, headers) { console.info('onCompleteItem', fileItem, response, status, headers); }; uploader.onCompleteAll = function() { console.info('onCompleteAll'); }; The callback function: onCompleteItem is where i want to update the selectedComponent object however within the scope of that function i am unable to get the variables of scope My question is how will i be able to update my variable after the file has uploaded? A: make sure that the $scope is loaded in your controller: .controller('AppController', ['$scope', 'FileUploader', function($scope, FileUploader) { and after that you can update the value of the $scope.selectedComponent from anywhere in this controller. $scope.selectedComponent = "not uploaded"; uploader.onCompleteItem = function (fileItem, response, status, headers) { $scope.selectedComponent = "upload complete"; };
A 10-year-old Pakistani schoolgirl has claimed a world record for being the youngest ever person to scale a 7,000m peak and now intends to climb Mount Everest. Selena Khawaja's conquest of 7,027m (23,054ft) Spantik in the Karakoram range last month comes only two-and-a-half years after she first started leisurely walks in the mountains with her father. Her climbing exploits have seen her nicknamed 'Mountain Princess' in Pakistan's media. Driven on by her father as expedition companion, she now intends to become the youngest person ever to climb to the roof of the world. Her young age means she has more than two-and-a-half years left to beat the current Everest record, but aims to make an attempt next summer if she can get funding. “I like the views better than anything,” Selena explained to the Telegraph at her home in Abbottabad, in Pakistan's Khyber Pakhtunkhwa province. Selena trains in her father's Abbottabad gym credit: Saiyna Bashir for the Telegraph Her July ascent of Spantik, also known as Golden Peak, has been verified by the Alpine Club of Pakistan. “We are meeting soon for her certification process,” said spokesman Karrar Haidri. The climb was also praised by Pakistan's government. “Selena Khawaja has made Pakistan proud by scaling Spantik peak”, a statement said. Selena and her father, Yousaf, began hiking up the nearby mountain of Miranjani for fun in 2017 and he quickly noticed that she was getting faster with every trip up the 2,992m peak. Mr Khawaja, a 59-year-old fitness instructor and nutritionist, said: “My plan was to get her into some kind of sport, but I didn't know which. When we used to go to trips up Miranjani, I realised in six months she had halved her time.” Selena and her father Yousaf credit: Saiyna Bashir for the Telegraph Pakistan sees the confluence of the Hindu Kush, Himalya and Karakoram ranges and is a haven for mountaineers. Selena has since worked her way up 5,000m and 6,000m mountains. Mr Khawaja went on: “She is very good at climbing. At some points she is faster and at other times I am faster. At some points she tells me 'Papa slow down a little bit!' and I say to her 'In a year you will be saying Papa speed up!'” As well as training in the picturesque mountains around Abottabad, Selena also works out in the gym and fitness centre her father runs. Mr Khawaja admits that at first Selena's mother was anxious about the climbing and whether her daughter was too young. But he said their success had won her over. Guinness World Records said it did not monitor a record for the youngest person to climb a 7,000m peak and only held endurance records for those aged 16 and above. A spokeswoman said: “Therefore, at 10 years old, Selena would be below the minimum age threshold for a record of this nature. Nevertheless, her achievement is very impressive.” The youngest conquest of Everest was carried out by 13-year-old Californian Jordan Romero in 2010. His ascent triggered a debate about whether children should be exposed to the rigours of high altitude climbing, with some medics calling it child abuse.
'Obamacare' opposition fading Support for full repeal of national health care reform has faded in recent months. As for repeal, only about one in four say they want to do away with the law completely. Among Republicans support for repeal has dropped sharply, from 61 percent after the elections to 49 percent now. Also, 43 percent say they want the law changed so it does more to re-engineer the health care system. Fewer than one in five say it should be left as it is. The stats display an important nuance that was often left out of the media narrative on the midterm elections: The disappointment with health care reform came from the left as well as from the right. Opposition to the health care bill never would have exceeded 50 percent if not for the liberals who believed it represented a sell-out to the insurance industry. This, of course, does not mean the GOP will not hold a symbolic vote on repealing the bill. It is still an extremely important vote to its most active supporters, including the Tea Party contingent. Follow The Sconz on Twitter or Facebook to get regular updates on city and state politics. Please send anonymous tips, interview requests or any other comments to jcraver@isthmus.com.
Vince Gilligan Would Love to See a Saul Goodman ‘Breaking Bad’ Spin-Off (Join the Club) Bob Odenkirk’s Saul Goodman is one the best characters on television like ever and it seems like Breaking Bad’s creator Vince Gilligan understands that. “I would love to see a Saul Goodman spin-off show when it’s all said and done,” Gilligan told Entertainment Weekly. He continued: “I think that would present itself pretty nicely, storywise. While Breaking Bad is by design a show that is finite and limited in its scope — it’s a story of transformation that cannot go on forever — I think a Saul Goodman show could have great legs. I love the idea of a lawyer who will do anything to avoid going to court. He’s always going to settle on the courthouse steps.” Now all Saul needs to do is stay alive. Gilligan explains: “No viewer should breathe a sigh of relief that Saul won’t expire by the end of Breaking Bad.” Adding: “Everything is on the table… Who knows where Breaking Bad will take us?” When asked, Odenkirk agreed: “Saul has got to survive this show first. And if he doesn’t, then maybe it can be done as a prequel.” Or maybe we’ll have Zombie Saul, Attorney At Law, in which the show merges with The Walking Dead. All of these are great ideas!
“Most of us don’t understand the idea of self-government enough to be properly astonished by it.” — Eric Metaxas, author of ‘If You Can Keep It’ We absolutely need to be astonished by the idea of self-government – or we might soon lose it. Frighteningly, the evidence points to our losing it: Roughly 75 to 80 percent of high school students fail on basic tests of civics and history. Some 70 percent of adults fail, too. Many local elections have turnouts in the low teens, if not worse. And have you seen those person-on-the-street interviews where folks can’t answer fundamental questions about America or its leaders? What happens to a self-governed nation when so many of the “selves” have tuned out? We need to always remember that we have two lives: a private one and a public one – the latter being the attention we pay to, and the amount of involvement we have in, the important events and issues in our communities, country and world. Most of us are blessed with rich, full, even overindulged private lives. How’s your public life? And shame on anyone who tries to tell you that civics and citizenship are boring. Indeed, in the movie ‘The American President’, Michael Douglas plays a president of the U.S. who is trying to get his young daughter excited about civics class. He has her read the first few phrases of the Constitution: “We the People of the United States, in order to form a more perfect union…” “See?” Douglas’ character says. “Grabs you right off the bat. It’s a page-turner!” He’s absolutely right. This self-government thing is exciting stuff – especially when you consider the alternative: Well over 95 percent of everyone else who has ever lived on this planet has toiled under a king, dictator, junta or some other heavy-handed and absolute authority. This is the first nation in history where the founding documents declare, in writing, that the individual is sovereign over his or her own life. We are the freest people in history. And we had darn well better be astonished by it if we want it to endure. What can we do to keep the Statue of Liberty’s torch lit? Plenty. First, let’s pump up our public lives. Let’s dedicate ourselves to these three things: • Character • Brotherhood • Citizenship These are the three legs of the self-governance stool – the qualities and virtues that make self-governance possible to begin with. It all begins with character. “Our Constitution was made only for a moral and religious people,” John Adams eloquently pointed out. “It is wholly inadequate to the government of any other.” In short, to work on the country, we need to work on ourselves. Second, get involved as much as you can – in both public and private civic endeavors: local government, political campaigns, nonprofits and more. Keep up on the news. Write your elected leaders and newspaper editors. Run for office or support the candidate of your choice. If you’ve never experienced an election night as a campaign supporter, you don’t know what you’re missing! A self-governed nation is only as good as the quality and attentiveness of its citizens. “That is the wonderful, spectacular genius of it all – and the terrible, sobering danger of it all, too,” writes Eric Metaxas. There are some things we must do as a country, too, to ensure that “government of the people, by the people, for the people, shall not perish from the earth.” Civics – the inspiring, exhilarating, page-turning kind Michael Douglas was talking about – must be taught in every school. Our young simply must be taught to appreciate our unique and blessed history – especially as it compares to the unfortunate and desperate history of the rest of the world from the very beginning. Our public and private leaders should lead us in a national dialogue about character, brotherhood, citizenship – and the seat of the self-governance stool: responsibility. Houses of worship have been made to believe they must be silent on matters of governance. Poppycock. The spiritual underpinning of our founding, embodied by the “Great Awakening” is undeniable and inseparable from our destiny. Far from prohibiting churches from participating in our national dialogue, they must understand that they are essential to it. It would help, too, if the nation’s businesses promoted civics and good citizenship much as they advocate for the United Way. And would a more energized, active citizenry not benefit businesses as much as it does the nation? Most important, get excited! Allow yourself to be astonished by this country and the unprecedented liberty we’ve been bequeathed. And with a soaring sense of gratitude, but sober responsibility too, let’s “mutually pledge to each other our Lives, our Fortunes, and our sacred Honor” to keep freedom’s fire blazing. The National Archives and Records Administration was formed in 1934 and is charged with preserving the nation’s historical documents. America’s charters of freedom are on display in its Washington headquarters. CHALLENGES Some 75-80 percent of American youths fail on tests of basic civics. Adults also fail at a rate of 71 percent. A nation of free people cannot govern themselves if they’ve lost the blueprint for that self-governance. We have private and public lives. We’ve indulged, often over-indulged, our private lives, yet have neglected our public lives – by failing to vote faithfully, stay up on the news and newsmakers and pitch in in our communities. OPPORTUNITIES Luckily, the opportunities for civic involvement are limitless. Join a civic club, volunteer for a political candidate, attend government meetings, write your leaders and newspaper editors and more. We simply must do a better job of teaching the basics of American history, American government and civics in our schools. Our new presidential administration could lead a push for it, and the First Lady could even make it her cause. There are myriad books and other sources of information on the unique nature of this republic we love. One of our favorites is the book ‘If You Can Keep It’, by Eric Metaxas.
Does a structured free recall intervention reduce the effect of stereotypes on performance ratings and by what cognitive mechanism? The purpose of this article was to extend previous work on the effect of racial biases on performance ratings. The 1st of 2 studies examined whether a structured free recall intervention decreased the influence of negative racial biases on the performance ratings of Black men. Results indicated that without the intervention, raters who endorsed a negative stereotype of Black men as managers evaluated Black men more negatively. However, the structured free recall intervention successfully reduced these effects. The second study examined in more detail the cognitive mechanisms underlying the success of the intervention. Results are consistent with the assumption that the reduction of the influence of racial biases under structured free recall conditions is a consequence of a modified strength threshold for retrieval of behaviors from memory.
Resources drive the world … Main menu Monthly Archives: November 2013 The Newcastle Electromagnetics Interest Group (NEMIG) is pleased to announce an event entitled ‘Electromagnetism without fields’, on 6/12/13 in M.4.13 (CPD Room) at 1:30 – 3:00 pm. A talk followed by discussion session will be held by NEMG and external speaker Dr. Charles (John) Carpenter BSc DSc FIET CEng, Visiting Research Fellow, Bristol University. A short abstract of the talk is; Electrical engineers commonly regard electromagnetism as a difficult subject, because field theory is seen as fundamental to it. The talk explores a different approach, first explored by Maxwell, which does not depend on the field equations. It helps to clarify many different concepts, including the induction of EMF, and the different methods of electromagnetic power transfer. Dr. Carpenter has a wide-ranging interest in electromagnetic theory, following on from an industrial experience in electrical machines and actuators. His Published work includes the numerical solution of field problems, methods of calculating forces and EMFs, machine losses, and equivalent circuits. More recently, his papers have centred on fundamentals, and, in particular, on the consequences of using the potentials, instead of the field vectors, as base electromagnetic variables. This has many implications, including teaching and understanding, particularly for those not wishing to specialise in field theory. We welcome all to this event and hope to see you there, this is sure to be a very interesting and informative event!
Signed and numbered 72/250. Limited edition in slipcase. No dust jacket as issued. Protected in clear Mylar cover. Bubble wrapped and shipped in a box. We do not stock or sell ex-library or Book Club editions. A
Danny Buggs Daniel Buggs (Lightning) Position: WR Height: 6-2 Weight: 188 lbs. Born:April 22, 1953 in Duluth, GAHigh School: AvondaleCollege: West Virginia (school history) (Buggs college stats) Drafted by the New York Giants in the 3rd round (62nd overall) of the 1975 NFL Draft.
Q: Change some field separators in awk I have a input file 1.txt joshwin_xc8@yahoo.com:1802752:2222: ihearttofurkey@yahoo.com:1802756:111113 www.rothmany@mail.com:xxmyaduh:13@;:3A and I want an output file: out.txt joshwin_xc8@yahoo.com\|\|o\|\|1802752\|\|o\|\|2222: ihearttofurkey@yahoo.com\|\|o\|\|1802756\|\|o\|\|111113 www.rothmany@mail.com\|\|o\|\|xxmyaduh\|\|o\|\|13@;:3A I want to replace the first two ':' in 1.txt with '\|\|o\|\|', but with the script I am using awk -F: '{print $1,$2,$3}' OFS="\|\|o\|\|" 3.txt But it is not giving the expected output. Any help would be highly appreciated. A: Perl solution: perl -pe 's/:/\|\|o\|\|/ for $_, $_' 1.txt -p reads the input line by line and prints each line after processing it s/// is similar to substitution you might know from sed for in postposition runs the previous command for every element in the following list $_ keeps the line being processed For higher numbers, you can use for ($_) x N where N is the number. For example, to substitute the first 7 occurrences: perl -pe 's/:/\|\|o\|\|/ for ($_) x 7' 1.txt A: Following sed may also help you in same. sed 's/:/\|\|o\|\|/;s/:/\|\|o\|\|/' Input_file Explanation: Simply substituting 1st occurrence of colon with \|\|o\|\| and then 2nd occurrence of colon now becomes 1st occurrence of colon now and substituting that colon with \|\|o\|\| as per OP's requirement.
Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy. The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele ("allelic exclusion"). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position -1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.
--- author: - 'Emiko <span style="font-variant:small-caps;">Hiyama,</span>$^{1}$[^1] Hideo <span style="font-variant:small-caps;">Suganuma</span>$^{2}$ and Masayasu <span style="font-variant:small-caps;">Kamimura</span>$^{3}$' title: \| Four- and Five-Body Scattering Calculations of\ Exotic Hadron Systems --- Introduction: importance of the wave function of multi-quarks ============================================================= From the viewpoint of Elementary Particle Physics, the lattice QCD calculation is one of the most standard approaches to investigate hadrons including multi-quarks. However, it is rather difficult to extract the “wave function" of hadrons in the lattice QCD calculation because it is based on the path-integral, where all contributions of possible states are summed up and only vacuum expectation values can be obtained. Needless to say, the wave function is one of the most important quantities in quantum physics, and, of course, also in Quark-Hadron Physics. In particular for multi-quark systems, the analysis with the quark wave function is necessary to clarify whether the multi-quark hadron is an exotic resonance state or a two-hadron scattering state. Thus, to extract the state information (the wave function) of hadrons, we need a reliable calculational method for multi-quark systems instead of lattice QCD. One of the attractive methods is the constituent quark-model calculation, since it seems workable up to several hundred MeV excitation, and its precise calculation for multi-quark systems can be done with the Gaussian Expansion Method (GEM) [@Hiyama2003; @Hiyama2006]. In Nuclear Physics, a precise calculational method for bound and scattering states of various few-body systems using GEM [@Hiyama2003] has been developed by two of the present authors (E.H. and M.K.) and their collaborators, and has successfully been applied to light nuclei, light hypernuclei, exotic atoms/molecules and so on [@Hiyama2003]. Using GEM within the framework of a constituent quark model, Hiyama [et al.]{}[@Hiyama2006] investigated for the first time scattering and resonance states of the five-quark system $uudd{\bar s}$ under the explicit NK scattering boundary condition. It was made clear that there appears no $\frac{1}{2}^\pm$ resonance state around the reported energy of ${\rm \Theta}^+(1540)$ [@Nakano03; @Dzierba05; @Oka04]. In this paper, we perform the similar precise calculation of the five-quark system $uudd{\bar s}$ with $J^\pi=\frac{1}{2}^\pm$ and $J^\pi=\frac{3}{2}^\pm$ using the linear confinement potential, which is more appropriate as indicated by lattice QCD calculations [@TS0102; @Okiharu]. Furthermore, we apply the same method to the four-quark system $c{\bar c}q{\bar q}$ in connection with X$^0$(3872) [@X3872] and discuss about possibility of any bound/resonance state near the ${\rm D}^0 {\rm \bar D}^{0}$ threshold. Five-body quark-model calculation for ${\rm \Theta}^+(1540)$ ============================================================ We study the five-quark system $uudd{\bar s}$ by solving the five-body Schrödinger equation $ ( H - E )\, \Psi_{J^\pi M} = 0 $ including the NK scattering channel explicitly, as was done in Ref.2). We here take a standard non-relativistic quark-model Hamiltonian with the linear-type confining potential $V_{\rm conf}$ and the color-magnetic potential $V_{\rm CM}$: $$V_{\rm conf}(r_{ij}) = - \frac{\lambda^a_i}{2}\,\frac{\lambda^a_j}{2} (\frac{3}{4}\sigma~r_{ij} + v_0 ), \ V_{\rm CM}(r_{ij})=- \frac{\lambda^a_i}{2}\,\frac{\lambda^a_j}{2} {{\xi_{\alpha}} \over {m_i m_j}}\, e^{- r_{ij}^2/ \beta^2 } \, \mbox{\boldmath $\sigma$}_i \cdot \mbox{\boldmath $\sigma$}_j. % \, . \label{Vcm}$$ Using the parameters listed in Table I, we can well reproduce masses of ordinary baryons and mesons as shown in Table II and III, and well reproduce or predict hadron properties, [e.g.]{}, $\mu_{\rm p} \simeq 2.75{\rm nm}$ (exp. 2.78nm), $\mu_{\rm n} \simeq -1.80{\rm nm}$ (exp. $-$1.91nm), $\mu_{\rm \Lambda} \simeq -0.60{\rm nm}$ (exp. $-$0.61nm), $\mu_{\rm \Sigma^0} \simeq 0.81{\rm nm}$, $\mu_{\rm \Omega} \simeq -1.84{\rm nm}$ (exp. $-$2.02nm) for the magnetic moment. Note here that the form of the linear-type confining potential $V_{\rm conf}$ is appropriate as an approximation of the Y-type linear three-quark potential indicated by lattice QCD [@TS0102; @Okiharu], although the adopted value of the string tension $\sigma \simeq$ 0.56GeV/fm is smaller than the standard value $\sigma \simeq$ 0.89GeV/fm. parameter $m_u$, $m_d$ $m_s$ string tension $\sigma$ $\beta$ $v_0$ $\xi_\alpha$ --------------- -------------- -------- ------------------------- --------- ----------- ---------------------- adopted value 330MeV 500MeV 0.56 GeV/fm 0.5fm $-$572MeV 240MeV$\times m_u^2$ : Parameters of the present constituent quark model with a linear-type confining potential. baryon N $\rm \Delta$ $\rm \Lambda$ $\rm \Sigma$ $\rm \Xi$ $\rm \Omega$ N\ ------------------------- ----- -------------- --------------- -------------- ----------- -------------- ------ calculated mass \[MeV\] 939 1235 1064.8 1129 1324 1539.5 1462 empirical mass \[MeV\] 939 1232 1115.7 1191 1318 1672.5 1440 : Calculated masses of typical baryons obtained with the present constituent quark model. meson $\omega$ $\rho$ K\* K $\pi$ ------------------------- ---------- -------- ------- ------- ------- calculated mass \[MeV\] 759 759.3 864.4 457.9 152 empirical value \[MeV\] 782.7 775.5 892 496 138 : Calculated masses of typical mesons obtained with the present constituent quark model. Now, we perform an almost precise quark-model calculation with GEM for multi-quark systems and clarify whether each obtained state is a resonance or a continuum scattering state through the phase-shift analysis in the model calculation. For the five-quark system $uudd\bar s$ with the energy $E$, the total wave function is given as $$\Psi_{J^\pi M}(E)= \Psi^{\rm (NK)}_{J^\pi M}(E) + \sum_{\nu=1}^{\nu_{\rm max}} b_J^{(\nu)}(E) \Phi^{(\nu)}_{J^\pi M}(E_\nu).$$ The first term is the NK scattering component expressed by $$\begin{aligned} \Psi_{J^\pi M} ^{\rm (NK)}(E)= {\cal A}_{1234}\! \big\{ \big[ \big[\phi_{\frac{1}{2}}^{\rm (N)}(123) \phi_0^{\rm (K)}(45)\big]_{\frac{1}{2}} \chi_L({\bf R}_1)\big]_{J^\pi M} \big\}. \; \label{elastic}\end{aligned}$$ The second term describes five-body degrees of freedom in the interaction-region amplitude which vanishes asymptotically. The amplitude is expanded using a nearly complete set of five-body eigenstates, $\{\Phi^{(\nu)}_{J^\pi M}(E_\nu)\} (\nu=1-\nu_{\rm max})$, constructed by diagonalizing the total Hamiltonian as $ \langle \,\Phi^{(\nu)}_{J^\pi M}(E_\nu) \, \| H \| \, \Phi^{(\nu')}_{J^\pi M}(E_\nu') \,\rangle = E_\nu\, \delta_{\nu \nu'}. $ Here, each of $\Phi^{(\nu)}_{J^\pi M}(E_\nu)$ is described as a superposition of $L^2$-type five-body Gaussian basis functions written in all the Jacobi coordinates $c=1-5$ as shown in Fig.1. By employing 15,000 five-body basis functions, [i.e.]{}, $\nu_{\rm max}=15,000$, the eigenfunction set $\{\Phi^{(\nu)}_{J^\pi M}(E_\nu)\}$ forms a nearly complete set in the finite interaction region. The eigenfunctions $\Phi^{(\nu)}_{J^\pi M}(E_\nu)$ stand for discretized continuum states of the five-body system, and are called “pseudostates" in the scattering theory. It is known that most of the pseudostates do not actually represent resonance states but melt into non-resonant continuum states when the scattering boundary condition is imposed to the total wave function. We actually perform the precise quark-model calculation including all the pseudostate terms in (2.2), and calculate the phase shift $\delta$ in the NK elastic scattering N+K$\to$N+K for $J^\pi=\frac{1}{2}^\pm, \frac{3}{2}^\pm$ channels, respectively. For $J^\pi=\frac{1}{2}^\pm$, all the pseudostates located at $0 - 450$ MeV above the NK threshold melt into non-resonant continuum state when the NK scattering boundary condition is imposed, which means the strong coupling between those pseudostates and the NK scattering state. We show in Fig.2 the calculated phase shift $\delta$, and find no resonance for $0 - 450$ MeV above the NK threshold, [i.e.,]{} $1.4-1.85 $ GeV in mass region around ${\rm \Theta}^+(1540)$. We find a sharp resonance for $J^\pi=\frac{1}{2}^-$ and a broad one for $J^\pi=\frac{1}{2}^+$ around 1.9GeV in Fig.2, although their energies are too high to be identified with the ${\rm \Theta}^+(1540)$. For the $J^\pi=\frac{3}{2}^\pm$ states, we find no resonance up to 500 MeV above the NK threshold. Note that these results on the absence of low-lying pentaquark resonances with $J^\pi=\frac{1}{2}^\pm, \frac{3}{2}^\pm$ are consistent with the lattice QCD results in Refs.9) and 10). As for the presence of $\frac{1}{2}^-$ penta-quark resonance around 1.9GeV, Ref.11) shows a consistent lattice QCD result indicating a $\frac{1}{2}^-$ penta-quark resonance around 1.8GeV. To conclude, there is no five-quark resonance with $J^\pi=\frac{1}{2}^\pm, \frac{3}{2}^\pm$ below 1.85GeV. Instead, the quark-model calculation predict a five-quark resonance state of $J^\pi=\frac{1}{2}^-$ with the mass of about 1.9GeV and the width of $\Gamma \simeq$ 2.68MeV. Four-body quark-model calculation for X$^0$(3872) ================================================= With GEM, we analyze four-quark systems $c{\bar c}q{\bar q}$ for $I=0,1$ in a quark model to investigate X$^0$(3872)[@X3872], which may have the tetraquark structure as $c{\bar c}u{\bar u}$ [@Swanson]. Note here that, if X$^0$(3872) is an $I=1$ state, it is manifestly exotic and there should exist its isospin partners X$^\pm$ ($c{\bar c}u{\bar d}$ and $c{\bar c}d{\bar u}$) around 3.87GeV. For the calculation of four-quark charmed systems, we adopt the quark-quark interaction of Ref.13), which effectively includes the exchange effect of Nambu-Goldstone bosons. With $m_c \simeq$ 1752MeV, $m_{u,d} \simeq$ 313MeV and $m_s \simeq$ 555MeV, the quark model leads light hadron masses as $m_\rho\simeq$ 772.8MeV, $m_\omega\simeq$ 696.3MeV and $m_\pi\simeq$ 148.7MeV, and the calculated (experimental) masses of charmed mesons are $m_{\rm D}\simeq$ 1897.6(1867)MeV, $m_{\rm D^}\simeq$ 2017.1(2008)MeV, $m_{{\rm J}/\psi}\simeq$ 3096.5(3097)MeV and $m_{\eta_c}\simeq$ 2989.1(2980)MeV. For the four-quark calculation, we employ all the 18 sets of the Jacobi coordinates of the four-body system.[@Hiyama2003] We show in Fig.4 the three important sets describing the $c{\bar u}$ and ${\bar c}u$ correlations ($c=1$), the $c{\bar c}$ and $u{\bar u}$ ones ($c=2$) and the $cu$ and ${\bar c}{\bar u}$ ones ($c=3$). The four-body Gaussian basis functions are prepared in the Jacobi sets $c=1-18$ and the four-body pseudostates $\Phi^{(\nu)}_{J^\pi M}(E_\nu)$ are obtained by diagonalizing the four-quark Hamiltonian using nearly 13,000 Gaussian basis functions. For the phase shift calculation, we consider the scattering channels ${\rm D}^0+{\rm \bar D}^{0}$ and J/$\psi$ + $\omega$ for $I=0, J^\pi=1^+$, and ${\rm D}^0+{\rm \bar D}^{0}$ and J/$\psi$ + $\rho$ for $I=1, J^\pi=1^+$. For the $I=0$ states, we find a very sharp resonance, dominantly having the ${\rm D}^0 {\rm \bar D}^{0}$ component, slightly below the ${\rm D}^0 \,{\rm \bar D}^{0}$ threshold. In this calculation, however, the J/$\psi$ $\omega$ threshold energy is much lower than the experimental value by 86 MeV. We find that if the quark-quark interaction is artificially adjusted so as to reproduce the experimental value of the J/$\psi$ $\omega$ threshold, neither bound nor resonance state appears. In fact, the result seems rather sensitive to the quark-quark interaction, and we need better interaction to obtain definite conclusions for $I=0 $ states. For the $I=1$ states, we obtain several pseudostates near the ${\rm D}^0 {\rm \bar D}^{0}$ threshold region, but all of them disappear when the scattering boundary condition is switched on. The resultant scattering phase shift by the full coupled-channel calculation is given in Fig.3, which shows no resonance behavior. We thus find no $c\bar cq\bar q$-type tetraquark resonance with $I=1$ in mass region of 3.87$-$4.0GeV. In this way, the almost precise quark-model calculation using the Gaussian Expansion Method (GEM) is a powerful tool to clarify the state properties of multi-quark systems, which is a theoretical search for exotic hadron resonances. Acknowledgements {#acknowledgements .unnumbered} ================ E.H. acknowledges Profs. A. Hosaka, H. Toki and M. Yahiro for useful discussions. The authors are thankful to the Yukawa Institute for Theoretical Physics at Kyoto University, where stimulating discussions were made about the present work during the YKIS2006 on “New Frontiers on QCD". [99]{} E. Hiyama, Y. Kino and M. Kamimura, Prog. Part. Nucl. Phys. [51]{} (2002) 223. E. Hiyama, M. Kamimura, A. Hosaka, H. Toki and M. Yahiro, Phys. Letters [B633]{} (2006). LEPS Collaboration, T. Nakano [et al.]{}, Phys. Rev. Lett. [91]{} (2003) 012002. For an experimental review, for instance, A. Dzierba [et al.]{}, J. Phys. Conf. Ser. [9]{} (2005) 192. For a theoretical review, for instance, M. Oka, Prog. Theor. Phys. [112]{} (2004) 1. T.T. Takahashi [et al.]{}, Phys. Rev. Lett. [86]{} (2001) 18; Phys. Rev. [D65]{} (2002) 114509. F. Okiharu [et al.]{}, Phys. Rev. [D72]{} (2005) 014505; Phys. Rev. Lett. [94]{} (2005) 192001. Belle Collaboration (S. -K. Choi [et al.]{}), Phys. Rev. Lett. [91]{} (2003) 262001. N. Mathur [et al.]{}, Phys. Rev. [D70]{} (2004) 074508. N. Ishii [et al.]{}, Phys. Rev. [D71]{} (2005) 034001; Phys. Rev. [D72]{} (2005) 074503. T.T. Takahashi, T. Umeda, T. Onogi and T. Kunihiro, Phys. Rev. [D71]{} (2005) 114509. E.S. Swanson, Phys. Lett. [B588]{} (2004) 189; N.A. Tornqvist, Phys. Lett. [B590]{} (2004) 209. J. Vijande, F. Fernandez and A. Valcarce, J. Phys. [G31]{} (2005) 481. [^1]: e-mail address: hiyama@cc.nara-wu.ac.jp
This Plotly tutorial will show you how you can use plotly to easily create stunning data visualizations with R. Impress your boss, co-workers and friends with interactive, high quality charts and graphs today! Getting Started With Plotly This chapter will introduce you to plotly and how you can use R and plotly together to create stunning data visualizations. Getting Fancy With Plotly In this chapter you will bring your plotly skills to the next level. Learn how to use plotly to create heatmaps and 3D surface plots, a choropleth map, and how to add slides. There is even a short meet and greet with ggplotly, the interactive sister of ggplot2.
using GammaJul.ReSharper.EnhancedTooltip.DocumentMarkup; using JetBrains.Annotations; using JetBrains.ProjectModel; using JetBrains.ReSharper.Daemon.CSharp.Errors; using JetBrains.ReSharper.Psi; using JetBrains.ReSharper.Psi.CodeAnnotations; using JetBrains.ReSharper.Psi.ExtensionsAPI.Resolve; namespace GammaJul.ReSharper.EnhancedTooltip.Presentation.Highlightings.CSharp { [SolutionComponent] internal sealed class AccessRightsInTextWarningEnhancer : CSharpHighlightingEnhancer<AccessRightsInTextWarning> { protected override void AppendTooltip(AccessRightsInTextWarning highlighting, CSharpColorizer colorizer) { ResolveResultWithInfo resolveResult = highlighting.Reference.Resolve(); IDeclaredElement declaredElement = resolveResult.DeclaredElement; if (declaredElement == null) return; colorizer.AppendPlainText("Cannot access "); colorizer.AppendElementKind(declaredElement); colorizer.AppendPlainText(" '"); colorizer.AppendDeclaredElement(declaredElement, resolveResult.Substitution, PresenterOptions.NameOnly, highlighting.Reference.GetTreeNode()); colorizer.AppendPlainText("' here"); } public AccessRightsInTextWarningEnhancer( [NotNull] TextStyleHighlighterManager textStyleHighlighterManager, [NotNull] CodeAnnotationsConfiguration codeAnnotationsConfiguration, [NotNull] HighlighterIdProviderFactory highlighterIdProviderFactory) : base(textStyleHighlighterManager, codeAnnotationsConfiguration, highlighterIdProviderFactory) { } } }
Q: How to change the directory for composer self-update --update-keys Using composer I try to change the directory for composer self-update --update-keys Because it always shows up the Exception: [ErrorException] file_put_contents(/var/www/webxx/.composer/keys.dev.pub): failed to open stream: No such file or directory All the posts which propose sudo and chmod 777 do not help because it s a managed server and I do not have access to the HOME DIR and please let's skip this long long discussion why in this case a user does not have write access to his own home dir. It s a debian with a confixx:) What I did via config in the composer.json is to change all dirs I can think of including of course the "home" and listing the config tells me it worked. But still it uses the /var/www/webxx/.composer/ The question is how to change this directory for composer self-update --update-keys without being root? A: You can define where Composer keeps it's files by setting the COMPOSER_HOME environment variable to the path you want. Link: https://getcomposer.org/doc/03-cli.md#composer-home
Molecular and immunological characterisation of a polymorphic cytosolic fatty acid binding protein from the human blood fluke of humans, Schistosoma japonicum. Most organisms obtain their fatty acids through their diet or by de novo synthesis, but human blood flukes belonging to the genus Schistosoma lack the oxygen-dependent pathways required for the synthesis of sterols and fatty acids so they are entirely dependent on their hosts for these and other complex lipids. Fatty acid binding proteins (FABPs) of the FABP/P2/CRABP/CRBP family of beta-barrel cytosolic lipid binding proteins (cLBP) appear to be particularly important to schistosomes in the uptake, transport and compartmentalisation of host-derived fatty acids and may provide important targets for immuno- and chemotherapy. Here we describe the isolation of a set of cDNAs prepared from the Asiatic schistosome, Schistosoma japonicum, which encode two groups of cLBPs based on sequence homology and unique cDNA restriction sites. Representative clones from the two groups, one encoding a complete Sj-FABP (F10), and the other encoding a deletion mutant (F25) were characterised at the nucleic acid level by Southern and Northern hybridisation analysis, and at the protein level by immunoblotting. The presence and size of introns in the genes encoding F10 and F25 were determined and, because of the interest in the Schistosoma mansoni FABP homologue (Sm14) as a putative vaccine candidate, the immunogenicity and protective efficacy of the two proteins were also evaluated. A particularly interesting finding was the degree of Sj-FABP amino acid sequence polymorphism found to occur within the S. japonicum worm population, which appears to be greater than that described from cLBPs from vertebrates or, indeed, any other group of organisms investigated to date.
Israel is launching a campaign to isolate Iran economically and to soften up world opinion for the option of a military strike aimed at crippling or delaying Tehran's uranium enrichment programme. Pressure will be applied to major US pension funds to stop investment in about 70 companies that trade directly with Iran, and to international banks that trade with its oil sector, cutting off the country's access to hard currency. The aim is to isolate Tehran from the world markets in a campaign similar to that against South Africa at the height of apartheid. Meanwhile, President Mahmoud Ahmadinejad is to be pursued in international courts for calling the Holocaust a myth, and saying Israel should be wiped off the map. The case will be launched under the 1948 UN convention on the prevention and punishment of the crime of genocide, which outlaws "direct and public incitement to genocide". Before flying to London to spearhead the mission to sell the sanctions, the Likud party leader, Binyamin Netanyahu, said: "A campaign to divest commercial investment from Iran, beginning with the large pension funds in the west ... either stops Iran's nuclear programme or it will pave the way for tougher actions. So it's no-lose for us." In December the UN ordered a ban on the supply of materials that could contribute to Iran's nuclear and missile programme, and an asset freeze on Iranian companies and individuals. But it stopped short of a full travel ban. Israeli defence sources claim that Iran is close to the point of no return in its uranium enrichment programme using gas centrifuges. A senior official said: "They currently have problems but if the programme is allowed to continue without interruptions we estimate they will have mastered the technology this year. We expect a declaration from them in the next month, possibly on February 21, the day of the Islamic Revolution, that they have reached significant achievements. "It will be a bluff, but it will have the potential of marketing Iran as a regional superpower. If they do it, a nuclear Iran will cast a long shadow over the whole of the Middle East; we will have Hizbullastan in Lebanon, Hamastan here, and Shiastan in Iraq." Military analysts speaking at an annual conference in Herzliya, near Tel Aviv, claimed that Israel was facing an "existential threat" from the Iranian uranium enrichment programme, which Tehran has consistently claimed was for a civilian nuclear fuel cycle. The only division of opinion was over the imminence of this threat.
Introduction ============ The Surgical Site Infection (SSI) is one of the most important postoperative complications. In 1992, the Surgical Wound Infection Task Force defined SSIs as infections of all the surgery-related sites, including the surgical wound and the organ that is operated on. The mortality of patients is 2\~3 times higher when SSI occurs, and the readmission rate is also higher.([@B1]) In 1999, the ASHP (American Society of Health-System Pharmacists) guideline recommended that prophylactic antibiotics be administered within only the first 24 hours after surgery.([@B2]) Long-term antibiotic use may encourage the growth of antibiotic-resistant strains and cause anaphylaxis, and it may also delay making a proper diagnosis by masking pre-existing infections.([@B3]) Despite these problems, long term use is still very common. A study evaluating 302 hospitals regarding prophylactic antibiotics use in Korea revealed that antibiotics were being administered for an average of 7.9 days after surgery. This study also showed that approximately 23% of patients receiving gastrectomy had inappropriate antibiotics administered.([@B4]) Also, many thoracic surgeons and orthopedic surgeons administer antibiotics until all the drainage catheters are removed. There is no evidence that administration of antibiotics according to the duration of the catheter drainage prevents SSI.([@B5],[@B6]) This kind of practice may be due to insufficient knowledge/information and a lack of an organized system that may facilitate reliable antibiotic administration. There have been studies that have recommended 24-hr short-term prophylactic antibiotic use in appendectomy cases or colon surgery cases.([@B7]-[@B10]) Further, it has been proven that for other gastrointestinal surgeries, 24 hr short term prophylactic antibiotics use is as effective as administering prophylactic antibiotics for 3 days or longer.([@B11]) However, most of the research on this in Korea has been limited to hepatobiliary surgery or colon surgery.([@B7]-[@B12]) We have previously reported the safety of short term prophylactic antibiotics after gastric cancer surgery as compared to that of longer usage,([@B13]) and we have been using short term prophylactic antibiotics since the time of that study. However, studies that have focused on the inclusion/exclusion criteria of short term antibiotics for gastric cancer patients are insufficient. We present here the clinical outcome of the patients who underwent short term use of prophylactic antibiotics after gastric cancer surgery in order to confirm the rationality of short-term prophylactic antibiotic usage and to determine the specific inclusion/exclusion criteria for this therapy. Materials and Methods ===================== 1. Study group -------------- One hundred three patients were diagnosed with stomach cancer from Oct 2007 to June 2008, and these patients were prospectively evaluated to be resectable according to preoperative study, and they all underwent gastrectomy combined with lymphadenectomy. The preoperative exclusion criteria were preoperative wound infection, severe organ dysfunction, an ASA (American Society of Anesthesia) score \>3, they were being treated with insulin or they had complicated DM, bleeding, perforation, obstruction from stomach cancer or a fever over 38℃ within 24 hours before surgery. The intraoperative exclusion criteria were emergency surgery, a co-operation of other organs, combined resection of the pancreas, liver or colon, open thoracic surgery, intraoperative organ damage and intraoperative transfusion. The postoperative exclusion criteria were a re-operation within 24 hours of the first surgery, and major complications not due to infection, requiring further antibiotics therapy. 2. Perioperative care --------------------- Open surgery was performed on all the patients. Central venous catheters were inserted preoperatively and they were kept inserted until the time of discharge. For the cases with a suspicion of venous catheter infection, the catheter was removed and it was cultured for phlebitis. Foley catheters were inserted after anesthesia and these were removed 1 day postoperatively after urinary catheter training. All patients were checked daily for signs of infection. Erythema or suppurative fluid discharge at the wound was classified as incisional SSI. Fever, tenderness, and radiologic evidence of fluid collection below the tender point was classified as organ space SSI. Other fever focuses such as respiratory tract infection, urinary tract infection, phlebitis, etc. were classified as fever focuses not due to SSI. 3. Antibiotics injection ------------------------ The 2^nd^ generation cephalosporin cefoxitin (Pacetin; Choongwae Pharma Corp., Seoul, Korea) was used as a prophylactic antibiotic. One gram was administered within 30 minutes before the first incision, and an additional 1 gram was administered intraoperatively when the operation time exceeded 3 hours. Postoperatively, 1 gram every 8 hours was given for 24 hours. The antibiotics were restarted after the initial 24 hours when there was fever over 38℃, leukocytosis or clear evidence of infection. 4. Statistical analysis ----------------------- Surgical site infection and variables were analyzed using the chi-square test or Fisher\'s exact test for proportions. Statistical analysis was performed by SPSS (Statistical Package for Social Science version 13.0, Chicago, IL, USA) and P-value \<0.05 was deemed statistically significant. Results ======= Fifteen of the 103 patients were excluded from study. Of the 6 subjects excluded preoperatively, the 5 cases with severe organ dysfunction had end-stage renal disease, a history of recent myocardial infarction or cerebral infarction, liver cirrhosis or atrial fibrillation. The patient with a high ASA score (4 points) had Parkinson\'s disease. Of the 6 patients who were excluded intraoperatively, 5 had combined surgery of other organs and 1 had damage to another organ. In cases with combined surgery, 4 had colon resection and 1 had combined distal pancreatectomy. The patient with organ damage experienced intestinal damage during adhesiolysis. For the 3 patients excluded postoperatively, two had re-operations due to postoperative bleeding and one had postoperative spleen infarction. As a result, 88 patients (85.4%) were chosen for the study. As noted before, 1 gram of cefoxitin was administered every 8 hours postoperatively for 24 hours. Eleven patients had antibiotics therapy restarted after the initial 24 hours. Of these 11 patients, 3 had fever of unknown origin for over 2 days, 1 had phlebitis, 1 had pneumonia, 3 had incisional deep infection of the fascia and muscles, 2 had anastomosis leakage and 1 had persistent ileus. A possible cause of fever for the 3 patients who had fever for over 2 days was atelectasis, so chest radiographs were taken. Chest radiographs and physical examination did not show any findings suggestive of atelectasis. The 3 patients were thoroughly evaluated for other possible reasons, but no origin was found. In all 3 cases, the fever spontaneously subsided between postoperative day 3 and 4. Seventy seven of the 88 (87.5%) subjects did not require further antibiotics therapy ([Fig. 1](#F1){ref-type="fig"}). The 88 subjects were classified by age, gender, the BMI, the complications, the extent of gastric resection, combined surgery, the extent of lymph node dissection and the operation time. The presence of SSI and fever after postoperative 2 days was assessed ([Table 1](#T1){ref-type="table"}). Of the 88 subjects, 18 were over the age of 70, and 70 were under the age of 70. In the over 70 group, there were 3 cases of SSI (16.7%), and there were 8 cases of SSI (11.4%) in the under 70 group. There were higher rates of SSI in the older group, but these results were statistically insignificant (P=0.689). Fifty six subjects had D2 dissection performed, and 32 subjects had D1+β dissection performed. Seven cases had SSI (12.5%) in the D2 dissection group, and 1 case had SSI in the D1+β group (3.1%). There were higher SSI rates with wider node dissection, but the difference between the 2 groups for SSI was statistically insignificant (P=0.503). Of the 88 subjects, 70 subjects had an operation time under 180 minutes and 18 patients had an operation time over 180 minutes. In the over 180 minute group, 5 patients (27.8%) had fever, and 6 patients (8.6%) in the under 180 minute group had fever. These results were statistically significant (P=0.043), and they showed that the subjects with a longer operation time had a higher rate of fever. Discussion ========== The SSI is an important complication after surgery. As the importance of patient factors related to SSI has recently come to light, there have been trials of individualized postoperative antibiotic therapy according to certain patient factors.([@B14]-[@B17]) Maintaining a normal body temperature before and after surgery, and providing a FiO~2~ over 80% in the operating room and the recovery unit have proven to increase the O~2~ saturation in the operation wound and to improve the WBC function, and so this decreases the rate of SSI. Also, previous studies have shown that controlling the blood glucose levels, regardless of a previous history of DM, decreases SSI and other surgical complications.([@B15]-[@B17]) It has been proven that prophylactic antibiotics are also effective for preventing SSIs.([@B18]) The use of prophylactic antibiotics is already widely acknowledged and this is being commonly practiced, but the route of administration, the duration of therapy and many other factors such as the site and method of surgery, the patient age, the operation time and the degree of intraoperative contamination must be considered when choosing the type of antibiotics. Antibiotic therapy given in accordance with various patient factors may have a result that greatly differs from that of the antibiotic therapy that is given without considering the patient. In this study, all the patients had pathologically confirmed stomach cancer, and they all underwent gastrectomy. The operation wounds of gastrectomies are considered clean-uncontaminated wounds, and all these patients require prophylactic antibiotics. We found that of the 88 subjects, 77 subjects did not require additional antibiotic therapy after 1 postoperative day, and this confirms the rationality of short-term prophylactic antibiotic therapy. Also, when analyzing the patients who required additional antibiotics after the initial 24 hours, we found that patients who had received longer operations showed fever after the postoperative second day. Also, older patients and patients who had received wider node dissection tended to have fever, but these properties did not show statistical significance. At the beginning of the study, we started with an exclusion criteria. These criteria were based on exclusion criteria commonly used for other types of surgery. As for the intraoperative criteria, we feared that prospectively enrolling patients who may be potential candidates of grave co-morbidities may have negative results. Among the 11 patients who required additional antibiotics, 3 patients had unexplained fever for over 2 days. As discussed earlier, all 3 patients were evaluated for possible causes of postop fever, but no origin was documented. In these cases the antibiotics were restarted to avoid possible aggravation of hidden causes. Whether unexplained fever warrants long term antibiotics is arguable. A limitation of this study is the one-armed study design. Before initiation of the study, our institution, like many others in Korea, administered prophylactic antibiotics quite empirically. Although this study lacks control group data (data of patients who received long term antibiotics), overall results show no significant discrepancies with the results of our previous patients, who had received long term antibiotics (data not shown). After confirming the feasibility of short term prophylactic antibiotics, we have started following the short term principle. Also, the choice of antibiotics is a limitation. For gastric cancer surgery, 1^st^ generation cephalosporin is sufficient.([@B19]) Before this study, we administered 2^nd^ generation cephalosporin as prophylactic antibiotics. In controlling the parameter of administration duration, we decided to lessen a variable by continuing the 2^nd^ generation cephalosporins. Feasibility of short term antibiotics with the recommended 1^st^ generation cephalosporins is unevaluated in this study. Despite the problems of long term antibiotics use discussed earlier, unwarranted long-term use is still very common. There are several factors that cause unnecessary long term antibiotics usage. This may be the result of a lack of an organized system for guiding prophylactic antibiotics administration. When there is no clinical pathway that guides the doctor when administering specific antibiotics for specific types of surgery, the antibiotic therapy is at risk of being changed on a case-by-case basis and at the whim of the ordering physician. Previous studies have shown that long term antibiotics use is largely the result of the uninformed orders given by residents or interns, and this in turn is the result of improper education.([@B20]) In 2005, the SIPP (Surgical Infection Prevention Project) was launched in the U.S. to lower the rate of SSI. The preliminary research has shown that during 32,000 cases of surgery, only in 55.7% of the cases were the prophylactic antibiotics given within 1 hour of the first incision. Based on these findings, an education program lasting about one year was started in over 50 centers, and the SSI rates were lowered by about 27%.([@B19],[@B21]) This shows that if the ordering doctor does not have accurate information on prophylactic antibiotics, then the preventable SSIs may not be prevented. To overcome these shortcomings, the duration of antibiotic therapy has recently become one of the factors for judging the quality of medical service in Korea. Many centers are also making guidelines and recommendations regarding antibiotics administration. As proven in this study, when the appropriate subjects are chosen, short-term prophylactic antibiotic therapy may reduce the adverse effects of long term antibiotics use and it may effectively prevent SSI. In conclusion, short-term prophylactic antibiotics therapy is effective when performing stomach cancer surgery, in cases without grave comorbidities or significant combined resection. The feasibility of short-term antibiotics when 1^st^ generation cephalosporins are used warrants further study. ![Inclusion criteria and exclusion critera. 103 patients had curative gastrectomy performed. 15 patients were excluded and 88 patients were chosen. 11 patients had antibiotics therapy restarted after the initial 24 hours. 78 patients did not need additional antibiotics therapy until discharge.](jgc-10-206-g001){#F1} ###### Results of analyzing the 88 patients who were injected with short term prophylactic antibiotics ![](jgc-10-206-i001) N = number; BMI = body mass index; LN = lymph node.
3D is the next step for TV and Spanish satellite operator Hispasat does not want to be left behind. The company has begun to test the technology through taking part in the project “3DLive". In this project the participants study and define the new broadcasting services of 3D via satellite. The project also analyzes the problems in relation to the new technologies of compression and image transmission in 3D by means of different types of networks (satellite, IPTV, etc.). “3Dlive” is co-financed by Spain's Ministry of Industry, Tourism and Commerce within the 'Plan Avanza I+D' for the Information Society. The project is being coordinated by the country's main telco Telefónica. The participation of the country's satellite operator means the beginning of new investigation lines for new services such as digital cinema in 3D and the reception of 3D TV in homes. In the frame of the DVB group Hispasat is part of a working group recently created to follow the evolution and developments in relation to this new TV format.
Q: which is best from this xml or json to use in web application all the devices I want to know that which technology is best use in web application desktop, mobile etc from this xml or json A: In my opinion JSON is easier to parse on the client (Javascript), and more concise (smaller size) so unless you really need to output XML for legacy reasons, go with JSON. (The question does not provide a lot of context so the answer's general too!)
A 3D/VR Bitcoin Blockchain Browser - gfredtech http://blockchain3d.info ====== johnhenry Back in the early 2000s there was a "3D" browser where you got to surf the web as a little man in a space suit who navigates by running along a road with while pages fly by the sky. If I had a faster computer and connection at the time, it might have been fun, but the UI seemed fundamentally detrimental to navigating the internet. Similarly, this is fun, but I would love to see a detailed write up on how this is used and what we can do with this representation that we cannot with others. Also, any chance you remember the name of that browser?
SAN FRANCISCO -- Marquese Chriss has been living in basketball purgatory over the last week after being waived by the Warriors for salary-cap purposes. Now, after signing a two-way contract to rejoin Golden State, Chriss is excited to be back with the team. "It feels good," Chriss said Thursday afternoon. "I feel welcomed, I feel wanted and I think being able to jump right into the flow of things is good for me." Under his current deal, Chriss will have 24 available days in the NBA. To maximize his time on the roster, the Warriors will hold him out of most practices, leaving him to work out on his own to stay in shape. Chriss' release last week was a result of Golden State's hard cap. Despite averaging 7.4 points and 5.4 rebounds in 37 games, he had the only non-guaranteed deal on the roster. With the Warriors up against the cap, coupled with the rise of guard Damion Lee, Golden State was forced to waive the big man hours before the Jan. 7 deadline to guarantee his deal. However, as teammates said their goodbyes, a message reverberated throughout the locker room: "If Marquese clears waivers, he'll be back." That optimism came true Wednesday afternoon when Chriss signed a two-way contract with the Dubs after clearing waivers, bringing the two sides back together. "I knew personally I wanted to be here but logistically I didn't know how it would work out, if it would even be possible," Chriss said. "So thankfully I am here, things worked out the way they were supposed to." Last fall, Chriss joined the team as a reclamation project, battling a rep of immaturity along the way. During his brief stint in Golden State, he has been seen as a model teammate, garnering praise from those around him. "Marquese has been in some tough situations and nobody ever wants to say ‘that wasn’t the right fit for a young guy,'" Warriors forward Draymond Green said. "It's always 'that young guy doesn't work for [us], he's not good enough to be in the league and that's that.'" [RELATED: Report: T-Wolves intensifying pursuit of trading for D-Lo] While Chriss is under a two-way deal, the Warriors are open to keeping the forward long term, which the forward said he'd be open to. "I hope so, I would love to be here," he said. "That's the plan. I would love to be here to spend a lot of time here creating a memory of myself in this organization and I'd love to be a part of what we're continuing to build so that's the end goal."
A A Over the past year, there has been renewed conversation about the possibility of bringing a Canadian Football League franchise to Atlantic Canada. You’ve likely seen the news coverage, or discussed this topic with your friends and family. Maybe you’ve even met with us. It’s time we introduced ourselves more broadly. We are Maritime Football Limited Partnership and we’re hoping to capitalize on the enthusiasm and momentum in the region to land a CFL franchise on the East Coast. We are an ownership group of three individuals – Anthony LeBlanc, the former owner and CEO of an NHL franchise with roots in New Brunswick; Bruce Bowser, a national business owner from Dartmouth; and Gary Drummond, an entrepreneur and former NHL owner and executive from Western Canada. This group has ownership experience and is connected to professionals in the sports and entertainment space, and specialists in the area of development and stadium construction. With the support of Atlantic Canadian advisers and our growing network in the region, we have been developing a plan and concept for both a team and multi-use stadium that Atlantic Canadians can truly be proud of. As Canada’s national league, the CFL aspires to establish franchises and build their brand from coast to coast. We’ve been working closely with the CFL and they tell us players want to play in Atlantic Canada, and beyond that, fans want the league to continue to grow and expand east. Grey Cup playoffs will grow to include an even number of teams, and CFL fans from across the country will have an opportunity to experience the enthusiasm and famous hospitality this region has to offer. Atlantic Canada will finally have an opportunity to be part of this annual national tradition. But in order to make this vision a reality, we need a stadium. A stadium is about more than football. It has to be. This can be an asset for Nova Scotia to leverage — to attract people and sustainable private investment; an entertainment venue; a training and research facility; and an anchor for international games and sporting events. Professional sports can be a catalyst for both economic growth and civic pride. Maritime Football Limited Partnership will be contributing significant private capital to help fund the construction and operation of the stadium. But let’s be clear: to make this vision a reality, a certain degree of public investment will be necessary. We’re learning about the challenges and opportunities for both Halifax Regional Municipality and the provincial government — and how this vision could align with their priorities and fit within planning frameworks. We’ve explored the desire of Atlantic Canadians to attend games and we’ve studied the proposed economic impact of a CFL franchise on the Nova Scotia economy. We’ve gleaned valuable information from the experiences of other jurisdictions. This is a big undertaking and there’s more work to do. We know we need to be thoughtful, we need to be deliberate, and most importantly, we need to be transparent. We will be providing regular updates and encouraging you to engage with us and share your questions and thoughts. Your feedback and participation throughout this process will be invaluable. Please follow us on Twitter (@MaritimeFtball) and sign up on our website to receive updates: www.maritimefootball.ca RELATED: CFL investors reveal preferred Halifax site, public funding ask
"NAKED VIOLENCE" "We picked them all up from their homes or the bars they hang out in." "We even checked the victim's register and they were the ones present." "The caretaker says she saw them all come and go." "She says she always counts them." "I'll show them to you now." "Correct me if I get it wrong, miss." "It seems to have appeared in the classroom." "Someone must have brought it in for a laugh." "A sip here and a sip there, they lost control and then we know what happened." "Latescent aniseed is the strongest liquor in the world." "85%!" "Therefore, if a kid touches a drop, he's drunk." "Even a hardened drinker would get drunk on just one sip." "Yes, it's true." "This strong alcohol... causes powerful psychic erythrism." "It burns your nervous system and takes you towards the world of violence and madness." "They forced me to go there, I've never found out why." " Isn't that right?" " Alright, good kid." "Will you tell the judge I'm a good kid?" "POLICE HEADQUARTERS" "Don't you want to know who pushed them to do it?" "No, I don't care." "I have more important matters to see to." "Everyday there's robberies, murders, more urgent matters." "All cases are the same, if they're unresolved." "Those kids..." "If one of them is the culprit, it'll come out in the trial." "Months will go by before the trial, they'll talk." "The only thing that's sure is that the teacher was tortured then murdered." "We've done our job, the culprits have been locked up." " He mentioned a woman." " I can't keep them here anymore." "Told you about a woman to get out of his cell, a kid who's told lots of lies in his life..." "That's not why." "They could have arranged that sex party anywhere in Milan without getting caught." "Such a monster can't be allowed to be free!" " If there is someone." " There is." "You have no proof." "They're blaming each other, that's proof." "It was even before Grassi mentioned it, now, with his confession, we've got even more to go on." "Let me look for this woman." ""CESARE BECCARIA, HOME FOR YOUNG OFFENDERS"" "See you tomorrow, or tonight, if anything comes up." "Photos of Carolino are circulating and there are road blocks everywhere." "Go on, say it:" ""He can't have gone far."" "Listen..." " Stay here the night." " Won't you be able to sleep?" "I'd like our first time together to be different." "It's fine this way." "How can I help him?" "When Carolino went up, they must have realized the police were there." "He probably took him to a secluded place." "He can't have gone far, he knows about the roadblocks." "He'll have taken him to a secluded place and he'll kill him." "If he could, he'd kill all of them." "He knows that when the others find out about Carolino, they won't say a word." "Do you think Carolina's still alive?" "THE END"
Supremacism Supremacism is an ideology which holds that a certain class of people is superior to others, and that they should dominate, control, and subjugate others, or are entitled to do so. The supposed superior people can be an age, race (classification of human beings) species, ethnicity, religion, gender, sexuality, language, social class, ideology, nation, or culture, or any other part of a population. Sexism Some feminist theorists have argued that in patriarchy, a standard of male supremacism is enforced through a variety of cultural, political, and interpersonal strategies. Since the 19th century there have been a number of feminist movements opposed to male supremacism, usually aimed at achieving equal legal rights and protections for women in all cultural, political and interpersonal relations. Racism Centuries of European colonialism in the Americas, Africa, Australia, Oceania, and Asia were justified by white supremacist attitudes. During the 19th century, the phrase "The White Man's Burden", referring to the thought that whites have the obligation to make the societies of the other peoples more 'civilized', was widely used to justify imperialist policy as a noble enterprise. Thomas Carlyle, known for his historical account of the French Revolution, The French Revolution: A History, which inspired Charles Dickens' novel A Tale of Two Cities, argued that European supremacist policies were justified on the grounds that they provided the greatest benefit to "inferior" native peoples. However, even at the time of its publication in 1849, Carlyle's main work on the subject, the Occasional Discourse on the Negro Question, was received poorly by his contemporaries. Before the outbreak of the American Civil War, the Confederate States of America was founded with a constitution that contained clauses which restricted the government's ability to limit or interfere with the institution of "negro" slavery. In the Cornerstone Speech, Confederate vice president Alexander Stephens declared that one of the Confederacy's foundational tenets was white supremacy over black slaves. Following the war, a secret society, the Ku Klux Klan, was formed in the South. Its purpose was to "restore" white supremacy after the Reconstruction period, even though there still was white, Protestant supremacy in the United States, at the time. The group preached supremacy over all other races, as well as supremacy over Jews, Catholics, and other minorities. According to William Nichols, religious antisemitism can be distinguished from modern antisemitism which is based on racial or ethnic grounds. "The dividing line was the possibility of effective conversion ... a Jew ceased to be a Jew upon baptism." However, with racial antisemitism, "Now the assimilated Jew was still a Jew, even after baptism ... . From the Enlightenment onward, it is no longer possible to draw clear lines of distinction between religious and racial forms of hostility towards Jews... Once Jews have been emancipated and secular thinking makes its appearance, without leaving behind the old Christian hostility towards Jews, the new term antisemitism becomes almost unavoidable, even before explicitly racist doctrines appear." One of the first typologies which was used to classify various human races was invented by Georges Vacher de Lapouge (1854–1936), a theoretician of eugenics, who published in 1899 L'Aryen et son rôle social (1899 – "The Aryan and his social role"). In this book, he classifies humanity into various, hierarchized races, spanning from the "Aryan white race, dolichocephalic", to the "brachycephalic", "mediocre and inert" race, best represented by Southern European, Catholic peasants". Between these, Vacher de Lapouge identified the "Homo europaeus" (Teutonic, Protestant, etc.), the "Homo alpinus" (Auvergnat, Turkish, etc.), and finally the "Homo mediterraneus" (Neapolitan, Andalus, etc.) Jews were brachycephalic like the Aryans, according to Lapouge; but exactly for this reason he considered them dangerous; they were the only group, he thought, which was threatening to displace the Aryan aristocracy. Vacher de Lapouge became one of the leading inspirations of Nazi antisemitism and Nazi racist ideology. The Anti-Defamation League and Southern Poverty Law Center condemn writings about "Jewish Supremacism" by Holocaust-denier, former Grand Wizard of the KKK, and conspiracy theorist David Duke as antisemitic – in particular, his book Jewish Supremacism: My Awakening to the Jewish Question. Kevin B. MacDonald, known for his theory of Judaism as a "group evolutionary strategy", has also been accused by the ADL and his own university psychology department of being "antisemitic" and white supremacist in his writings on the subject. Cornel West, an African-American philosopher, writes that Black supremacist religious views arose in America as part of black Muslim theology in response to white supremacism. In Africa, black Southern Sudanese allege that they are subjected to a racist form of Arab supremacy, which they equate with the historic white supremacism of South African apartheid. The alleged genocide and ethnic cleansing in the ongoing War in Darfur has been described as an example of Arab racism. For example, in their analysis of the sources of the conflict, Julie Flint and Alex de Waal say that Colonel Gaddafi, the leader of Libya, sponsored "Arab supremacism" across the Sahara during the 1970s. Gaddafi supported the "Islamic Legion" and the Sudanese opposition "National Front, including the Muslim Brothers and the Ansar, the Umma Party's military wing." Gaddafi tried to use such forces to annex Chad from 1979-81. Gaddafi supported the Sudanese government's war in the South during the early 1980s, and in return he was allowed to use the Darfur region as a "back door to Chad." As a result, the first signs of an "Arab racist political platform" appeared in Darfur in the early 1980s. In Asia, ancient Indians considered all foreigners barbarians. The Muslim scholar Al-Biruni wrote that the Indians called foreigners impure. A few centuries later, Dubois observes that "Hindus look upon Europeans as barbarians totally ignorant of all principles of honour and good breeding... In the eyes of a Hindu, a Pariah (outcaste) and a European are on the same level." The Chinese viewed the Europeans as repulsive, ghost-like creatures, and even as devils. Chinese writers also referred to the Europeans as barbarians. Germany From 1933 to 1945, Nazi Germany, under the rule of Adolf Hitler, promoted the idea of a superior, Aryan Herrenvolk, or master race. The state's propaganda advocated the belief that Germanic peoples, whom they called "Aryans", were a master race or a Herrenvolk that was superior to the Jews, Slavs, and Romani people, so-called "gypsies". Arthur de Gobineau, a French racial theorist and aristocrat, blamed the fall of the ancien régime in France on racial intermixing, which he argued had destroyed the purity of the Nordic race. Gobineau's theories, which attracted a strong following in Germany, emphasized the existence of an irreconcilable polarity between Aryan and Jewish cultures. Fundamentalism Christian Academics Carol Lansing and Edward D. English claim that Christian supremacism was a motivation for the Crusades in the Holy Land, as well as crusades against Muslims and pagans throughout Europe. The blood libel is a widespread European conspiracy theory which led to centuries of pogroms and massacres of European Jewish minorities because it alleged that Jews required the pure blood of a Christian child in order to make matzah for Passover; Thomas of Cantimpré writes of the blood curse which the Jews put upon themselves and all of their generations at the court of Pontius Pilate where Jesus was handed a death sentence: "A very learned Jew, who in our day has been converted to the (Christian) faith, informs us that one enjoying the reputation of a prophet among them, toward the close of his life, made the following prediction: 'Be assured that relief from this secret ailment, to which you are exposed, can only be obtained through Christian blood ("solo sanguine Christiano")." The Atlantic slave trade has also been partially attributed to Christian supremacism. The Ku Klux Klan has been described as a white supremacist Christian organization, as are many other white supremacist groups, such as the Posse Comitatus and the Christian Identity and Positive Christianity movements. Islamic Academics Khaled Abou El Fadl, Ian Lague, and Joshua Cone allege instances of Muslim or Islamic supremacism but they also note that the Qur'an and other Islamic documents always speak of tolerant, protective beliefs, which have been misused, misquoted, and misinterpreted by both Islamic extremists and Islamophobes. Examples of how supremacists have interpreted Islam include the Muslim participation in the African slave trade, the early-20th-century pan-Islamism promoted by Abdul Hamid II, the jizya and rules of marriage in Muslim countries being imposed on non-Muslims, the majority Muslim interpretations of the rules of pluralism in Malaysia, and "defensive" supremacism practiced by some Muslim immigrants in Europe. According to founder of the Muslim Brotherhood, Hassan al-Banna, “it is the nature of Islam to dominate, not to be dominated, to impose its law on all nations and to extend its power to the entire planet”. According to scholar Bernard Lewis, Classical Islamic jurisprudence imposes an open-ended duty on Muslims to expand Muslim rule and Islamic law to all non-Muslims throughout the world. William Kilpatrick in his book The Politically Incorrect Guide to Jihad posits that Islam, unlike other religions, positively commands its adherents to impose its religious law on all peoples, believers and unbelievers alike, whenever possible and by any means necessary. Despite being comparatively more tolerant than Christian Europe there were numerous incidents of massacres and ethnic cleansing of Jews and Christians in North Africa, especially in Morocco, Libya and Algeria where eventually Jews were forced to live in ghettos. Decrees ordering the destruction of synagogues were enacted during the Middle Ages in Egypt, Syria, Iraq and Yemen. At certain times in Yemen, Morocco and Baghdad, Jews were forced to convert to Islam or face death. While there were antisemitic incidents before the 20th century, antisemitism increased dramatically as a result of the Arab–Israeli conflict. After the 1948 Arab–Israeli War, the Palestinian exodus, the creation of the state of Israel and Israeli victories during the wars of 1956 and 1967 were a severe humiliation to Israel's opponents—primarily Egypt, Syria and Iraq. However, by the mid-1970s the vast majority of Jews had left Muslim-majority countries, moving primarily to Israel, France and the United States. The reasons for the exodus are varied and disputed. Jewish Ilan Pappé, an expatriate Israeli historian, writes that the First Aliyah to Israel "established a society based on Jewish supremacy". Joseph Massad, a Professor of Arab Studies, holds that "Jewish supremacism" has always been a "dominating principle" in religious and secular Zionism. Zionism was established with the political goal of creating a sovereign Jewish state where Jews could be the majority, rather than the minority which they were in all nations of the world at that time. Theodor Herzl, the ideological father of Zionism, considered Antisemitism to be an eternal feature of all societies in which Jews lived as minorities, and as a result, he believed that only a separation could allow Jews to escape eternal persecution. "Let them give us sovereignty over a piece of the Earth's surface, just sufficient for the needs of our people, then we will do the rest!" See also Notes Category:Discrimination Category:Ethnic supremacy Category:Fanaticism Category:Narcissism Category:Political theories Category:Prejudices Category:Racism
Exploring land recently released by ice (geologically speaking) Category Archives: Nature Without snowshoes I’d soon wear myself out walking over this field of new snow. Even with them it is a job reaching a place that offers a nice view of the glacier reflected in a partially frozen eddy. No little dog follows behind. She waits on the beaten path giving me her “are you crazy” look. Is she wise or lazy? It could be either given her age of eleven and a half years. She didn’t act her age as she leapt the car and galloped down the trail. When I caught with her, she was rolling on her back, a look of bliss showing on her snow-covered face. Yesterday’s storm added five inches of snow to that already coating the trailside trees and the ground. The added weight forced the alders over the trail where they form temporary barriers to me but not the low-slung Aki. The sun floats like a pearly disk in a flat gray sky and then muscles through briefly to throw cast shadows in the woods. We are alone on the moraine, having missing the morning rush of dog walkers who level the snowy trail for Aki. She sniffs the tracks left last night by the local beavers but we see no other sign of wildlife. The recent cold snap has all but silenced the river. There should be black-capped chickadees or juncos hunting for food but I hear nothing but faint airplane noise and the scraping of Aki’s paws as she digs in the new snow. Aki growls her way down our home street. I look around and can find no dog close enough to hear her trash talk. Then a furry black blur tears past us, gives Aki a ferocious snarl and ducks down a set of stairs. My little dog continues on, pulling like a sled dog down the street. I have to do a shuffle-slide to keep from falling. I wonder if the snow is energizing her. Quarter-sizes flakes drift down on us, melting on Aki’s back as soon as they touch it. It accumulates on the leafless limbs of alders and cottonwoods, making each tree look like an Escher print. We power up Gastineau Avenue, passing the owners of a jeep being helped by two garbage truck guys to free it from a snow bank. Further along the avenue an unkindness of ravens forms around an abandoned package of meat. One sits nearby on a sidewalk railing, plucking snowflakes out of the air with its beak. Over on Sixth Street the faces on a totem pole have new, white beards. Aki slips on the icy trail that hugs an oxbow curve of the Mendenhall River. The little dog barely notices her misstep. She is too interested in the scents left behind on this heavy-use dog-walking trail. The dogs that scented the trail have all gone. If not for the shouts of men tending the salmon smolt pens and the airplane noise, we might have some solitude. I am drawn to this trail on calm, sunny days when, as now, the river is at flood tide. Hungry seals might pop up at any time. Ducks could land any second. I look and find the great blue heron along the river shore. At first it stands tall and then curls back it’s long neck into a heat-conserving crouch. Backlit by the morning sun, it is only a black silhouette on the snowy beach. Last night’s hard freeze has preserved the prints of boots and paws left during yesterday’s thaw. Aki is light enough to trot across the crust without breaking through. But for me, it’s “crunch, crunch, crunch” or slip, slip, slip. The tide forces the river into low spots on the trail. We would be blocked by one if it not for a homespun bridge fashioned from driftwood. I use it to make a successful crossing but Aki stays put. I have to re-cross, pick up the little poodle-mix, and carry her across. We drop down to the river’s edge so I can enjoy views of the glacier and mountains reflected in the water. Aki is not impressed. We must be beyond the prime dog use area. After I carry her back across the little driftwood bridge, she dashes back the way we came. Aki shows more enthusiasm for this adventure than I feel as we leave the trailhead. Snow is turning to rain as the little dog and I head into the Treadwell woods. Aki minces down the trail, each step pushing through soaked snow to a thin layer of water beneath. Glad I am wearing waterproof boots, I slosh along behind her. The poodle-mix dashes toward a urine-yellow Rorschach design in the snow left by the dog of an early morning walker. Similar splotches mark the way to the beach. We slog past roofless ruins and twisted rails of the mining car tracks, all made almost beautiful by mantles of fresh snow. White on rust makes a pleasing combination. From its perch atop the old ventilation tower, our resident eagle watches us leave the woods and move onto the snow-covered beach. His puffed up chest feathers make me think of Buck Mulligan descending Joyce’s Dublin tower. Aki cares little for literary references so I don’t mention it to her. When a golden lab approaches, Aki waits in silence rather than barking her usual welcome. You are learning some caution little dog. The meeting goes well and she acts more like her old self when we meet a black-husky-mix. Maybe you are learning to discern rather than to trust that all dogs are potential friends. After the husky-mix follows its people into the woods, Aki and I have the beach to ourselves. The two ravens that usually greet us have flown. No belted kingfisher chits at us from an overhanging branch. No wind hurries away the loose pans of ice that float around the ruined wharf pilings. If I turn around I could see trucks being loaded at the barge dock across Gastineau Channel and the blocky shapes of the Juneau skyline. But ahead to the south there is only the white-covered beach dotted with broken pilings, Gastineau Channel, and glaciated mountains partially obscured by mist. We move south until we run out of beach. Yesterday the weather service promised that a foot of new snow would fall today. But sometime during the night moist air from the Pacific pushed up the temperature to above freezing. It’s snowing now but rain is not far away—rain that will soften the lake ice and wash away the snow we have been enjoying for the past few weeks. There is only one thing for a little dog and her people to do—try to sneak in one more ski adventure. We drive out to Mendenhall Lake and park near Skater’s Cabin, which is across the lake from the glacier and its mountain consorts. Low clouds dump snow on the lake and obscure the view of anything more than a kilometer away. The resulting flat light would make it hard for us to see the trail, which is already filling in with soft, wet snow. We opt to ski through the campground. This pleases Aki because it is a popular dog use area. On a downhill section of the trail, Aki flies by me as she follows her other human. In seconds they are out of sight. I see them again after I round a turn and begin a gentle uphill climb. At the top I learn from Aki’s other human that a goshawk had just flown low across the trail in front of them. Last winter Aki and I had watched a goshawk rip off strips of flesh from a snowshoe hare. I wonder if Aki just saw the bid bird again. I also wonder why the goshawk flew in front of them instead of me. On the Kuskokwim, where we once lived, the elders preached that the second boat always gets the moose. Moose and other animals will often stay hidden in the woods while the first boat or skier passes by. They can often be caught on the trail by a person dawdling along behind. Most of the time the elders are right. I see a lot while dawdling. Aki has me worried. I’m pulling on my boots near the front door. Normally my little dog would be here, waiting for me to fasten on her harness. Is she worried that a dog will go after here on today’s walk. She appears, tail wagging, when I slip on a warm parka. Relieved, I drive us north on the Douglas Highway, which offers filtered views of Gastineau Channel. Aki groans when I stop the car to watch pans of new ice riding the incoming tide up channel. The poodle-mix jumps out of the car when we reach the trailhead and trots down to the beaver pond. This time she freely follows me onto the ice and even dashes ahead after I cross the pond and start up a muskeg stream. There is nothing unusual about the scenery. The stream leads us onto a muskeg meadow dotted with small bull pines. We could be on any one of a dozen such meadows. But this one is unreachable until the pond and stream freeze over. In a month, or even a week, the ice will melt, closing off access to the meadow. While Aki catalogues the smells, I take off my hat and listen. It’s all silence at first and then, from far off float the working songs of wrens and ravens. This is not Aki’s favorite type of adventure. Few dog walkers use the trail so she finds little scent to sniff. But I am ready for some solitude and a chance to use my skis as exploring tools, not sport’s equipment. From my point of view, we have been spending way too much time lately on the Mendenhall Lake ski tracks. My little dog had treasured every moment of it. I slide my skis across Peterson Creek and around a salt chuck (lake) to the small waterfall that drains it. To conserve energy, Aki trots in my tracks, darting ahead only once when she spots movement in the spruce forest that borders the salt chuck. It’s probably one of the many otters that den nearby. Careful not to break through the thin ice covering the waterfall, I lead Aki around a rocky headland to where we can see Lynn Canal. It is empty except for a single golden eye duck, which gives me a hard look before flipping into the water. After crossing into the forest and over a frosty meadow Aki and I watch a skier being pulled up Peterson Creek by two husky dogs. Aki makes a half-hearted dashed toward the trio but is soon stopped by deep snow. We drop down onto the creek and head for the car and are halfway there when the huskies approach from behind. Aki turns back to bark hello. One of the huskies clamps her in his jaws and then quickly lets go. Aki howls an alarm and runs back to me. Now she is asleep in her house with nothing wounded but her pride.
Popular The Pasir Ris-Punggol cycling trail would be familiar to cyclists living in the two districts. However, it can be a pretty remote trail to find if you live in the Pasir Ris end and do not know it. If you're cycling in the nighttime, it's best to equip yourself with a strong bike head lamp as it can get pretty dark on certain parts of the trail.
Q: How to insert a new node to a single-linked list, where we do not have a pointer pointed to its head? Given a pointer that points to an intermediate node (non-head, non-tail) on a single-link list . How to insert a new node just before the node pointed to by the given pointer ? Example, Given single-linked list: A -> B -> C -> D -> E Given a pointer pointed to C (ptr = &C), and a new node F, how to get A -> B -> F -> C -> D -> E Attention: we do not have pointers pointed to A. Thanks A: You should be able to implement this by inserting a new C node to the right, and writing F in the data field of the initial C node. A: Obviously, It can't be done. If you need that capability, use a doubly-linked list. Otherwise, always pass along a pointer to the head of the list.
Q: How to print out the cookie value in HTML? I am working on a website for number guessing. The overview of the website is shown as follows: enter image description here In setCookiesA.php, there are two cookies called c(color) and maxNum(the maximum number of guesses) stored. After storing the cookies, player will be redirected to GuessingA.php. The code is shown as follows: <?php setCookie("c",$_GET["itemChosen"],time()+(86400 * 365), "/"); setCookie("maxNo",$_GET["noGuess"],time()+(86400 * 365), "/"); header("Location:GuessingA.php"); ?> After going to GuessingA.php, the cookie value color should be printed out in the sentence "You have chosen the ??? channel for guessing" (??? represents the color) The partially completed code is shown below. <?php session_start(); if (!isset($_SESSION["ans"])) { } else { } $continue = true; ?> <!DOCTYPE html> <html> <head> <title> Guessing game </title> </head> <body> <h1> Welcome </h1> <p> You have chosen the $_COOKIE[c] channel for guessing</p> <h2> The answer </h2> <form method="post" action="<?php print htmlspecialchars($_SERVER['PHP_SELF'])?>"> <p> Type your guess here: <input type="text" name="guess" /> <input type="submit" value="submit" <?php if (!$continue) { print("disabled=\"disabled\""); } ?> /> </p> </form> <h2> Your guess: </h2> </body> </html> I considered using javascript function found in google to get the cookie value, but it did not work. function readCookie(name) { var nameEQ = name + "="; var ca = document.cookie.split(';'); for(var i=0;i < ca.length;i++) { var c = ca[i]; while (c.charAt(0)==' ') c = c.substring(1,c.length); if (c.indexOf(nameEQ) == 0) return c.substring(nameEQ.length,c.length); } return null; } The function created by myself to print out the color in the body part. function change() { var color=readCookie(c); color.innerHTML="You have chosen the " +color+" channel for guessing"; } How to get the cookie value? Thank you very much. A: <p> You have chosen the $_COOKIE[c] channel for guessing</p> You are just writing text. There's no PHP code there. Look at what you did here: <form method="post" action="<?php print htmlspecialchars($_SERVER['PHP_SELF'])?>"> Do that! <p> You have chosen the <?php print htmlspecialchars($_COOKIE['c']); ?> channel for guessing</p>
Other Colours Details The STORM Arin is designed to take you from desk to dancefloor. This petite watch sits on a sleek mesh strap with an edge to edge red dial. In true STORM style it’s finished with Swarovski Crystals making it the perfect accessory all year round.
Product Description The EXFIL LTP™ is a Lightweight, Tactical, Polymer bump helmet. It offers a stable, comfortable platform for mounting night vision and other accessories while providing the best impact protection in the market. The built-in NVG shroud utilizes an integrated Wilcox® insert, machined from 6061-T6 aircraft aluminum billet, which dramatically improves durability over plastic shrouds while ensuring an extremely precise interface with NVG mounting arms. It features an innovative padding system developed exclusively for and optimized around the EXFIL helmet design, along with our CAM-FIT™ retention system that uses easily adjustable cam-lock sliders and a micro-adjustable Boa® dial.
What's the big deal? Page Tools John Garnaut cuts through the politics of the free trade agreement with the United States to find the winners and losers. Mark Vaile arrived in Washington in the aftermath of the Iraq war knowing that no American administration had ever owed so much to an Australian government. The Trade Minister planned to spend a week talking with America's Trade Representative, Bob Zoellick, and return home with an historic trade deal. What followed was a lesson in George Washington's "great rule" of international relations: political connections with foreign nations will be trumped by commerce. Vaile wanted to quickly end American protectionism on sugar, dairy and beef, in that order. These alone would account for the majority of benefits Australia might hope to gain from any bilateral trade deal with the United States. High on his list was for the US to push aside the Jones Act, a curious legal anachronism preventing foreign boats from navigating between any two American ports. It was this trade barrier that meant Tasmania's world class superferries could never find a market in the US. AdvertisementAdvertisement Vaile also wanted a commitment from Zoellick to relax work visa requirements for Australian accountants, engineers and other professionals (and their spouses), allowing them to effectively sell their services to the US. These five goals were all towards the top of Vaile's negotiating list. But after two exhausting weeks the Americans had hardly budged on any of it. Despite Vaile's scurrying between his Washington hotel and the Trade Representative's office, the to-do list was as long as when he had arrived. Importantly, Zoellick insisted on provisions involving the Pharmaceutical Benefits Scheme (PBS), local media content and quarantine - all of which Vaile had previously promised would not be affected by any trade agreement. But some Australians stood to benefit. It was a question of weighing competing interests. On February 8, after just 11 months of negotiations, the Prime Minister, John Howard, picked up the phone to George Bush and sealed the deal. HOWARD'S trade deal with the US split his negotiating team. It has since split farmers, business people, the Labor Party and the free trade community. Political commentators and editorial writers have lined up mainly in support, economics editors have mainly opposed. Business people have attacked public interest groups, economists have attacked each other's work, film stars have cried in front of politicians and the Government has been praised and pilloried from all directions. Howard says the deal will set Australia up for the next 50 years. One study, by the Centre for International Economics for the Department of Foreign Affairs and Trade, estimated the deal was likely to add $58 billion to the economy over 20 years, measured in today's dollars. A study by the National Institute of Economic and Industry Research, for the Australian Manufacturers Workers Union, found the deal was likely to reduce economic output by $47 billion over the same period. The distance between the two conclusions is a cool $105 billion - equivalent to the annual economic output of Queensland. Most independent economists, such as Philippa Dee, who recently left the Productivity Commission to join the Australian National University, estimate the economic reality to lie about halfway between the two. It may be instructive that the Government overlooked the commission when seeking experts to evaluate the deal. Ian Macfarlane, governor of the Reserve Bank, ducked a broad question about its worth at a parliamentary hearing in June. But when asked specifically about changes to investment laws, which the Centre for International Economics says would create most of the benefits from the deal, he said: "I do not know about these little movements at the margin." WHATEVER the economic and sovereignty concerns, debate is now shifting towards the larger political picture. "The nature of these agreements is more about building strategic relationships than the net dollar value," says Mark Thirlwell, program director for international economy at the Lowy Institute. If negotiating the bilateral deal has damaged Australia's multilateral trading credentials, as some economists argue, then that is a "sunk cost" which won't be made worse by going ahead with the agreement now. John Edwards, chief economist in Australia for investment bank HSBC, says ratifying the agreement could give Australia a seat at the table of any future Asia-Pacific trading bloc. "I do think there is a tidal wave of FTA deals within the region and we need to be part of this." But others, such as Dee, warn that the trade deal contains precedents on agriculture, rules of origin, intellectual property, media and pharmaceutical benefits that could make it more difficult for Australia to protect its interests in other forums. The Opposition Leader, Mark Latham, will decide, probably next week, whether the deal is to sink or survive. He could use economic and geo-political arguments to support a decision either way, or he could reject the deal for social policy reasons. However, influential Labor colleagues Stephen Conroy and Kim Beazley are pressuring him to defer instead to domestic politics and evade the anti-American tag that Howard has pinned to his chest so successfully.
1. ROS Involvement in Cell Pathophysiology {#sec1} ========================================== Oxidative stress is a molecular deregulation in reactive oxygen species (ROS) metabolism involved in the pathogenesis of several diseases. Oxidative stress is no longer considered as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production \[[@B1]\]. Reactive oxygen species such as superoxide, hydrogen peroxide, and peroxynitrite are generated by all mammalian cells and have been recognized for many decades as causing cell damage by oxidation and nitration of macromolecules, such as DNA, RNA, proteins, and lipids. Moreover, ROS can also promote cell signaling pathways modulated by growth factors and transcription factors, therefore regulating cell proliferation, differentiation, and apoptosis \[[@B2]\], which are important processes for proper cell functioning \[[@B3]\]. At physiological concentrations they facilitate the signal transduction derived from receptor tyrosine kinases and transcriptional factors such as NF-E2-related factor-2 (Nrf-2) leading to antioxidant gene expression \[[@B4]\]. The instability of an unpaired electron in its valence shell causes the high reactivity of superoxide. Superoxide has been implicated in numerous pathological processes, including cancer, cardiovascular disease (e.g., atherosclerosis and stroke), and acute and chronic diseases due to microbial infections. Superoxide can directly or indirectly damage DNA through oxidation \[[@B5]\], directly inactivate cellular antioxidants enzymes such as catalase and glutathione peroxidase \[[@B6]\], and activate proinflammatory nuclear factor jB (NF-jB) \[[@B7]\]. However, superoxide gives rise to other ROS that possess different redox chemistries, and, thus, different physiological and pathophysiological effects. For example, superoxide is rapidly reduced, both spontaneously and enzymatically, to H~2~O~2~. Unlike superoxide, H~2~O~2~ has no net charge; so, it is more lipid-soluble, with the potential to diffuse through organelles and cellular membranes reaching sites distant from its source. H~2~O~2~ modifies cellular proteins via oxidation of cysteine, methionine \[[@B8]\], and genetic material \[[@B9]\]. However, perhaps the major dangerous properties of H~2~O~2~ are in its ability to generate more reactive molecules. For instance, in the presence of transition metals, H~2~O~2~ can generate the highly reactive OH•. The OH• is highly reactive and will indiscriminately oxidize the nucleotides causing breaks and lesions of DNA \[for review see \[[@B10]\]\], which are processes involved in carcinogenesis. The oxidation of lipids by OH• may influence many physiological processes and contribute to cellular dysfunction, such as oxidation of lipids by peroxidation \[[@B11]\], during cardiovascular disease \[[@B12]\]. One of the most important and fast redox reactions in biology is between superoxide and the nitric oxide (NO) radical giving rise to ONOO^−^. ONOO^−^ is an oxidizing and nitrating molecule that has been implicated in cancer \[[@B13]\] and other acute \[[@B14]\] and chronic \[[@B15]\] diseases. ROS levels in tumor cells are controlled in a particular way, which stresses the importance of the development of novel ROS-targeted anticancer therapies. As with every mechanism involved in both normal cell function and the development of disease, strategies to counteract ROS must take into account their critical importance in the normal functioning of the organism \[[@B1]\]. Further understanding of the biological mechanisms among oxidative stress, tumor growth, and metastasis could contribute to the advancement of cancer treatment. For example, angiogenesis is another important factor for tumor growth and metastasis, and ROS has a key role in angiogenesis regulation \[[@B16]\]. After all, an emerging concept suggests that ROS modulate the immune cells functions that infiltrate the tumor environment and stimulate angiogenesis \[[@B2]\]. These oxidative processes have been implicated in many diseases in addition to cancer. Overproduction of ROS is involved in the development of a number of diseases, which range from neurological such as Parkinson\'s \[[@B17]\] and Alzheimer\'s disease \[[@B18]\], to psychiatric disorders such as schizophrenia \[[@B19]\] and bipolar disorder \[[@B20]\], and to a majority of cardiovascular diseases \[[@B21]\]. 2. NADPH Oxidases as ROS Sources {#sec2} ================================ Several enzymes produce ROS, including the mitochondrial electron transport chain, nitric oxide synthases (NOSs), cytochrome P450 reductase, and xanthine oxidase. However, for all of these systems, ROS production takes place as a byproduct of the main catalytic function of the enzyme/system or from a dysfunctional variant of the enzyme. In contrast, NADPH oxidases are the only enzymes whose primary function is to generate superoxide/ROS \[[@B2]\]. NOX family proteins are the catalytic, electrontransporting subunits of the NADPH oxidase enzyme complex. The NOX family consists of seven members, NOX1--5, and two dual oxidases (Duox), Duox1 and Duox2 ([Table 1](#tab1){ref-type="table"}). The NOX isoforms contain FAD and NADPH binding sites, two heme molecules and six transmembrane \[[@B22]\] spanning alpha helices with cytosolic N and C-termini. The Duox isoforms also contain the same domains; however, a seventh transmembrane domain and peroxidase homology are present. They are differentially expressed and regulated in various tissues and have different subcellular localizations (reviewed in \[[@B23]\]). NOX1, NOX2, and NOX5 appear to produce mainly superoxide NOX4, mainly H~2~O~2~ \[[@B24]\]. All NOX isoforms have been reported to bind to one or more additional components. p22phox appears to be a general binding partner for NOX1--4. NOX1 and 2 also bind the small GTPase, Rac. Moreover, NOX1 binds the cytosolic subunits, NOX organizer 1 (NOXO1), and NOX activator 1 (NOXA1). NOX2 binds the respective homologues, p47phox and p67phox, and also the cytosolic protein, p40phox \[[@B22], [@B25]\]. NOX4 was reported to bind to the polymerase (DNA-directed) delta-interacting protein 2 (PolDip2) \[[@B26]\]. In addition to these established NOX binding partners, the tyrosine kinase substrate with 4/5 SH3 domains (Tks4/5) \[[@B27]\] and protein disulfide isomerase (PDI) were recently suggested to bind to both NOX1 and 4 \[[@B28]\]. Two maturation factors specific for Duox (DuoxA1 and DuoxA2) have also been described \[[@B22]\]. NOX catalytic subunits are differently regulated: NOXA1 plays a key role for NOX1 activation \[[@B29]\], p67phox for NOX2 \[[@B30]\], and calmodulin for NOX5 \[[@B31]\]. In contrast, NOX4 is constitutively active, and modulation of its expression may thus be a major activity regulator. ROS produced by NOXs have been shown to affect all other possible sources of ROS, leading to their dysfunction and to a further increase in ROS generation, forming a vicious cycle of oxidative stress. For example, increased O~2~ ^•−^ generation by NADPH oxidase induces mitochondrial oxidative damage via structural changes to the inner mitochondrial membrane and disturbs flow in the electron transport chain which enhances ROS production \[[@B32]\]. 3. NOX and Pathophysiology {#sec3} ========================== The oxidant signaling involving NADPH oxidase has important roles in cell biology participating in intracellular signaling of cell differentiation and proliferation. These mechanisms are important in tissue repair and tumorigenesis, processes where cell proliferation occurs, but when poorly controlled the generation of ROS is dangerous. Indeed, NADPH oxidase-mediated cell proliferation has been observed in a wide range of cell types including those found in blood vessels, kidney, liver, skeletal muscle precursors, neonatal cardiac myocytes, lung epithelial cells, gastric mucosa, brain microglia, and a variety of cancer cells. For example, NOX may stimulate Akt activation also by inactivating the phosphatase PTEN, a direct negative regulator of the PI3K/Akt pathway \[[@B33]\]. Therefore, NADPH oxidase-mediated redox signaling may amplify diverse signaling pathways triggered in tissue repair processes such as cell proliferation, wound healing, angiogenesis, or fibrosis. Recent studies also suggest that NADPH oxidase is involved in differentiation and proliferation of stem cells. Currently, little is known about whether ROS regulate different signaling pathways in stem cells and differentiated cells and whether ROS play a different role in these cells \[[@B16]\]. Thus, modulating NADPH oxidase may have significant impacts on regenerative medicine and tissue engineering, such as growing heart muscle. At first, cellular stresses may induce NOX-dependent ROS generation as an alert system that drives the cells into a relatively stress-resistant status by integrating and amplifying the stress signals, as preconditioning against further cellular challenges \[[@B34]\]. The double-edged sword property of NOX adds another level of complexity for therapeutic targeting of this enzyme. The mechanisms of NOX-mediated redox signaling may be either enhancing stress resistance through prevention of ischemia-reperfusion injuries and accelerating wound healing, or avoiding the stress-induced cytotoxicity for iper-proliferative diseases, such as cancer. Therefore, a therapeutic modulation of NOX activity has to be developed taking in account the disease, the stage of disease, the tissue localization area, the NOX isoforms, and the NOX intracellular localization. 4. NOXs and Diseases {#sec4} ==================== NADPH oxidase has received much attention as a major cause of oxidative stress leading to vascular disease. Moreover different NOX subunits have been suggested to play a role in cancer, lung fibrosis, stroke, heart failure, diabetes, and neurodegenerative diseases \[[@B22]\]. NOX-derived ROS can lead to pathology through differential ways: for example, spatially confined levels of ROS that interfere with a particular signaling pathway, and high levels (local or systemic) that are directly cytotoxic, causing apoptosis, or disturbing redox-sensitive signaling cascades. 4.1. Vascular Diseases {#sec4.1} ---------------------- NADPH oxidases are ubiquitously expressed in tissues but are the major source of superoxide anions observed in the vasculature \[[@B1]\]. Thus, similarly to ROS, NOX proteins have both beneficial and harmful effects. They are important signaling molecules which regulate vascular tone, expression, proliferation, migration, and differentiation. On the other hand, cardiovascular risk factors and vascular diseases increase ROS and contribute to atherosclerosis, vascular dysfunction, hypertension, vascular hypertrophy, and thrombosis. With respect to low and spatially confined ROS overproduction, NOX1 is a good candidate to migrate into caveolae and there causes eNOS uncoupling and endothelial dysfunction, which is often associated with increased blood pressure and enhanced platelet aggregation as an early step in the development of atherosclerosis \[[@B35]\]. 4.2. Cancer {#sec4.2} ----------- NOX1, NOX2, and NOX4 are known to be expressed in multiple tumor cell types (see [Table 1](#tab1){ref-type="table"}). Tumor cells produce high amounts of ROS \[[@B36], [@B37]\] by NADPH oxidases to promote their own proliferation, through regulation of proliferative signaling kinases, such as cell survival factors, such as Akt and MEK-ERK pathway \[[@B38]\]. Recently, the role of cancer stem cells (CSCs) in cancer progression and metastasis has attracted much attention since CSCs are integral parts of pathophysiologic mechanisms of metastasis and chemo/radioresistance \[[@B16]\]. To date, molecular events that govern the survival and self-renewal of CSCs are poorly defined, but a link between ROS modulation and cancer stem cell metabolism seems to have a basis. Stem cells and also CSCs are known to reside in niches characterized by low ROS, a critical factor in maintaining stem cell properties such as self-renewal. Multiple signaling pathways in normal stem cells and CSCs can regulate ROS level and could be exploited against CSCs. Elucidation of ROS function in CSCs will enrich our knowledge of cancer development and metastasis. Moreover, ROS have also been shown to regulate angiogenesis through the release and actions of tumor-derived growth factors that induce endothelial cell proliferation. In fact, ROS production within tumor cells dramatically promotes the release of paracrine growth factors such as VEGF and the expression of its receptor, VEGF receptor-1 which, in turn, stimulate proliferation, migration, and tube formation in nearby endothelial cells \[[@B34]\]. NADPH oxidase within endothelial cells cooperates with growth factors, such as VEGF released by tumors, to stimulate endothelial cell proliferation and then angiogenesis. Thus, NOXs as ROS source in tumors and in endothelium may be considered novel targets for antiangiogenic treatment. 4.3. Inflammation {#sec4.3} ----------------- The oxidative burst of phagocytes has long been considered proinflammatory, causing cell and tissue destruction. Recent findings have challenged this inflammatory role of ROS, and now ROS are also known to regulate immune responses and cell proliferation and to determine T-cell autoreactivity. NOX2-derived ROS have been shown to suppress antigen-dependent T-cell reactivity and remarkably to reduce the severity of experimental arthritis in both rats and mice \[[@B39]\]. In fact, regarding these chronic inflammatory diseases (rheumatoid arthritis) there is increasing evidence that ROS can often help to modulate inflammation, ensuring that it does not become too prolonged \[see review \[[@B40]\]\]. In retrospect, this is also suggested by the pathology of chronic granulomatous disease (a condition characterized by inborn defects in the phagocyte O~2~ ^•−^ generating NADPH oxidase), there is an increased risk of infection due to an inability to kill certain microorganisms; this is in addition to a severe dysregulation and prolongation of inflammation. Thus, stopping ROS production can be deleterious. On the other hand, ROS can cause severe cartilage damage and the ability of nuclear factor erythroid 2 p4-5-related factor 2 to enhance endogenous antioxidant defenses in response to the inflammation may play a significant ameliorative role. The same may be true in sepsis; some ROS may help but too many can cause harm \[see review \[[@B40]\]\]. Finally, NADPH oxidase-derived ROS are also crucial players of tumor anti-immunity regulating specialized subsets of immune cells such as macrophages and T lymphocytes. Thus, NOXs could represent a novel molecular link between chronic inflammation and angiogenesis during cancer \[[@B2]\]. NOX2 is connected to the innate immune response \[[@B41]\], including to fungal infections \[[@B42]\] and adaptive immune response at the level of both T cells and antigen-presenting cells \[[@B43]\]. Thus, NOX2 inhibition leads to an improvement of diseases involving a significant inflammatory response. On the other hand, the essential immune functions of NOX2 have to be preserved \[[@B35]\]. 4.4. Organ Failure {#sec4.4} ------------------ ROS are generally thought to play an important role in the pathophysiology of organ failure \[[@B22]\]. For example, in liver and intestinal tissue injury, there is some indication for a pathogenetic role of NOX2-derived ROS by neutrophils \[[@B44], [@B45]\]. With respect to high levels of ROS produced by NOX4, they can be directly cytotoxic or cause apoptosis inducing heart ischemic stroke. On the other hand, regarding the NOX4 role on pressure overload of the heart, NOX4 might be responsible of both acute damage of the cardiomyocyte and subacute protection of the heart by promoting angiogenesis \[[@B35]\]. 4.5. CNS Diseases {#sec4.5} ----------------- ### 4.5.1. Ischemic Stroke {#sec4.5.1} In a gerbil model of global cerebral ischemia-reperfusion injury, NOX inhibition by apocynin strongly diminishes damage to the hippocampus \[[@B46]\]. Stroke size was markedly reduced in NOX2-deficient mice \[[@B47]\], while increased NOX2 expression in diabetic rats was associated with an aggravated ischemic brain injury \[[@B48]\]. ### 4.5.2. Alzheimer\'s Disease, Parkinson\'s Disease, and HIV Dementia {#sec4.5.2} NOX2 seems to have a role in inflammatory neurodegeneration diseases, including Alzheimer\'s disease and Parkinson\'s disease \[[@B49], [@B50]\]. In the case of Alzheimer\'s disease, amyloid precursor protein fragments released from neurons activate NOX2 -dependent ROS generation by microglia cells leading to death of neighboring neurons \[[@B51]\]. Several studies suggest similar mechanisms, involving NOX2, in Parkinson\'s disease \[[@B52], [@B53]\]. Microglia activation is also thought to be a key element in the development of dementia \[[@B54]\], and a role of NOX2 activation in animal model of dementia has been suggested \[[@B55]\]. Microglial NOX2-derived ROS have also been implicated in the progression of the demyelinating disease through phagocytosis of myelin and damage to the myelin sheath \[[@B56]\]. In periventricular leukomalacia, the combination of NOX2-derived superoxide and inducible nitric oxide synthase-derived nitric oxide leads to the formation of peroxynitrate and thereby to the killing of oligodendrites \[[@B57]\]. 5. Antioxidant Therapy {#sec5} ====================== Classically, oxidative stress has been defined as an imbalance between the endogenous production of reactive oxygen compounds and the antioxidative potential of cells \[[@B58]\]. But the low or apparent lack of clinical effectiveness of ROS-scavenging approaches is not entirely explained. It can be due to the partial removal of selected harmful endproducts by ROS-scavengers. Furthermore, antioxidants, including vitamins, reaction with superoxide anions is slower than NO. Moreover, it does not take into account that cellular events leading to disease primarily occur in individual cellular compartments \[[@B3]\]. 5.1. NOX Inhibition (See [Table 2](#tab2){ref-type="table"}) {#sec5.1} ------------------------------------------------------------ The main sources of ROS include redox enzymes such as the respiratory chain, xanthine oxidase, lipooxygenase, cyclooxygenase, and NADPH oxidases, and these systems are continuously interacting with each other. Due to the complex mechanisms involved in the activation of NADPH oxidases, these enzymes can be targeted on several different levels of their activity. Firstly, decreasing NADPH oxidase expression can inhibit them. Also, the activation of NADPH oxidase can be decreased by blocking the translocation of its cytosolic subunits, when present, to the membrane. Another possibility is inhibition of the p47phox subunit, either by preventing its phosphorylation using PKC inhibitors or by blocking its binding to other subunits. A decrease of signal transduction and inhibition of Rac 1 translocation has also been demonstrated to decrease ROS generation \[[@B3]\]. Several compounds have been used, including apocynin, diphenylene iodonium (DPI), and 4-(2-aminoethyl)-benzensulfonylfluorid (AEBSF). However, it has become apparent that these inhibitors are not specific for NOX \[[@B59]\] and not selective for single NOX isoforms. One of the first inhibitors used in model studies was diphenyliodonium (DPI), which is very potent (although in micromolar range) but lacks specificity. DPI is a general flavoprotein inhibitor, also inhibiting, for example, xanthine oxidase and eNOS \[[@B60]--[@B62]\], as well as cholinesterases and a calcium pump \[[@B63]\]. AEBSF is primarily a serine protease inhibitor \[[@B64]\]. Its greatest drawback is however toxicity. Later studies involved apocynin, a naturally occurring NADPH oxidase inhibitor originally isolated from the roots of Picrorhiza kurroa. Apocynin cannot be used as selective NADPH oxidase inhibitor due to its direct antioxidant and several off-target effects \[[@B60]\]. Apocynin is an orally active agent that can block NADPH oxidase assembly in membrane but requires a reaction with peroxidase for its activation, and therefore does not work immediately \[[@B65]\]. Apocynin reduces ROS production in models of arthritis, asthma, and hypertension, abolishing the increase in vascular O~2~ ^•−^ and preventing endothelial dysfunction \[[@B66]\]. However, effects of apocynin are not specific, as it has been reported to affect arachidonic acid metabolism \[[@B67]\], to increase glutathione synthesis, and to activate the AP-1 transcription factor \[[@B68]\]. In addition, it has recently been shown to be a direct ROS scavenger in certain experimental conditions \[[@B69]\]. The use of natural antioxidants represents a promising new approach for NOX inhibition. Polyphenols represent more than 10000 compounds occurring naturally in foods and the recommendation for a polyphenol rich (green tea/red wine/fruits/vegetables/whole grain foods) diet in the prevention of cardiovascular disease is still valid \[[@B70]\]. It was found that polyphenols, apart from their well-known superoxide radical scavenging abilities, decrease NADPH oxidase activity \[[@B71]\] in a number of tissues including vessels and platelets \[[@B72]\]. Moreover, novel polyphenolic compounds are being investigated which lack typical superoxide scavenging properties and directly inhibit NADPH oxidase. Recent studies with berberine, a plant alkaloid \[[@B73]\], revealed an inhibition of NADPH oxidase activity and reduction of gp91phox mRNA expression in macrophages. Also, emodin, an active component extracted from rhubarb and rhein, reduced ROS generation \[[@B74]\]. Similar effects were observed by treatment with 3-(4′-hydroxyl-3′,5′-dimethoxyphenyl)propionic acid (HDMPPA), the active ingredient in kimchi, ellagic acid, a polyphenol present in fruits and nuts \[[@B75]\], and dihomo-γ-linolenic (ω-6) acid \[[@B76]\]. The inhibitory effect of flavonoids (kaempferol, morin, quercetin, and fisetin) on the respiratory burst of neutrophils was observed by Pagonis et al. \[[@B77]\] as early as in 1986. A Ginkgo biloba extract containing flavonoids, among other compounds, was tested by Pincemail et al. \[[@B78]\] for its effect on the release of ROS (superoxide anion radical, hydrogen peroxide, and hydroxyl radical) during the stimulation of human neutrophils by a soluble agonist. The extract slowed down the oxygen consumption (respiratory burst) of the stimulated cells by its inhibitory action on NADPH oxidase \[[@B79]\]. The extract was also able to reduce the activity of myeloperoxidase contained in neutrophils. Moreover, it had free radical scavenging activity. A higher number of hydroxyl substituents are an important structural feature of flavonoids in respect to their scavenging activity against ROS, while C-2,3 double bond (present in quercetin and resveratrol) might be important for the inhibition of ROS production by phagocytes \[[@B80]\]. The bark of magnolia has been used in oriental medicine to treat a variety of remedies, including some neurological disorders \[[@B81]\]. Magnolol (Mag) and honokiol (Hon) are isomers of polyphenolic compounds from the bark of Magnolia officinalis, and have been identified as major active components exhibiting antioxidative, anti-inflammatory, and neuroprotective effects. It has been reported that exposure of Hon and Mag to neurons for 24 h did not alter neuronal viability, but both compounds inhibited superoxide production, a pathway known to involve NADPH oxidase. This study highlighted the important role of NADPH oxidase in mediating oxidative stress in neurons and microglial cells and has unveiled the role of IFNγ in stimulating the MAPK/ERK1/2 signaling pathway for activation of NADPH oxidase in microglial cells. Hon and Mag offer anti-oxidative or anti-inflammatory effects, at least in part, through suppressing IFNγ-induced p-ERK1/2 and its downstream pathway \[[@B81]\]. Incubation of human neuroblastoma cells with nonpolar blueberry fractions obstructed the coalescing of lipid rafts into large domains disrupting NOX assembly therein and abolishing ROS production \[[@B82]\]. In fact, this NOX inhibiting bioactivity in crude blueberry extracts partitioned into a polyphenol-devoid fraction lacking virtually any antioxidant capacity and prevented proper assembly of the multisubunit NOX complex interfering with the coalescence of large lipid raft domains. Prodigiosin, a microbial pigment, and some derivatives suppressed NOX activity most likely by disrupting Rac function \[[@B83], [@B84]\], and inhibition of NOX by the alkaloid sinomenine is unclear at best \[[@B85]\]. In an oxygen-glucose deprivation and reoxygenation (OGD/R) model, pretreatment with green tea polyphenols (GTPP) and their active ingredient, epigallocatechin-3-gallate (EGCG), protects PC12 cells from subsequent OGD/R-induced cell death \[[@B86], [@B87]\]. GTPP stimulates laminin receptor and thereby induces NADPH oxidase-dependent generation of ROS, which in turn induces activation of PKC resulting in preconditioning against cell death induced by OGD/R. Resveratrol is a naturally occurring polyphenol, which has vasoprotective effects in diabetic animal models and inhibits high glucose (HG-) induced oxidative stress in endothelial cells. It has been reported that HG induces endothelial cell apoptosis through NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol \[[@B88], [@B89]\]. Other NOX inhibitors are VAS 2870, VAS 3947, GK-136901, plumbagin, and polyphenolic derivative S17834 \[[@B90]\]. Plumbagin, a plant-derived naphthoquinone, has been shown to exert anticarcinogenic and antiatherosclerosis effects in animals. Plumbagin inhibits NADPH-dependent superoxide production in cell lines that express NOX4 oxidase \[[@B91]\]. Although its exact mechanism of action remains unclear, the inclusion of a napthoquinone structure within the molecule may be responsible for its ROS scavenging abilities \[[@B90]\]. Plumbagin inhibited the activity of NOX4 in a time- and dose-dependent manner in HEK293 and LN229 cells directly interacting with NOX4 and inhibiting its activity \[[@B91]\]. Indeed, plumbagin has been reported to exert anticancer activity on osteosarcoma cells by inducing proapoptotic signaling and modulating the intracellular ROS that causes induction of apoptosis \[[@B92]\]. Moreover plumbagin-induced AMPK activation might be the key mediator of plumbagin\'s antitumor activity \[[@B93]\]. Furthermore, PI5K-1B plays a crucial role in ROS generation and could be a new molecular target of plumbagin \[[@B94]\]. At last, plumbagin can exert its function in depleting glutathione (GSH) levels that led to increase in ROS generation \[[@B95]\]. Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions and shows benefits in models of neurodegenerative disease, cancer, and arthritis, although its mechanism of action is incompletely understood. Authors demonstrated that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely, inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome \[[@B96]\]. 6. Conclusions {#sec6} ============== Accumulating evidence clearly indicates that NADPH oxidases are critical molecular targets for dietary bioactive agents for prevention and therapy of different pathologies. The development of specific and not toxic inhibitors of NADPH oxidases and their redox signaling network (kinase, transcription factors, and genes) could provide useful therapeutic strategies for the treatment of oxidative stress dependent processes such as cancer and other degenerative diseases. In fact, classical antioxidant therapies have been demonstrated inadequate since the importance of ROS in physiology has been ignored leading to the lack of clinical benefits. Indeed, further research into selective molecular inhibitors interfering with NADPH oxidase activation are warranted. The selective targeting of dysfunctional NADPH oxidase homologs appears to be the most suitable approach, with the potential to be far more efficient than the one with nonselective antioxidants having only ROS scavenging properties. NOX enzymes, however, are very complex with numerous specific targets within each isoform. More information is needed on how these proteins are targeted to different subcellular compartments and how this transport process is regulated. It is encouraging, however, that single bioactive dietary agents can directly and indirectly influence most, if not all, of the myriad targets within NOX family. Additionally, many of these dietary agents appear to exhibit some degree of specificity for redox deregulated cells while unaffecting normal cells balance. Moreover, the protective effects of some single agents could be potentiated and/or synergized by other dietary agents. While encouraging, there are many considerations that remain, such as the issue of appropriate dose of each agent, appropriate timing and duration of exposure, importance of cell type specificity, relative bioavailability of each agent, and potentially adverse side effects and interactions. The author does not have a direct financial relationship with the commercial identities mentioned in the paper that might lead to a conflict of interests. This work was supported by Grants from MIUR PRIN, 2009, Project, 200938XJLA_002. ###### NOX isoforms and pathology \[modified from \[[@B22], [@B23]\]\]. Characteristic Binding partners Intracellular localization Tissue distribution Implication in pathology ---------------- ---------------------------------------------------- --------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------------------------------- NOX1 p22^phox^, NOXO1, NoxA1, Rac1, PDI, TKS4/5\* Caveolae on the plasma membrane, redoxisomes Colon epithelia VSMCs, endothelial cells, uterus, placenta, prostate, osteoclasts, retinal pericytes, neurons, astrocytes, microglia Colon cancer, prostate cancer, gastrointestinal inflammation, hypertension, restenosis after angioplasty NOX2 p22^phox^, p67^phox^, p40^phox^, p47^phox^, Rac1/2 Phagosomes, cytoskeleton, lamellipodia, redoxisomes Phagocytes, CNS, endothelium, VSMCs, fibroblasts, cardiomyocytes, skeletal muscle, hepatocytes, hematopoietic stem cells Gastrointestinal inflammation, hypertension, myocardial injury, restenosis after angioplasty, melanoma, diabetes, neurodegenerative diseases NOX3 p22^phox^, NOXO1 Plasma membrane Inner ear, lung endothelial cells, fetal tissues Hearing loss, pancreatic cancer NOX4 p22^phox^, PDI, TKS4/5, Poldip2\* Focal adhesions, nucleus, endoplasmic reticulum, mitochondria Ubiquitously expressed but highly in the kidney Pancreatic cancer, melanoma, diabetes NOX5 Ca^2+^, Hsp90, CaM^\#^ Internal membranes, plasma membrane Lymphatic tissue, testis, VSMCs, endothelial cells, spleen, uterus, and prostate Atherosclerosis prostate cancer, pancreatic cancer Duox1 Ca^2+^, DuoxA1 Plasma membrane Thyroid, respiratory epithelium Thyroid dysfunction, cystic fibrosis Duox2 Ca^2+^, DuoxA2 Plasma membrane Airway epithelial, colon, salivary gland Thyroid dysfunction, cystic fibrosis \*Recently, the protein polymerase (DNA-directed) delta-interacting protein 2 (Poldip2) was identified to bind and to increase the activity of NOX4. Further, protein disulfide isomerase (PDI) and a p47phox analogue tyrosine kinase substrate with 4/5 SH3 domains (Tks4/5) have been reported to bind and activate NOX1 and NOX4. NOX4 is the only isoform that produces hydrogen peroxide instead of superoxide. ^\#^The NOX5 protein contains four N-terminal calcium-binding sites that regulate activation of the enzyme. Activity of NOX5 can be further supported by the binding of Hsp90 or Calmodulin to the C-terminus of the protein. ###### NOX inhibitors. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Name and origin Mechanism of action NOX isoform selectivity Other pharmacological effects References ------------------------------- ------------------------------------------------------------------------------- ------------------------- ---------------------------------------------------------------------------------------------------------------------- -------------------- AEBSF\ Inhibits p47^phox^ assembly with oxidase subunit NOX2 Proteases inhibitor \[[@B64]\] synthetic Apocynin\ Inhibits p47^phox^ assembly with membrane NOX2 H~2~O~2~ scavenging \[[@B65]\] picrorhiza kurroa Berberine\ Inhibition of gp91^phox^expression NOX2 Enhancement of SOD activity \[[@B72]\] Berberis Blueberry derived polyphenols Disrupts NOX assembly in lipid rafts NOX2 Minimal if any ROS scavenging capacity \[[@B82]\] Celastrol\ Inhibition of association between cytosolic subunits and the membrane subunit Mostly Nox1 and NOX2 None reported \[[@B96]\] Tripterygium wilfordii DPI Flavoprotein inhibitor No selectivity Inhibits NOS, xanthine oxidase, NADH ubiquinone oxidoreductase, NADH dehydrogenase, cytocrome P450 oxidoreducatese \[[@B60]--[@B63]\] EGCG\ Inhibits the expression of NADPH oxidase subunits No selectivity ROS scavenging capacity and ENOX proteins function as terminal oxidases of plasma membrane electron transport (PMET) \[[@B87]\] green tea Emodin\ NADPH oxidase p47^phox^ activation NOX2? Interfere with electron transport process and in altering cellular redox status \[[@B74]\] and rhein Rhubarb Ginko biloba Inhibition of Rac1- and p47^phox^-mediated NADPH oxidase activation NOX2? Increases the expression of Cu-Zn superoxide dismutase heat shock protein 70 \[[@B79]\] HDMPPA\ Downregulates expression of p47^phox^ and Rac1 NOX2? Preservation of NO bioavailability \[[@B75]\] Fruits and nuts kimchi Magnolol and honokiol\ Inhibit ERK pathway unknown Inhibit NO production \[[@B81]\] magnolia Plumbagin Unknown Nox4 ROS scavenger \[[@B90]--[@B95]\] Prodigiosin\ Inhibits the binding of p47^phox^ and Rac to the membrane components NOX2? Reduces gp91(phox) and iNOS expression \[[@B82]--[@B84]\] microbial pigment Resveratrol\ Decreases NADPH oxidase expression (p47^phox^) NOX2? Free-radicals-scavenging \[[@B88], [@B89]\] red wine S17834 Unknown NOX2 NOX4 None reported \[[@B90]\] Sinomenine\ Inhibits p47^phox^translocation to the cell membrane NOX2? Minimal interaction with opiate receptors \[[@B85]\] Sinomenium\ acutum ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- [^1]: Academic Editor: Cristina Angeloni
[Clinical experiences with nimodipine (Bay e 9736)]. In 27 patients, who suffered from SAH from a ruptured cerebral aneurysm direct operation and treatment with Nimodipine (Bay e 9736) was performed. Nimodipine was given intravenously over ten days (30 micrograms/kg bodyweight/hour) and thereafter orally over four days in diminishing dosages. There were no noteworth side effects. In comparison with a group of nine similar patients who were not given Nimodipine the study shows that Nimodipine is not able to reduce angiographic spasm or brain oedema in CT-scan. In spite of that the general recovery with Nimodipine was better than in the control group. The worse the initial neurological symptoms are, the more effective Nimodipine seems to be. The study shows that treatment should begin between the first and sixth day after SAH, at least two days before operation and at the latest two days after the onset of secondary spasm.
The only information he has been able to get since comes from a link that was there saying that the suspension was due to a violation of Blogspot’s terms of service. Lost blog. Lost mail. What violation? No clue. Cooper does blog about sex - also death, violence, male escort tales and abandoned things, plus a “GIF novel” made up of GIFs found online. Maybe he did violate some term of service. If so, where is the warning, or explanation, or opportunity to export his content? He hasn't gotten any response to queries. he even had a lawyer contact Google. I have several blogs on Blogger and I don't like this. Plenty of others are angry or would like an explanation. If this happened to me, I couldn't afford a lawyer to battle Google. I wouldn't get articles about me or in my defense from newyorker.com or nytimes.com or theguardian.com. My own experience with Google doing some evil was when - without warning and without any way to get an an explanation or recourse (Sound familiar?) - my Google Adsense account was suspended "for life." (read my post on that) Why? Our best guess was that because we had been hit with a server attack, they viewed it as some way of boosting our ad "hits."
Outcomes in rheumatoid arthritis (RA) are the result of disease activity operating over time (Table [1](#T1){ref-type="table"}). In general, the higher the level of disease activity, the more rapidly the adverse outcomes will occur and, often, the more severe the outcomes will be. All disease-modifying antirheumatic drug therapy has as its goal the reduction or elimination of disease activity and, consequently, the reduction or elimination of adverse outcomes. ###### Functional outcome in rheumatoid arthritis ------------------------------------------------------------------------------------------------- Is a dichotomous or binary event that can be thought of as representing an underlying continuum Is defined by a time variable Is both a patient outcome and a disease outcome May be defined by an observed or latent variable Can be identified using area under the curve methods Can be identified using the sustained level method ------------------------------------------------------------------------------------------------- Outcomes are discrete or binary events. Work disability is such an event, as is reaching a certain level of Health Assessment Questionnaire (HAQ) \[[@B1],[@B2]\] impairment or having an average HAQ score of 2 for a period of 1 year. Although events are binary (0 or 1), they can be thought of as part of an underlying, unobserved continuum. For example, a patient can be increasingly work impaired until the point when the patient can no longer work and becomes work-disabled. At that point, the outcome changes from 0 to 1. Outcomes are also events that are associated with and defined by duration of illness. For example, the proportion of patients work-disabled at 10 years is a meaningful description, but the proportion of patients work-disabled without a duration designator is meaningless and cannot be interpreted. In addition to requiring time as part of the definition of outcome, outcome implies a sense of permanency. Outcomes are irreversible (mortality, joint replacement) or are at least very difficult to reverse (work disability). For functional disability to truly be an outcome measure, it must be present for a sustained period at a defined level. Outcomes can be further separated as to whether they are disease outcomes or patient outcomes. Although these groupings may overlap, patient outcomes refer to those outcomes that have meaning to the patient. For example, the level of functional disability or the ability to work are important patient outcomes, but the number of erosions or the level of interleukin-6 are not. Outcomes, like variables, can be observed or latent. An observed variable can be measured directly, such as age, sex, or HAQ score. An observed outcome refers to events like work disability, death, the number of erosions, or the level of HAQ disability. Variables can also be unobserved or latent, in which case they represent the underlying construct or continuum that was mentioned earlier. Latent (unobserved) variables cannot be directly measured. An example of a latent variable is happiness. Examples of latent outcomes in rheumatology are structural damage and disablement. Although we can measure aspects of structural damage (e.g. the presence of erosions), we cannot measure the full spectrum of structural damage because it includes abnormalities to tendons, ligaments, and muscles throughout the body. Similarly, disablement or disability refers to the full range of human activities. Latent variables are important because they are what we really want to understand but can only approach approximately with observed variables like erosion scores or HAQ scores. Figure [1](#F1){ref-type="fig"}, a model of disease activity and outcome, illustrates these issues. Observed variables are enclosed in rectangles, and latent variables in rounded rectangles or ovals. In this illustration, dysfunction stands for the unobserved outcome of functional status. ![A partial causal model of disease activity and outcome in rheumatoid arthritis. Rectangles represent observed variables, and ovals and rounded rectangles represent latent (unobserved) variables. ESR/CRP, erythrocyte sedimentation rate/C-reactive protein; HAQ, Health Assessment Questionnaire; SF-36, Medical Outcomes Study Short Form 36; QOL, quality of life; JT, joint.](ar547-1){#F1} In many instances in rheumatology, we are forced to accept the variables we can observe rather than the underlying concepts we wish to measure. We do not have good measures for the latent variable functional ability, so we are forced to accept surrogates like HAQ score or functional scores from the Medical Outcomes Study Short Form 36 \[[@B3],[@B4]\] or Arthritis Impact Measurement Scales \[[@B5]\]. When we accept surrogates, we introduce substantial error because these measures are only approximate measures of function or disability. The HAQ, for example, can be quite abnormal in individuals with little apparent functional loss, and can be normal in individuals with substantial and obvious dysfunction \[[@B2]\]. Because of the problems in ascertaining a latent outcome, researchers often preferentially measure observed outcomes such as work disability \[[@B6]-[@B10]\], joint replacement surgery \[[@B11]\], income \[[@B12]\], or death \[[@B13]-[@B16]\]. Yet these outcomes also have their problems because they often take too long to occur, because they may not apply to all patients, and because they do not touch on the day-to-day substance of RA. Another very common approach to outcome measurement is to use observed variables as surrogates. For functional disability, the central outcome in RA, the HAQ becomes the key functional surrogate variable. Although we have spoken of the HAQ as the central outcome variable in RA, it is really a dual-purpose variable, one purpose representing the short-term result of the inflammatory process of the illness, as shown in Figure [1](#F1){ref-type="fig"}. Its usefulness in clinical trials occurs because of its primary role as a measure of the inflammatory process. It is not surprising, then, that its second purpose can be a predictor of outcome (Fig. [2](#F2){ref-type="fig"}). In fact, of all clinical variables, the HAQ is the best predictor of outcomes such as mortality, work disability, joint replacement, and economic loss. ![A partial causal model of disease activity and outcome in rheumatoid arthritis that includes well-defined outcomes. Rectangles represent well-defined outcomes, and ovals represent latent (unobserved) variables. The figure demonstrates the multivariate nature of outcome and the central role of disability in rheumatoid arthritis.](ar547-2){#F2} For the HAQ to be considered as an outcome measure rather than a process measure, it must be representative of sustained impairment. But it is not easy to ascertain sustained impairment. Sustained impairment implies regular longitudinal observation, the first problem. A second problem is that HAQ values are not well conditioned and smooth, but tend to jump around. This has been the subject of a number of recent papers \[[@B2],[@B17],[@B18]\], and is illustrated in Figures [3](#F3){ref-type="fig"} and [4](#F4){ref-type="fig"} (inset), where HAQ values may vary significantly from observation to observation. ![The course of a single RA patient over 13 years of illness. Circles represent HAQ scores. Note the wide-ranging variability of the HAQ scores. Although it is difficult to give meaning to these HAQ scores or analyze them, the AUC (triangles) provides smoothing that allows further analysis. The AUC represents the total burden of RA over time, and can be used to define functional disability as an outcome. See text for details. RA, rheumatoid arthritis; HAQ, Health Assessment Questionnaire; AUC, area under the curve.](ar547-3){#F3} ![The course of a single RA patient over the first 19 years of illness. Circles represent HAQ scores. For increased visibility, the insert provides HAQ scores on the appropriate scale. Note the wide-ranging variability of the HAQ scores. The AUC (triangles) provides smoothing that allows further analysis. The AUC represents the total burden of RA over time, and can be used to define functional disability as an outcome. The bi-directional arrow in the insert provides another method to define functional disability: a sustained level of disability over a defined time period. In this illustration disability is defined as an HAQ score of 2 or greater over a period of at least 2 years. See text for details. RA, rheumatoid arthritis; HAQ, Health Assessment Questionnaire; AUC, area under the curve.](ar547-4){#F4} A number of approaches may be used to better define HAQ scores, including smoothing and summarizing or condensing. One method to better define HAQ scores involves measuring the area under the curve (AUC) of HAQ scores (long diagonal line of Figs [3](#F3){ref-type="fig"} and [4](#F4){ref-type="fig"}). Notice that the irregularity of the HAQ scores (bottom of Fig. [3](#F3){ref-type="fig"} and inset of Fig. [4](#F4){ref-type="fig"}) is removed by the AUC measurement. The AUC is a measurement of the sustained burden of functional loss on the individual. To use it as an outcome measure, a cut-off value must be chosen. For example, we might decide that a patient with 10 AUC units in 10 years or 8 AUC units in 7 years has sustained clinically important functional impairment. One limitation of this method occurs when we are dealing with left censored data, as is often the case in rheumatology. In such an instance, we may choose to use as our measuring period (time variable) the time the patient is under our observation. We can alternatively choose to impute the AUC values before the patient came under our observation, perhaps using the average observed HAQ score. To do this, however, introduces additional error that may or may not be acceptable depending on the uses of the data. Another method of determining outcome with the HAQ is to require that a certain value of the HAQ be sustained for a defined time period. In Figure [4](#F4){ref-type="fig"} (inset), the horizontal bidirectional arrow indicates a sustained period of HAQ disability defined by a value of at least 2 for at least 2 years. The investigator frequently does not have longitudinal data. Is it correct to take a single value or a few values and infer that they represent HAQ outcome? Given the variability of the HAQ scores in Figures [3](#F3){ref-type="fig"} and [4](#F4){ref-type="fig"}, using a single measure will lead to an imprecise and inefficient measure of outcome. Additionally, it confounds the separate definitions of process and outcome measures. Inferences about functional disability ====================================== All recent disease-modifying antirheumatic drugs have been shown to reduce HAQ disability over the duration of their clinical trials \[[@B19]-[@B23]\]. Is it reasonable to infer outcome differences based on shorter term results and results that come from clinical trials, knowing that clinical trials may not be representative of actual results in the community? The best that can be said is that it is a starting point, perhaps an indication of what we might expect to see if drugs actually worked as well in practice as they do in randomized clinical trials. Using data from Figure [4](#F4){ref-type="fig"}, if the HAQ score was reduced by 0.25 units (an amount of reduction shown in most recent trials), then the total AUC of disability would be reduced from 36.28 disability years to 31.76 disability years, a reduction of 4.52 disability years. Using our definition of a HAQ score of 2 or greater for at least 2 years, disability would be postponed in this patient by 4.62 years. Small changes in HAQ levels can thus translate into important, clinically meaningful changes in outcome if all of the assumptions noted in the present paper hold. The importance of longitudinal studies is that they provide the validation or refutation of the extrapolation of clinical results to the full population of RA patients in the community. Abbreviations ============= AUC = area under the curve; HAQ = Health Assessment Questionnaire; RA = rheumatoid arthritis.
Questions? One of eastern China's best known green teas. The sliver sprouts of the tea are neatly coiled and give this tea it's recognizable appearance. The tea is fresh and clean tasting with a hint of hazelnuts while the cup features a pale hue. Price (2 oz Pouch): $15.95 Price (4 oz Pouch): $28.71 Price (8 oz Pouch): $54.23Product Code:200760-06 Tea Size*: Qty: Description Originating in eastern China, this tea features budsets that measure 1.5 - 2cm in length. The spiral shaped leaves yield an attention worthy cup, with tender tippy budsets. This tea is one of our favorites.
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With the unfolding global coronavirus pandemic leading to people being confined to their homes, borders being shut and economic instability, it can be hard not to feel overwhelmed by the state of the world at the moment. The good news? Even in times of stress and anxiety, you can take proactive steps to lift your mood. The science of emotions is incredibly complicated, but it is also well-studied. Over the years, BBC Future has interviewed dozens of world-leading experts in psychology who shared with us practical, everyday tips for coping better with stress. We recently trawled through the research. Here are some of the top tips we found – some of which may surprise you. 1. Distract yourself. It’s easy to run over and over the topic that’s stressing us out, whether that’s the new coronavirus outbreak, the state of the climate or something else. But stopping people from ruminating on a recent stressful event – by offering a distraction – can lower their blood pressure back to normal levels quicker than offering no distraction. 2. If you meditate, be aware that it might not work for everyone. In times like these, many people might find meditation and mindfulness helpful. But others might not – for precisely the reason above. For some people, practicing stillness might simply invite rumination. It can be difficult not to think about stressful events when trying to clear our minds. This may be why evidence for the benefits of mindfulness and meditation is patchy. For those people, a more compelling distraction than meditation might be required. 3. Reframe the situation. How we interpret our emotions is largely down to how they’re framed – in other words, the context. While talking about his 2017 book Happy, Derren Brown gives the example of a tennis player going into a match thinking “I must win”. If they set an expectation that winning is everything, if they start to lose, they feel like an abject failure. This is a trap perfectionists tend to fall into, and it’s why perfectionists tend to respond with more guilt, shame and anger when they feel they aren’t succeeding. They may even be more likely to give up. The player who goes into a match thinking “I will play the best I can”, however, believes that they are less hurt by losing, so long as they are doing their best. The signs of failure are interpreted differently by both players based on the expectations that they set for themselves. It’s worth thinking about how you can apply this in your daily life: can each moment or day be about doing the best you can in a stressful situation (“I will practice proper hygiene and social distancing”), rather than focusing on an outcome out of your control (“I will not and cannot get sick”)? That control part is key. Stressful situations are often beyond our control, and we create anxiety and worry when we try to control what we can’t. Focusing on what can be controlled, on the other hand, can decrease feelings of anxiety. 4. Don’t obsess over being positive or happy. This one may seem counterintuitive: it can be a bad idea to chase positive emotions. Actively pursuing happiness can lead to the reverse effect. For one thing, the more we focus on our own happiness, the less we focus on the happiness of the people around us, which has been shown to contribute to feelings of isolation and disconnection. There is also a link between searching for happiness and feeling that time is slipping away. And again, if you’re focused on an outcome like “I must feel happy”, you may feel worse about yourself if you don’t succeed – even though it’s perfectly natural to have a more difficult time feeling happy in stressful times.
Media Molecule 'stepping away from LittleBigPlanet' Will focus on some new ideas, says studio director. Media Molecule is to step away from the franchise which catapulted it to fame, confirming it is to focus attentions on new ideas. According to a Tweet from Edge - attending a GameLab 2011 session hosted by Media Molecule studio director Siobhan Reddy - the UK-based developer is "stepping away from Little Big Planet to focus on some new ideas". What comes next for Media Molecule will be of great interest to PlayStation fans. VideoGamer.com Analysis Media Molecule is the creator of LittleBigPlanet, but it certainly isn't the only studio to be involved with the franchise: Sony's Cambridge Studio developed the PSP title, while Double11 and Tarsier Studios are working on bringing the cute platformer to PlayStation Vita.
Yall pls share this if you’ve shared the posts about college kids literally crying at the register when buying their textbooks bc holy gotdam shit every time I see that post it has a billion notes but the solutions get none Like I don’t normally beg for notes but This info can keep people in school when they’d otherwise leave
Priyanka Chopra’s Whistle Dance For Onscreen Husband Rahul Bose The recent Sunday brunch attended by the star cast of Dil Dhadakne Do was no ordinary meet. At the beautiful day, despite the hot weather the brunch held at Turf in Mumbai had good food, good music, good memories shared which were just few of the biggest attractions. However one thing was sure, the star cast of the film is obsessed with dancing! We saw Anil Kapoor’s famous dance move, Ranveer Singh’s energectic dance but most of all we caught a glimpse of Priyanka Chopra’s impromptu dance for onscreen hubby Rahul Bose! During the brunch songs from the film Dil Dhadakne Do were being played at the big screen and as soon as the song ‘Gallan Goodiyaan’ started playing, PeeCee sprung from her seat and broke into an awesome dance. It was no ordinary dance though! Turns out, Priyanka was waiting for the exact moment in the song where RahulBose makes an entry whistling and dancing. PC got up at the exact moment and enacted Rahul very well whistling and dancing like no one’s watching! The stars took to their Twitter account to share this cute but naughty moment. Rahul Bose tweeted, “@priyankachopra shows me how to do it right! #GallanGoodiyaan #DDDMusicBrunch.” To which the Mary Kom star replied, “Lol @RahulBose1 no one does it like u bose!!” Priyanka and Rahul’s characters in the film, Ayesha Mehra and Manav are wife and husband who although are married to each other do not share the bond of love. Rahul Bose who has done a series of serious and intense films like Chameli, Shaurya and I Am will be seen doing something he hasn’t done in quite some time. The actor had earlier tweeted warning his followers that after almost 21 years, he has ‘briefly’ whistled and dance in a film. Dil Dhadakne Do releases on June 5, 2015. Well we are definitely loving this onscreen couple, what about you?
Perceived threat as a cognitive component of state anxiety and confidence. This study was designed to test propositions from the 1990 competitive anxiety model proposed by Martens, Vealey, and Burton. Specifically, the relationships among perceived threat and state responses of anxiety, confidence, and efficacy were examined to assess whether perceived threat might explain anxiety and confidence in 52 intercollegiate female volleyball players. Somatic anxiety was significantly correlated with perception of importance of both outcome and personal performance while uncertainty regarding personal performance was significantly related to cognitive anxiety. In addition, perceived threat was significantly related to state self-confidence and self-efficacy.
-4, c in descending order. j, c, -4 Let l = 0.36 - -0.34. Let a = 1 - l. Let d be 5/(-6) - (-4)/6. Sort d, a, -0.5 in decreasing order. a, d, -0.5 Let u be (-4)/(-6)42/126. Suppose 6 = 2p, -7p + 4p = -3l - 12. Suppose -2b = -3q, -5q + b = 3b. Sort l, q, u. l, q, u Suppose w - 111 = -110. Put -26, -4, w in descending order. w, -4, -26 Suppose 4r - 2s = 7r - 9, 2r - 6 = -3s. Put 5, -5, r, -4 in descending order. 5, r, -4, -5 Let b(u) = u*2 + 22u + 101. Let l be b(-16). Put -11, -2, l in increasing order. -11, -2, l Suppose 2z + 3u - 13 = 0, 0z + z = -5u + 10. Let c = -395 + 392. Sort z, -1/9, c, -2. c, -2, -1/9, z Let z = 148 - 152. Sort -6, 1/3, z in decreasing order. 1/3, z, -6 Let w = -11 + 15. Let d be (-19620)/234 - (8/(-26))/(-2). Let t = -105 - d. Put t, w, -1 in descending order. w, -1, t Suppose -4n - 19 = -3x, 1 = x + 3n - 1. Let k(y) = -5y*3 - 2y - 1. Let t be k(-1). Sort x, 4, t in decreasing order. t, x, 4 Suppose -32y - 117 = 43. Put 0, y, 5, -33 in decreasing order. 5, 0, y, -33 Let m = 16 - 30. Let a(r) = 2r*3 - 3r*2 + 2r + 2. Let f be a(0). Put f, -4, m, -5 in increasing order. m, -5, -4, f Let g = -2.35 + 2.05. Let p = 0.69 - -0.31. Sort g, p, 33 in decreasing order. 33, p, g Let l = -53 + 35. Let d = 38 + -59. Let n = l - d. Sort n, -0.11, -5/4 in ascending order. -5/4, -0.11, n Suppose 12m = 3m + 9. Sort 2, m, -0.5. -0.5, m, 2 Let z(n) be the first derivative of -n*4/4 - 7n*3/3 - 7n*2/2 + 6n + 5. Let d be z(-6). Let b be (1 + (-44)/d)3. Put 4, b, -4 in decreasing order. 4, -4, b Let o(v) = 4v*3 + 2 - v - 6v*2 + 0v - 3v3. Let p be ((-5)/(10/12))/(0 + -1). Let t be o(p). Put t, -5, 4 in descending order. 4, t, -5 Let y be (45/27)/(-1 + 8/6). Let i(f) = f3 - f - 8. Let n be i(0). Put n, 1, y in descending order. y, 1, n Let c = -0.1 + 0.17. Let s = -19 + 33. Let a = -18 + s. Sort -1/7, a, c in descending order. c, -1/7, a Let j = -11 - -11.1. Let a = -3.68 - -3.69. Put 5, j, a in descending order. 5, j, a Let b = -2.5 - -2. Let w = -2758 - -2759. Put w, 0.1, b in decreasing order. w, 0.1, b Let r = -85 + 134. Let q = -54 + r. Put q, 2/13, 3, -0.5 in ascending order. q, -0.5, 2/13, 3 Let h be (-3 - 40/(-15))/((-1)/3). Suppose -3k - 3 = 3. Sort -3, k, h in increasing order. -3, k, h Let s(z) = -3z + 17. Let o be s(6). Let d = -8 - -6. Let p = d - 3. Sort o, p, 1 in descending order. 1, o, p Let g(w) = 4w - 2. Let k(v) = 3v - 1. Let d(z) = 4g(z) - 5k(z). Let n be d(3). Let s(y) = y2 + 8y + 17. Let t be s(-5). Sort n, -3, t. -3, n, t Suppose 0 = -32t + 26t - 30. Sort t, 1, 157 in ascending order. t, 1, 157 Let r = -157/323 + 7/19. Let d = 0.6 + -0.87. Let c = d + 1.27. Sort r, 4, c. r, c, 4 Let t = 1.07 + 9.33. Let d = t - 5.4. Put -2/7, d, 3, -5 in ascending order. -5, -2/7, 3, d Let h = 3719/12 - 1145/4. Sort h, -0.5, 1/2 in descending order. h, 1/2, -0.5 Let m = 12 - 7. Let l(d) = -d*3 - 4d*2 - 4d - 1. Let f be l(-3). Sort m, f, -4. -4, f, m Let s = -1036 + 1036.3. Put 4, s, 433 in ascending order. s, 4, 433 Let f(x) = x*3 - 14x*2 + 14x - 18. Let v be f(13). Suppose h + 10 = 3h. Put v, h, -2 in decreasing order. h, -2, v Suppose -2396 + 951 = 17f. Sort f, 2, 4, 1. f, 1, 2, 4 Let i = -20 + 17.4. Let r = -2.6 - i. Sort 1/5, r, -2/11 in ascending order. -2/11, r, 1/5 Let z be (3/30)/((10/25)/2). Sort -2, z, 1/33. -2, 1/33, z Let x = -3 + -3. Let w = x + -2. Sort w, -1, 1/5 in ascending order. w, -1, 1/5 Let t be 3 + (3 + -3)/4. Suppose -3x + 60 = x - 5v, 4x = -tv + 28. Suppose 3u = -2u - x. Sort u, -5, 2. -5, u, 2 Let v = 0.172 - 0.672. Sort 2/3, v, 76 in decreasing order. 76, 2/3, v Let w be (8/(-52) - 20/208)-4. Sort w, -5, -2, 22. -5, -2, w, 22 Let o = -6888/65 - -106. Put o, -2/3, -0.5, -1/5 in descending order. o, -1/5, -0.5, -2/3 Let w = 30.73 - 31. Let n = w + 4.27. Put 1/8, n, -1 in descending order. n, 1/8, -1 Let a = 3/47 - -20/423. Sort -0.3, a, -6, -1 in decreasing order. a, -0.3, -1, -6 Let l be 88/(-72) + (11/9 - 1). Suppose -2k - 15 = 3k. Let f be 15/20(1 - k). Sort l, 4, f. l, f, 4 Let y be (2 + (-14)/6)/((-1)/12). Let h = -12 - -9. Put 0, y, h in descending order. y, 0, h Suppose 5w - 10 = -m + 4, w = -5m + 94. Let h = m - 18. Sort 5, 1/4, h in descending order. 5, h, 1/4 Let l be (24/(-9))/(-1(-8)/(-6)). Put -5, -1, 19, l in increasing order. -5, -1, l, 19 Suppose 0 = -l + 3l - 18. Suppose -lf + 10f = 6. Let c(h) = h*2 - 6h + 5. Let k be c(f). Sort k, -4, 4 in decreasing order. k, 4, -4 Suppose 19 = -2g - 3b, -4g + 2b = -5g - 11. Let y = g - -6. Suppose 4k = 3k + 4a - 4, -3a + 3 = k. Put y, -3, k in decreasing order. y, k, -3 Suppose -5l + 484 = 5m + 1354, 3m + 540 = 3l. Put -5, m, 0 in decreasing order. 0, -5, m Let p = 0.184 - 0.284. Let a = -2.4 + 2. Sort a, p, 1 in ascending order. a, p, 1 Let u(p) be the second derivative of p3/2 - 35p*2/2 + 7p - 4. Let n be u(12). Suppose l + 4 = -2j, -l + 6 = -3l - 2j. Sort l, 3, n in decreasing order. 3, n, l Let n be (-2)/6 - (-26)/6. Let t be -41 - (1 + -19)/3. Let i = -32 - t. Sort i, 5, n. i, n, 5 Let w = 9 - 6.8. Let r = w - 2.3. Let b = -0.1 - -0.1. Sort 2/7, r, b in increasing order. r, b, 2/7 Let q(j) = j - 9. Let x be q(0). Let b be 9/6(-24)/x. Suppose 2 = 4h - g, 3h + 3 - 2 = 2g. Sort 2, b, h. h, 2, b Let k(j) = 3j*2 - 28j + 31. Let n be k(8). Put n, 0, 4, 0.3 in descending order. 4, 0.3, 0, n Let t = 0.3 + 0.7. Let k = -25 - -25. Suppose -4i = -5y, -2i + 22 = 3y - 0i. Sort y, t, k. k, t, y Suppose -32k + 9 + 87 = 0. Suppose 32 = -12b + 92. Sort -3, b, k, -5. -5, -3, k, b Suppose 5 = i + 1. Suppose 6q + 10 = 4q - 2m, -im - 14 = q. Let p(k) = 2k*2 - 10k - 5. Let t be p(5). Sort t, q, 0 in increasing order. t, q, 0 Let w be 14/(-30) - 6/(-45). Suppose 5 - 9 = -3i - 2o, -4o = -20. Sort 3, i, w in ascending order. i, w, 3 Let l = -7.8 + 8.8. Put l, 0, 15 in increasing order. 0, l, 15 Let a be (3/(-6) + 1)2. Sort a, 5, 4, -14 in increasing order. -14, a, 4, 5 Let d(q) = 17 - 26 + 32 - q*2 - 22q. Let c be d(-23). Put 5, -5, c, -3 in decreasing order. 5, c, -3, -5 Let x be 2 - (-7)/1 - 0. Suppose 0m = -3m - 180. Let s = -422/7 - m. Sort s, x, -0.5. -0.5, s, x Let o(x) = 3x - 4. Let f be o(-4). Let i be (-3)/(-3)(-28)/7. Sort 4, i, f, -5 in increasing order. f, -5, i, 4 Let q be (15/(-6) - -2)-6. Suppose -2b - q + 13 = 0. Suppose 0 = 4g - bg + 3, -g = 3m - 3. Sort 1, -5, m. -5, m, 1 Let b = -9.9 - -0.9. Let w = 95 + -88. Let n = w + b. Put n, 3, 1/3 in descending order. 3, 1/3, n Let a(i) = -5i + 43. Let w be a(11). Let j be 0 + (0 - w/(3/1)). Let h(n) = n*2 - 6n + 3. Let t be h(5). Put t, 1, j in increasing order. t, 1, j Let g(n) = -n*2 + 1 - 10n + 6 + 2 - 24. Let z be g(-7). Suppose 2y + 38 - z = 0. Sort 2, y, -2 in ascending order. y, -2, 2 Let a = 389 - 394. Put -2, 1, 0, a in decreasing order. 1, 0, -2, a Let v = 0.026 - 0.236. Let f = v + 2.21. Let y be 2/((-2)/(-5)) + 0. Sort 3, f, y in descending order. y, 3, f Let y be (-4)/42 - (-2)/(-6). Let j be -2 + (-226)/10 - (-6)/(-15). Let w = -19 - j. Sort y, 2, w in descending order. w, 2, y Let i be ((360/84)/(-15))/(3/(-7)). Sort 16, 0.2, -0.1, i in decreasing order. 16, i, 0.2, -0.1 Suppose 0 = 2u - 4 + 10. Let a be (-2)/(-4)96/4. Suppose x + a = -4r, -2 = -2r - r + 2x. Sort r, -1, u in increasing order. u, r, -1 Let n be (-1 + 4)/(6/(-72)). Let k = n + 357/10. Let t = 0.2 + -1.2. Sort k, 0.2, t in increasing order. t, k, 0.2 Let l(k) = -k3 + k2 - k - 3. Let r be l(4). Let f = r + 61. Put f, 4, 0 in descending order. f, 4, 0 Let a(x) = -x*3 + 2x*2 - 2x + 1. Let p be a(2). Let q(j) = j*2 + 23j + 126. Let m be q(-13). Let o be ((-8)/6)/((-2)/6). Sort p, o, m in increasing order. m, p, o Let v = -13 - -7. Let l = v - 0.5. Let c = 1.5 + l. Sort c, 2, 4. c, 2, 4 Suppose 0 = 10z - 2z + 128. Let t = 13 + z. Sort 0.3, 1, t, 15 in decreasing order. 15, 1, 0.3, t Let z = 48 - 46. Let n = 7 - 11. Put 3, z, -14, n in decreasing order. 3, z, n, -14 Let r = -1322 - -1324. Let h(u) be the first derivative of u*4/4 + 7u*3/3 + 2u*2 - 3u - 2. Let g be h(-6). Sort 4, g, r in decreasing order. g, 4, r Let y = 49 + -27. Let k = 22.6 - y. Let u = 0.4 - k. Put
[Experimental model of Parkinson disease: mechanisms and anatomo- pathological characteristics of MPTP neurotoxicity]. MPTP administration induces a fairly selective lesion of substantia nigra dopaminergic neurons both in animals and humans. This characteristic of MPTP has led to the best available model of Parkinson's disease and neuronal degenerations. MPTP toxicity is actually provoked by MPP+ which results after oxidation by MAO-B. Possible mechanism of action of MPP+ include: 1) Mitochondrial lesion. 2) Free radicals generation. 3) Trapping of MPP+ by highly melanized neurons. This article reviews the mechanisms of toxicity by MPTP and its neuropathological characteristics.
Introduction {#s1} ============ Palmitoylation (or protein S-acylation) is a reversible post-translational lipid modification which involves addition of the fatty acid palmitate onto specific cysteine residues [@pgen.1000748-Smotrys1]. Some post-translational lipid modifications such as myristoylation and prenylation serve to localize otherwise soluble proteins to the cytoplasmic surfaces of cellular membranes. In contrast, palmitoylation substrates are proteins that are already membrane associated, and the modification acts to increase or stabilise membrane affinity or to traffic the protein to specific membrane domains. In particular, palmitoylation results in localization of the protein to lipid rafts; domains of the plasma membrane rich in cholesterol and sphingolipids. Furthermore, as palmitoylation is reversible, it allows for membrane localization or trafficking to be dynamically regulated. This has best been demonstrated in synapses, where palmitoylation regulates membrane localization and activity of the AMPA receptor [@pgen.1000748-Hayashi1] and GABA~A~ receptor [@pgen.1000748-Keller1]. Palmitoylation of the post-synaptic density protein PSD95 permits clustering of the protein at synapses and regulates synaptic strength [@pgen.1000748-ElHusseini1]. A recent global study of the neural palmitoyl-proteome highlights the breadth of targets that are rapidly modulated by palmitoylation [@pgen.1000748-Kang1], further emphasizing the importance of this modification in dynamic biological processes. Members of the zinc finger, DHHC containing (ZDHHC) protein family have recently been shown to promote palmitoylation of intracellular proteins in yeast and in mammalian cells [@pgen.1000748-Lobo1]--[@pgen.1000748-Fukata1]. These palmitoyl-acyl transferases (PATs) are predicted membrane proteins possessing a cysteine-rich domain and a putative zinc finger with a characteristic Asp-His-His-Cys (DHHC) motif, required for activity. This family is encoded by 24 genes in both mouse and humans, of which 23 are orthologous pairs. Assaying individual target proteins against the entire repertoire of PATs indicates that there is substrate specificity; each substrate is primarily modified by a subgroup of structurally similar ZDHHC proteins [@pgen.1000748-Fukata2]. Although some human ZDHHC genes have been implicated in cancer [@pgen.1000748-Oyama1],[@pgen.1000748-Ducker1], genetic evidence for function of these genes is limited to neurological disorders. ZDHHC8 shows association with schizophrenia in humans and neurophysiological deficits in mice [@pgen.1000748-Mukai1]--[@pgen.1000748-Mukai2]. X-linked mental retardation is associated in a few patients with loss of expression of ZDHHC15 [@pgen.1000748-Mansouri1] and in others with frameshifts, splice or missense mutations of ZDHHC9 [@pgen.1000748-Raymond1]. Recently, the Drosophila ortholog of Zdhhc8 (App) was shown to play a key role in patterning and growth control of imaginal discs [@pgen.1000748-Matakatsu1]. However, very little is known about specific palmitoylation functions during normal mammalian development. Several lineage-restricted stem cell populations exist in the adult skin and contribute to renewal of only their own specific niche under normal steady-state conditions [@pgen.1000748-Clayton1]. Their progeny proliferate, migrate and terminally differentiate along the lineages of the interfollicular epidermis (IFE), hair follicle and sebaceous gland [@pgen.1000748-Fuchs1]. The cornified layer of postnatal skin is constantly shed and replenished by progeny of the epidermal stem cells in the basal IFE, which proliferate, differentiate and migrate suprabasally. Similarly, hair shafts are shed and replaced in a cycle of regression (catagen), rest (telogen) and regeneration (anagen). During each anagen, stem cells, residing in the permanent bulge region, are mobilized to provide hair follicle progenitors, which differentiate into eight different lineages that make up the hair shaft (consisting of the medulla, cortex and hair shaft cuticle), the inner root sheath (IRS) (consisting of the inner root sheath cuticle, Huxley\'s and Henle\'s layers), the companion layer cells and the outer root sheath (ORS). Also within the permanent portion of the follicle is the sebaceous gland which produces lipid-rich sebum to lubricate the skin and hair, in addition to providing antibacterial activity. Sebum is released by disintegrating sebocytes that are continuously replaced from progenitors in the periphery of the gland. These three stem cell lineages require a precise balance of self-renewal and differentiation of their committed progeny. However under certain experimental conditions or genetic manipulations, stem cells from one niche can contribute to hair, IFE and sebaceous gland lineages [@pgen.1000748-Blanpain1],[@pgen.1000748-Claudinot1], highlighting the interdependence of these epidermal compartments in maintaining homeostasis. The depilated mutation (dep, MGI:94884) results in a recessive phenotype characterized by variable hair loss, with thinner and shorter hairs remaining in a greasy coat. Recombination experiments show that the phenotype is due to a defect in the epidermis, rather then the dermis [@pgen.1000748-Mayer1]. Here, we genetically map and further characterize the dep mutant and show that it carries a single amino acid deletion in Zdhhc21, resulting in loss of PAT activity. A detailed study of the phenotype demonstrates that lack of palmitoylation by Zdhhc21 results in hyperplasia of the IFE and sebaceous glands and delayed differentiation of the hair shaft. Furthermore, we identify Fyn, a member of the Src family of tyrosine protein kinases required for keratinocyte differentiation, as a direct palmitoylation target of Zdhhc21 and demonstrate its mislocalization within dep mutant follicles. Results/Discussion {#s2} ================== Mutation in Zdhhc21 causes the dep phenotype {#s2a} -------------------------------------------- The location of the dep mutation has previously been defined by complementation against a set of chromosomes bearing deletions centred on the Tyrp1 gene [@pgen.1000748-Rinchik1]. The endpoints of those deletions defining the proximal and distal boundaries of the candidate interval were further refined using polymorphic markers on mice carrying the deletion chromosome opposite a Mus spretus chromosome [@pgen.1000748-Smyth1],[@pgen.1000748-Simpson1]. The candidate location of dep, defined by the deletions 46UThc proximally and 1OZ distally, is only 160kb in length and contains all or part of just 3 genes: Zdhhc21, Cer1 and Frem1 ([Figure 1A](#pgen-1000748-g001){ref-type="fig"}). Two of these have existing established mutations. ![Identification and transgenic rescue of the dep mutation.\ (A) Mapping the dep interval against the b-del complex. When dep is crossed with the b-IOZ deletion mutant (purple), offspring exhibit the hairloss phenotype. When crossed with the b-46UTHc deletion mutant (yellow), the hairloss phenotype disappears, indicating that the dep mutation lies within the genomic interval between the distal breakpoints of the 2 deletions. (B) Schematic of Zdhhc21 protein with dep C-terminal 3bp deletion resulting in the loss of a single highly conserved residue, phenylalanine (F) at position 233. The cysteine-rich domain containing a conserved DHHC motif is shown in blue on the cytoplasmic side. (C) The BAC clone RP23-76J17, which harbors the intact genomic sequences of Zdhhc21 and Cer1 successfully rescues the dep phenotype, shown at 6.5 weeks. (D) Transgenic dep mutant skin appears histologically normal and correct timing hair follicle differentiation is also restored. (E) Non-transgenic mutant littermate control.](pgen.1000748.g001){#pgen-1000748-g001} Frem1 is associated with 2 ENU-induced alleles and the classical mutation head blebs (heb) [@pgen.1000748-Smyth2] which result in an embryonic blebbing phenotype, and is a mouse model for Frasers Syndrome. Furthermore, a genetic complementation analysis between a Frem1 mutant (bfd) and dep produces normal mice (personal communication, Monica Justice), indicating Frem1 is not allelic to dep. There are several knockout mutant alleles of Cer1 but none of these exhibit the dep phenotype [@pgen.1000748-Shawlot1]--[@pgen.1000748-Belo1]. We have sequenced all known exons of both Frem1 and Cer1 in dep DNA have found no mutations. Additionally no non-coding RNAs are annotated or predicted within this interval (miRBase: microrna.sanger.ac.uk, Ensembl: [www.ensembl.org](http://www.ensembl.org), VEGA: [vega.sanger.ac.uk](http://vega.sanger.ac.uk)). However, sequencing of the 7 exons of Zdhhc21 (MGI:1915518) in dep mutants revealed a 3-bp deletion which results in the deletion of a single, highly conserved, phenylalanine residue (del-233F) close to the C terminus of the protein ([Figure 1B](#pgen-1000748-g001){ref-type="fig"}). Although this deletion was the only coding alteration found in the candidate interval, it remained possible that an undetected non-coding mutation could affect expression of genes outside the interval. To establish the causative link between Zdhhc21 and the dep phenotype, we generated transgenic mice containing the bacterial artificial chromosome, RP23-76J17, containing only Zdhhc21 and Cer1 ([Figure 1A](#pgen-1000748-g001){ref-type="fig"}). When crossed onto a dep background, this transgene rescues the hair phenotype to a smooth and shiny dorsal coat, indistinguishable from wild-type, whilst the hair of nontransgenic littermates retains the greasy and disorderly dep phenotype ([Figure 1C](#pgen-1000748-g001){ref-type="fig"}). Later in life, non-transgenic mutant littermates lose their hair, whilst the transgenic mice do not. Skin sections of transgenic rescued mice show a normal histological appearance, confirming that the dep phenotype is fully rescued ([Figure 1D and 1E](#pgen-1000748-g001){ref-type="fig"}). Zdhhc21-del233F is mislocalised and lacks PAT function {#s2b} ------------------------------------------------------ Zdhhc21 has previously been demonstrated to have palmitoyl transferase (PAT) activity. Among 23 Zdhhc members tested, endothelial nitric oxide synthase (eNOS, Nos3) [@pgen.1000748-FernandezHernando1] and lymphocyte-specific protein tyrosine kinase (Lck) [@pgen.1000748-Tsutsumi1] were found to be robustly palmitoylated by Zdhhc21. Using these substrates, we examined whether the dep mutant Zdhhc21 protein retains PAT function. To test PAT activity, plasmids encoding tagged wild-type and mutant Zdhhc21 proteins were cotransfected with plasmids expressing Lck or eNOS (Nos3). Palmitoylation of substrates was assessed by metabolic labeling with \[^3^H\]palmitate followed by SDS-PAGE and fluorography [@pgen.1000748-Fukata1],[@pgen.1000748-Fukata2]. Wild-type Zdhhc21 protein enhanced both eNOS and Lck palmitoylation, whilst the del233F protein showed no enhancement over background palmitoylation. A second mutant protein, C120S, in which the cysteine residue in the conserved DHHC motif was mutated, was also inactive in this assay ([Figure 2A](#pgen-1000748-g002){ref-type="fig"}). ![dep mutation disrupts PAT activity and localization of Zdhhc21.\ (A) \[^3^H\]Palmitate fluorography of individual Zdhhc21 (wild type, dep and C120S) HA-tagged constructs co-transfected with eNOS or Lck into HEK293 cells. Increased incorporation of \[^3^H\]palmitate into targets is observed with the wild type construct. Neither mutant shows palmitoylation activity above background. Immunoblots using anti-HA (Zdhhc21 constructs), anti-myc (eNOS) and anti-Lck control for loading. (B--I) Immunofluorescence of primary keratinocytes transfected with wild type (B--E) and dep (F--I) HA-tagged Zdhhc21 cDNAs. (B,F) Epidermal marker Keratin 14 (red) and anti-HA (green) antibody staining. While wild type protein shows discrete and compartmentalized localization, the mutant protein is diffuse. (C,G) cis-Golgi network marker GM130 (red) and anti-HA (green) antibody staining. (D,H) trans-Golgi marker Tgn138 (green) and anti-HA (red). (E,I) ER marker PDI (green) and anti-HA (red).](pgen.1000748.g002){#pgen-1000748-g002} As mislocalisation of the mutant protein could affect its function in vivo, we examined the cellular localization of tagged variants of Zdhhc21 proteins in cell culture. In primary keratinocytes, HA-tagged wild type Zdhhc21 localizes to highly specific cytoplasmic structures, which co-localise with the cis-Golgi marker GM130, consistent with previous studies showing localization of other Zdhhc proteins to the Golgi ([Figure 2C](#pgen-1000748-g002){ref-type="fig"}) [@pgen.1000748-Fukata1],[@pgen.1000748-FernandezHernando1]. In contrast, Zdhhc21-del233F colocalizes with the endoplasmic reticulum (ER) marker, protein disulfide isomerase (PDI), demonstrating that dep mutant protein is unable to target specifically to the Golgi and appears to be trapped in the ER. ([Figure 2I](#pgen-1000748-g002){ref-type="fig"}). We further verified these observations by transfection in NIH-3T3 cells, and demonstrated the mislocalisation and lack of PAT activity of additional mutant forms of the protein ([Figure S1](#pgen.1000748.s001){ref-type="supplementary-material"}) Zdhhc21 is a PAT expressed in epithelial tissues {#s2c} ------------------------------------------------ To define the target tissue in which PAT function is required for normal hair development, Zdhhc21 mRNA and protein expression were analyzed at embryonic and postnatal time-points related to hair follicle morphogenesis and cycling. In the developing skin, Zdhhc21 expression could not be detected prior to hair follicle induction (E13.5) or early morphogenesis (E14.5) (data not shown). Expression of Zdhhc21 is initially detected in the inner root sheath (IRS) of developing vibrissae follicles at E16.5 ([Figure S2](#pgen.1000748.s002){ref-type="supplementary-material"}) and later in the developing IRS of E18.5 pelage follicles (data not shown). Postnatally, Zdhhc21 exhibits two patterns of expression in distinct layers of more distal post-mitotic lineages in the hair bulb. Strong ubiquitous cellular expression of Zdhhc21 is detected in a single layer of the IRS ([Figure 3A](#pgen-1000748-g003){ref-type="fig"}). Double immunofluorescence with antibodies against trichohyalin (AE15) ([Figure 3A](#pgen-1000748-g003){ref-type="fig"}) or Gata3, which is expressed only in Huxley\'s layer and the IRS cuticle ([Figure 3D](#pgen-1000748-g003){ref-type="fig"}), demonstrated partial co-localization with trichohyalin but not Gata3, indicating Zdhhc21 is expressed in Henle\'s layer, the outermost IRS layer. A second Zdhhc21 expression domain, marked by punctate staining, is found predominantly in the outermost layer of cells expressing hair cortex keratins (AE13-positive) ([Figure 3B](#pgen-1000748-g003){ref-type="fig"}, white arrowhead) and Foxn1-positive cells ([Figure 3C](#pgen-1000748-g003){ref-type="fig"}, white arrowhead), indicative of the hair shaft cuticle. A less prominent but similarly punctate pattern is found in the adjacent Gata3-positive IRS cuticle cells ([Figure 3C and 3D](#pgen-1000748-g003){ref-type="fig"}, yellow arrowhead). As in cell culture, these Zdhhc21-positive punctae colocalize with cis-Golgi marker GM130 in vivo suggesting that the protein in these cells is active in palmitoylation ([Figure 3E](#pgen-1000748-g003){ref-type="fig"}). Importantly, while Zdhhc21 transcript expression is not altered in dep follicles ([Figure S2D and S2E](#pgen.1000748.s002){ref-type="supplementary-material"}), mutant Zdhhc21 protein is mislocalized in both cuticle lineages where it shows diffuse staining ([Figure 3F](#pgen-1000748-g003){ref-type="fig"}, [Figure S3](#pgen.1000748.s003){ref-type="supplementary-material"}). Together, the loss of in vivo Golgi localization of Zdhhc21 in dep mutants and the resulting mutant hair shaft phenotype suggest that Zdhhc21 function is primarily required in the cuticle layer. Both patterns of hair follicle expression are hair cycle dependent; expression of Zdhhc21 cannot be detected in telogen ([Figure S2J](#pgen.1000748.s002){ref-type="supplementary-material"}) or very early anagen follicles, but it is first expressed in nested layers of the IRS and cuticle of anagen and catagen follicles ([Figure S2](#pgen.1000748.s002){ref-type="supplementary-material"}). Comparable cyclic expression of Zdhhc21 during this postnatal hair cycle is also observed in dep mutant skin. Notably, the onset of expression in differentiating lineages in the anagen follicles correlates with the first sign of abnormal morphology ([Figure S3](#pgen.1000748.s003){ref-type="supplementary-material"}). ![Zdhhc21 expression is restricted to differentiated post-mitotic lineages of hair follicles.\ Confocal slices (1µm) of Zdhhc21 protein expression in wild type (A--E) and dep (F) P28 anagen follicles. (A) Ubiquitous Zdhhc21 (red) expression colocalizes with the outermost layer of AE15 (green) expression. (B) Punctate Zdhhc21 staining (red) colocalizes with the outermost layer of AE13 expression (green: weaker than inner cortex expression) and (C) Foxn1 expression (white arrowhead). (D) Single foci of Zdhhc21 staining (red: yellow arrowhead) per cell of the IRS cuticle is seen in the innermost Gata3-positive layer (green). (E) In wild type skin, punctae of Zdhhc21 (red) colocalize with GM130 (green), whilst diffuse staining is observed in dep mutants (F). Arrowheads mark same region in single channels.](pgen.1000748.g003){#pgen-1000748-g003} Outside the cycling portion of the hair follicle, we find specific cellular Zdhhc21 protein strongly present in the degenerated remains of the IRS surrounding the isthmus, in the permanent portion of the follicle ([Figure S2I](#pgen.1000748.s002){ref-type="supplementary-material"}). Importantly, expression of Zdhhc21 mRNA or protein cannot be detected in the bulge, IFE or in the sebaceous gland at any stage of the hair cycle. Zdhhc21 is required for epithelial homeostasis {#s2d} ---------------------------------------------- The dep phenotype can be identified macroscopically within the first postnatal week as a greasy and disorderly hair distribution, as previously reported [@pgen.1000748-Mayer1]. To determine the cellular basis of the observed abnormalities, we conducted histological and molecular analyses of skin samples at a range of developmental stages. Dorsal skin from dep embryos at E14.5 and E18.5 have follicle morphology and numbers comparable to wild type ([Figure 4G and 4J](#pgen-1000748-g004){ref-type="fig"} and data not shown), indicating that Zdhhc21 function is dispensable for hair follicle patterning and morphogenesis. The first abnormalities in dep mice are observed shortly after birth where mild sebaceous gland hyperplasia and slight thickening of the IFE develop at P5. While dep mutants appear to progress through the first hair cycle normally ([Figure 4H and 4K](#pgen-1000748-g004){ref-type="fig"}), by telogen, defects in the permanent portions of dep skin are apparent and include thickening of the IFE and a dilated infundibulum ([Figure 4I and 4L](#pgen-1000748-g004){ref-type="fig"}). By the onset of the second hair cycle around P28, the dep follicles are growth retarded and immature compared to littermates ([Figure 4A and 4D](#pgen-1000748-g004){ref-type="fig"}) coincident with the onset of Zdhhc21 expression ([Figure S3](#pgen.1000748.s003){ref-type="supplementary-material"}). In addition, the thickening of IFE and sebaceous gland hyperplasia appear more prominent ([Figure 4D](#pgen-1000748-g004){ref-type="fig"}, arrowed). Staining for lipids reveals enlarged sebaceous glands with an excess of sebum ([Figure 4E and 4F](#pgen-1000748-g004){ref-type="fig"}), underlying the greasy appearance of the coat at this stage. In some dep animals, from P28 onwards, small epidermal cysts containing keratinized material can be observed in the upper portion of the dermis (not shown). Given the hyperplastic changes observed in the upper portions of dep follicles, we asked whether the closely associate bulge stem cell niche was also perturbed. Keratin 15 (K15) is a marker for these cells, and indeed, the K15-positive population is expanded in dep mutants, although its expression remains restricted to the bulge niche, suggesting that changes in the size and shape of the dep bulge during the hair cycle could impact progenitor allocation to various epidermal compartments ([Figure S5F and S5L](#pgen.1000748.s005){ref-type="supplementary-material"}, data not shown). ![Zdhhc21 is required for epidermal differentiation and patterning.\ dep mutant skin displays pronounced defects postnatally associated with anagen stages of hair cycle including abnormal hair follicle differentiation, and interfollicular and sebaceous hyperplasia. Stages shown: anagen P28 (A--F), late embryonic morphogenesis E18.5 (G,J), early catagen P14 (H,K) and telogen P21 (I,L). Hematoxylin and eosin staining (A,D,G--L). Oil-Red-O staining of cryosections (B,E). Nile red wholemount staining of P28 tail skin(C,F). Insert in (A) shows histology of a "hairless" dorsal region at P28: note the more severe follicular phenotype. Filled arrowheads mark the interfollicular epidermis and open arrowheads point to examples of sebaceous glands.](pgen.1000748.g004){#pgen-1000748-g004} The hyperplastic phenotype of dep IFE and sebaceous glands is most prominent during anagen in younger skin, when growth stages of the hair cycle are highly synchronized. To determine whether this hyperplastic phenotype was due to increased proliferation of these non-follicular compartments, we carried out BrdU pulse labeling cohorts of P32 gender-matched animals. These studies revealed a small but significant increase in the fraction of BrdU positive dep IFE cells (8.314±1.493, n = 2, p\<0.005) compared with heterozygous (6.790±1.8223, n = 2) or wild type controls (6.686±1.711, n = 2) ([Figure S4L](#pgen.1000748.s004){ref-type="supplementary-material"}). A greater increase in percentage BrdU positive cells was observed in dep sebaceous glands (11.46±2.784, n = 2, p\<0.05) compared to controls (heterozygous: 6.881±2.499; wild type: 7.882±2.868). A concomitant decrease of BrdU labeling is observed in dep mutant follicles during anagen ([Figure S4K](#pgen.1000748.s004){ref-type="supplementary-material"}). Additional proliferation markers, including the M-phase marker phospho-histone H3 and a general marker Ki67 identifying all phases of the cell cycle, confirm this change in proliferation is relatively small and is restricted to the basal compartment ([Figure S4A, S4B, S4C, S4D, S4E, S4F, S4G, S4H, S4I, S4J](#pgen.1000748.s004){ref-type="supplementary-material"}). We asked whether aberrant terminal differentiation of keratinocytes in the IFE also contributes to the dep phenotype, such that an expanded progenitor pool contributing to the IFE could result in an increase in cell number in the stratified layers. Immunolabelling of basal cell markers p63 and keratin 5 (K5) showed an expansion of this progenitor compartment ([Figure 5A, 5B, 5C, and 5E](#pgen-1000748-g005){ref-type="fig"}). Furthermore, p63-positive cells were found in thickened K10-positive spinous layer in dep skin ([Figure 5D and 5F](#pgen-1000748-g005){ref-type="fig"}, arrowed). The terminal differentiation markers loricrin and filaggrin were only slightly expanded in dep mutants ([Figure S5A, S5B, S5G, S5H](#pgen.1000748.s005){ref-type="supplementary-material"}) indicating that differentiation in dep mutants occured but was significantly delayed. Interestingly, the transcription factor Gata3, which is normally expressed in the basal and suprabasal layers of the IFE where it directs keratinocyte and lipid based barrier differentiation programs [@pgen.1000748-deGuzmanStrong1],[@pgen.1000748-Candi1], is strongly reduced in dep IFE ([Figure 5G and 5H](#pgen-1000748-g005){ref-type="fig"}, arrowed) consistent with the observed delay in differentiation. Reduced levels of Gata3 in the dep IFE during anagen may contribute to defects in lipid biosynthesis required for barrier function, which may give rise indirectly to the hyperproliferative phenotype observed [@pgen.1000748-Proksch1]. However, unlike Gata3 knock-out skin [@pgen.1000748-deGuzmanStrong1], delays in the establishment of embryonic barrier function by dye penetration assays were not seen and keratinocyte terminal differentiation program in embryonic skin occurred normally ([Figure S6](#pgen.1000748.s006){ref-type="supplementary-material"}). Furthermore, phenotypes associated with impaired barrier function, including failure to thrive or red shiny skin, were not observed in dep neonates. These observations suggest that any barrier defects present in dep mutants are likely quite subtle and limited to a postnatal window. In contrast to the decrease in Gata3 and altered terminal differentiation, an increase in phospho-ERK staining, indicative of growth factor and integrin signaling linked to increased proliferation in the basal layer of the IFE [@pgen.1000748-Haase1], is observed in dep mutants ([Figure 5G and 5H](#pgen-1000748-g005){ref-type="fig"}, [Figure S5D, S5D′, S5D″, S5E, S5E′, S5J, S5J′, S5J″, S5K, S5K′](#pgen.1000748.s005){ref-type="supplementary-material"}, arrowed). These observations together suggest that the thickening of the IFE observed during anagen in dep mutants is due to continued division and delayed differentiation of the expanded basal progenitor compartment after leaving the basement membrane. ![Loss of Zdhhc21 disrupts balance between proliferation and differentiation in anagen interfollicular epidermis.\ P28 wild type (A,A′,C,D,G,H,K,L) and dep (B,B′,E,F,I,J,M,N) skin. dep mutants show expansion of K5+ (red), p63+ (green) progenitor compartment (A--D). p63+ progenitors (green) are expanded into terminally differentiating K10+ (red) layers of dep IFE (D,F). Expression of transcriptional regulator of differentiation Gata3 in the basal and suprabasal keratinocytes is greatly reduced or absent in dep IFE with a parallel increase in proliferative basal phospho-ERK signals (green; Gata3, red; phospho-p42/44, G,H). (G--H″) single channels of region of interest in merge shown in (G,H).](pgen.1000748.g005){#pgen-1000748-g005} The restricted expression of Zdhhc21 in the IRS and cuticle of the hair follicle is hard to reconcile with a direct effect on proliferation and differentiation in the IFE and sebaceous gland. One possibility is that the physiologically relevant palmitoylation targets are highly diffusible signals, or are regulators of such signals. Alternatively, Zdhhc21 may act locally in the follicle to indirectly impact non-follicular lineages as a consequence of hair abnormalities in dep mice. Such a phenomenon is seen in K14-Cre-induced knockout of the hair-follicle specific,transcription factor Dlx3, where the resultant abnormal and undifferentiated hair shafts are accompanied by hyperplastic sebaceous glands [@pgen.1000748-Hwang1]. Hair cycle signal transduction defects in dep mutants {#s2e} ------------------------------------------------------- As palmitoylation is usually involved in the regulation of dynamic processes, we investigated whether key signalling events throughout the postnatal hair cycle were affected in dep mutant skin. Bone morphogenetic protein (BMP) signalling is required for embryonic hair follicle development and postnatal hair cycling [@pgen.1000748-Botchkarev1]. Furthermore, conditional epidermal ablation of receptor BMPR1a [@pgen.1000748-Kobielak1]--[@pgen.1000748-Yuhki1] result in a hair loss phenotype associated with poorly differentiated hair follicles, and thickened IFE. However, no difference in expression of activated phospho-Smad1/5/8, mediators of canonical BMP signalling, was detected in mutant skin at various stages of the hair cycle ([Figure 6A and 6B](#pgen-1000748-g006){ref-type="fig"}, data not shown). Transforming growth factor beta (TGF-β) signalling also plays a key role in hair follicle development and cycling, as well as keratinocyte differentiation [@pgen.1000748-Foitzik1],[@pgen.1000748-Descargues1]. No difference in expression of activated canonical intracellular mediator phospho-Smad2 was observed in dep mutant follicles or IFE ([Figure 6E and 6F](#pgen-1000748-g006){ref-type="fig"}, data not shown). Recent studies have suggested a key role for palmitoylation in BMP- [@pgen.1000748-Leong1] or TGF- mediated signalling events [@pgen.1000748-Zuo1] via the non-canonical p38 MAPK arm; however, no alterations in phospho-p38 staining could be detected in dep mutants ([Figure 6C and 6D](#pgen-1000748-g006){ref-type="fig"}). These results suggest that despite the profound follicular phenotype of dep mutant mice, these key developmental signals required for adult hair cycle are not broadly affected. ![Anagen signalling is delayed in dep follicles.\ Wild type (A,C,E,G,I) and dep (B,D,F,H,J) P28 dorsal follicles. Several key signalling pathways required for postnatal hair development are not affected in dep mutants. Canonical BMP signalling (red; phospho-Smad-1/-5/-8, A,B), non-canonical BMP/TGF-β signalling (red; phospho-p38, C,D) and canonical TGF-β signalling (red: phospho-Smad-2/-3 E,F) are expressed in delayed dep follicles. Expression and nuclear localization of downstream canonical Wnt effectors β-catenin (green; β-catenin, G--J) and Lef-1 (red; Lef-1, I,J) are reduced in dep hair matrix and shaft (arrowed). Of the transcription factors regulating differentiation of anagen hair follicle lineages, expression of Wnt transcriptional target Foxn1 is reduced or absent in dep follicles (green; Foxn1 A,B), while Hoxc13 is expressed in all dep follicles (green; Hoxc13 C, D). Gata3 is expressed in all dep follicles although levels of expression may be slightly reduced. (green; Gata3 E,F). Along side merge panel are shown single channel of regions of interest to highlight staining.](pgen.1000748.g006){#pgen-1000748-g006} The range of phenotypes seen in dep animals is reminiscent of a reduction of Wnt signalling, which plays many important roles during hair development. Precise levels of β-catenin activation are required for differentiation into specific epidermal lineages. High levels of β-catenin signaling promote hair follicle formation [@pgen.1000748-Gat1],[@pgen.1000748-SilvaVargas1] and normal differentiation of the hair shaft [@pgen.1000748-Merrill1]. Low levels of Wnt/β-catenin signaling promote terminal differentiation of the IFE and sebaceous glands [@pgen.1000748-DasGupta1],[@pgen.1000748-Niemann1]. To determine whether a reduction in Wnt signalling is seen in dep mutant skin, we analyzed Wnt responses in embryonic and adult skin by immunohistochemistry. Wnt responses during embryonic hair follicle morphogenesis appear normal in dep embryos (data not shown). At the initiation of the first, synchronized, anagen phase (P24), prior to expression of Zdhhc21, both control and dep littermates show nuclear Lef1 in the dermal papilla and surrounding secondary hair germ ([Figure S7A, S7B, S7C, S7D](#pgen.1000748.s007){ref-type="supplementary-material"}). However, in dep mice, propagation of this anagen response appears defective and differentiation of the hair shaft and cortex is significantly delayed. By P28, at the onset of Zdhhc21 expression when wild type hair is well established in anagen, the delayed dep hair follicles fail to expand strong Lef1 and nuclear β-catenin expression in the matrix and precortex ([Figure 6H and 6J](#pgen-1000748-g006){ref-type="fig"}). Accordingly, the Lef1 transcriptional target, Foxn1, which regulates expression of hair specific keratins, is strongly reduced or absent from mutant follicles ([Figure 6A and 6B](#pgen-1000748-g006){ref-type="fig"}, [Figure S7I and S7K](#pgen.1000748.s007){ref-type="supplementary-material"}) as are acidic hair shaft keratins (AE13), ([Figure S7J and S7L](#pgen.1000748.s007){ref-type="supplementary-material"}) consistent with the delayed state of development. By contrast expression of homeodomain transcription factor Hoxc13, which also regulates expression of several hair shaft keratins, is still detected in all dep mutant follicles at this stage of anagen ([Figure 6C and 6D](#pgen-1000748-g006){ref-type="fig"}). Surprisingly, unlike the profound reduction in Gata3 expression observed in the dep IFE and similarities between follicular phenotype observed in conditional Gata3 mutant mice [@pgen.1000748-Kurek1], Gata3 is still detected in all dep follicles although at slightly reduced levels throughout anagen ([Figure 6E and 6F](#pgen-1000748-g006){ref-type="fig"}, [Figure S3](#pgen.1000748.s003){ref-type="supplementary-material"}). By P35, many dep follicles express levels of Lef1 and hair-shaft keratins comparable to controls, although the morphology of dep follicles remain misshapen and misoriented ([Figure S7M, S7N, S7O, S7P](#pgen.1000748.s007){ref-type="supplementary-material"}). Interestingly, some regions in dep mice continue to remain visibly "hairless", although histological analysis reveals normal numbers of retarded follicles which fail to proceed through anagen and form functional hairs ([Figure 4D](#pgen-1000748-g004){ref-type="fig"}, insert). Our data suggest that a number of signalling pathways required for epidermal homeostasis are disrupted in the absence of Zdhhc21 PAT activity. During the anagen phase of the hair cycle there is a reduction of Wnt responses in the hypoproliferative dep follicles and an increase in phospho-ERK signalling in the hyperplastic mutant IFE. Which of these phenotypes are direct or indirect consequences of the loss of Zdhhc21 palmitoylation remains to be addressed. Given we cannot detect Zdhhc21 expression outside the follicle, we suggest the follicular phenotype observed in dep mutants is the primary cause where defects in hair shaft differentiation during anagen perturb processes at a distance in the IFE and sebaceous glands. Importantly, palmitoylation may influence the quality and the quantity of a signalling event rather than acting as an absolute ON/OFF switch. This is in keeping with the observation that the amplification of Wnt responses during early anagen is very delayed, and not completely blocked, suggesting some threshold could be operating and is eventually met in mutant follicles. In vivo palmitoylation targets for Zdhhc21 {#s2f} -------------------------------------------- At the synapse, palmitoylation mediates dynamic changes in membrane associations of pools of target proteins involved in signaling, cell adhesion and trafficking [@pgen.1000748-Kang2]. Given the rapid remodeling observed in the hair cycle, it is tempting to speculate that similar processes are involved in the skin and to ask what are the biologically relevant targets of palmitoylation. It should be noted, that while several targets have been identified for each of the 23 Zdhhc PATs, each of these target so far is palmitoylated by multiple PATs, at least in vitro. This suggests a level of functional redundancy in the palmitoylation machinery exists. It also suggests that the dep phenotype could result from the loss of palmitoylation of one or more targets. We reasoned that any direct target of PAT activity must be expressed in the same cells in which we detect Zdhhc21 expression. One possibility is the known Zdhhc21 target, eNOS [@pgen.1000748-FernandezHernando1], which is expressed in the skin [@pgen.1000748-Sowden1]. However, observation of eNOS mutant mice indicates that this is not required for normal skin and hair development [@pgen.1000748-Shesely1], suggesting it is unlikely to be the key palmitoylation target of Zdhhc21 in skin. Given that Zdhhc21 expression is restricted to hair follicles but multiple epidermal lineages are affected in dep mutants, we asked whether diffusible Wnt proteins could be functional palmitoylation targets for Zdhhc21. Wnt proteins are known to be palmitoylated, and this modification is essential for their function [@pgen.1000748-Willert1]. However, this is believed to be mediated by the ER protein porcupine (PORC), a PAT unrelated to the Zdhhc family [@pgen.1000748-Kadowaki1]. Nevertheless, we tested three candidate Wnts (Wnt3a, 5a and 10a), which are expressed in domains that overlap with Zdhhc21 expression [@pgen.1000748-Reddy1]. Although these Wnts are predicted to have multiple palmitoylation sites (CSS-Palm, data not shown) [@pgen.1000748-Ren1], none are directly palmitoylated by Zdhhc21 (data not shown). Trafficking of Wnt ligands from the Golgi to endosomes requires the cargo receptor Wntless/Evi (Wls), a seven-transmembrane protein expressed in the Golgi [@pgen.1000748-Banziger1]. Sustained Wnt signaling also requires that this cargo receptor be recycled via the retromer complex. Similar cargo proteins have been shown to require DHHC-dependent palmitoylation for retrograde sorting [@pgen.1000748-McCormick1]. However, no palmitoylation of Wls by Zdhhc21 was detected in our co-transfection assay (data not shown). While it remains possible that Zdhhc21 acts locally in a subset of Wnt-responding cells in the hair follicle required for proper hair shaft differentiation (i.e. through modulation of receptor complexes or intracellular signal transduction), we have been unable to establish a direct link between palmitoylation and Wnt responses in this present study. While the Src family kinase, Lck, is a known target of Zdhhc21, it is not required for keratinocyte differentiation nor do Lck mutants have any gross skin phenotype [@pgen.1000748-Calautti1]. We therefore considered whether other related kinases that are epidermally expressed could be potential palmitoylation targets. Fyn is indeed expressed in the skin where it plays a role in keratinocyte differentiation in vitro and in vivo [@pgen.1000748-Calautti1], in part through down-regulating EGFR signaling [@pgen.1000748-Cabodi1]. The role for Fyn in hair follicle development and cycling remains unclear. Aged Fyn ^−/−^ Fak^+/−^ mice develop progressive hair loss with IFE and sebaceous gland hyperplasia, but this is not observed in Fyn ^−/−^ mutants [@pgen.1000748-Ili1]. We therefore tested GFP-tagged Fyn with a panel of Zdhhc PATs by co-transfection and metabolic labelling. Fyn is palmitoylated in our in vitro assay by Zdhhc2, 3, 7, 10, 15, 20 and 21 ([Figure 7A](#pgen-1000748-g007){ref-type="fig"}, data not shown). Palmitoylation of Fyn by Zdhhc21 results in efficient targeting of Fyn to the perinuclear region in HEK cells ([Figure 7B and 7C](#pgen-1000748-g007){ref-type="fig"}). Fyn is also subject to myristoylation, an irreversible covalent lipid modification involved in membrane targeting and signaling. Interestingly, we show a mutant Fyn construct lacking the myristoylation site (Fyn-G2A) cannot be palmitoylated by Zdhhc21 or correctly targeted ([Figure 7D and 7E](#pgen-1000748-g007){ref-type="fig"}), suggesting palmitoylation of Fyn is downstream of the myristoylation event. ![Zdhhc21 palmitoylation of Fyn is required for localization in vitro and in vivo.\ (A) \[3H\]Palmitate fluorography of subset of panel of all mammalian Zdhhc HA-tagged constructs co-transfected with Fyn::GFP into HEK293 cells. Increased incorporation of \[3H\]palmitate into targets is observed with Zdhhc15, −20 and −21. A myristoylation-deficient Fyn mutant is not palmitoylated following cotransfection with Zdhhc21 (G2A, final lane). (B--E) Immunofluorescence of HEK293 cotransfected with Fyn::GFP alone (B), Fyn::GFP and wild type HA-tagged Zdhhc21 cDNA (C), G2A mutant Fyn::GFP alone (D) and G2A mutant Fyn::GFP and HA-tagged Zdhhc21 (E). Zdhhc21 causes increased perinuclear accumulation of Fyn::GFP, a domain associated with localization of other palmitoylated targets including PSD-95 and GAP-43. This localization is not observed with G2A mutant Fyn::GFP (D). (F--I) Confocal images (0.5µm) of immunostaining of Fyn (red: F,G) and active SFKs (red: H--I) in P32 anagen dorsal hair follicles in wild type (F,H) and dep mutants (G,I). Arrowheads mark region of interest in IRS cuticle that are enlarged in single channel images (F′--I′) where Fyn localization to membranes between IRS cuticle cells is lost in dep mutants.](pgen.1000748.g007){#pgen-1000748-g007} To test whether Fyn was a viable in vivo target of Zdhhc21, we examined localization Fyn in wild type and dep follicles. In wild type anagen (P32) follicles, Fyn is initially expressed diffusely in the hair bulb becoming very discretely localized to membranes at junctions between cells of the IRS cuticle with differentiation ([Figure 7F and 7F′](#pgen-1000748-g007){ref-type="fig"}, arrowed). This localization is weaker and more diffuse in dep follicles ([Figure 7G and 7G′](#pgen-1000748-g007){ref-type="fig"}, [Figure S8A and S8B](#pgen.1000748.s008){ref-type="supplementary-material"}). These results were confirmed using an antibody which recognizes the active, phosphorylated forms of all Src-family kinases (SFKs) in addition to Fyn. The active SFKs show a broader expression pattern with striking membrane localization, including the junctions between cells of the IRS cuticle ([Figure 7H](#pgen-1000748-g007){ref-type="fig"}, [Figure S8C](#pgen.1000748.s008){ref-type="supplementary-material"}). In contrast, while general expression of active SFKs is not altered in dep mutant follicles, uniform active SFK is seen around cells of the IRS cuticle ([Figure 7I](#pgen-1000748-g007){ref-type="fig"}, [Figure S8D](#pgen.1000748.s008){ref-type="supplementary-material"}). Given that the Zdhhc21 Golgi-localization observed in the IRS cuticle of wild type follicles is lost in dep mutants and that Golgi-localization is dependent on auto-palmitoylation via the PAT activity of wild type Zdhhc21, our results suggest that Zdhhc21-mediated palmitoylation of Fyn is required in vivo for Fyn\'s discrete localization in the differentiating IRS cuticle. It is interesting to note that in the despite the proliferation and differentiation defects observed in the dep mutant IFE, and Fyn\'s established role in keratinocyte differentiation, the localization of Fyn in the dep IFE is normal, although it is delayed as expected given the expanded basal compartment in dep mutants ([Figure S8E and S8F](#pgen.1000748.s008){ref-type="supplementary-material"}). Our data demonstrates that Fyn is a direct palmitoyaltion target for Zdhhc21 in vitro and dysregulation of Fyn occurs in vivo in dep mutant follicles. In assessing the dep phenotype, it is worth noting that the consequences of dysregulated palmitoylation may not mirror those of gene ablation studies, as palmitoylation has the potential to modulate cell signaling in a complex manner. Furthermore, the phenotypic features of dep mice extend beyond those likely caused by the loss of Fyn activity, correlating with the broad substrate specificity of different Zdhhc proteins. To comprehensively tackle the functional requirement of Zdhhc21, the use of global approaches, recently applied in yeast, will be necessary to compare the palmitoylated proteome of dep mutant and wild type cells [@pgen.1000748-Roth2]. This study is the first to highlight a role for palmitoylation in mammalian development and homeostasis. We have demonstrated that loss of Zdhhc21 function in dep mutants results in defects in all three epidermal lineages, including hyperplasia of the IFE and sebaceous glands with a delay in hair follicle differentiation. Given the highly restricted pattern of Zdhhc21 expression to the differentiating hair follicle, our results demonstrate that defective palmitoylation can have far-reaching effects disrupting epidermal homeostasis by altering the balance between proliferation and differentiation. Although the full identity of direct and biologically relevant palmitoylation targets in the skin remains unknown, we show Zdhhc21 can directly palmitoylate Fyn in vitro and this modification affects Fyn localization both in vitro and in vivo. Future studies into the distinct and overlapping roles of additional Zdhhc members will help to fully understand the role of palmitoylation in modulating key signals during development. Materials and Methods {#s3} ===================== Ethics statement {#s3a} ---------------- Mice were maintained in accordance with MRC Guidelines "Responsibility in the Use of Animals for Medical Research" (July 1993) and research licenced by the UK Home Office under the Animals (Scientific Procedures) Act 1986. Mouse husbandry and BAC transgenics {#s3b} ----------------------------------- Animals were maintained in SPF environment and on a C57BL/6J background. Genomic DNA extracted from ear clips or tail biopsies was used for PCR genotyping. For dep, exon 7 of Zdhhc21 was amplified by standard PCR to yield a 249bp fragment that was run on the ABI310 genetic analyzer to detect the deletion. The dep genotyping primer sequences were: 5′-FAM-AGCTGACTGAAGGGCACC-3′ (Exon 7F) and 5′-AAAACCTGTAACGCATTTCCA-3′ (Exon 7R). For transgenic rescue, purified RP23-76J17 BAC DNA (BAC PAC Resource Center (BPRC), the Children\'s Hospital Oakland Research Center Institute, CA) was injected into homozygous dep embryos. The presence of the BAC was genotyped using three markers, including CmR specific to the plasmid, as well as two markers at both ends of the BACs, amplifying the border between the BAC carrier plasmid and BAC genomic region. For timed matings for embryonic samples, the morning of vaginal plug was counted as 0.5 (E0.5). For postnatal timepoints, a set of gender-matched wild type, heterozygous and mutant littermates were aged accordingly from the day of birth 0 (P0). Deletion mapping {#s3c} ---------------- Mapping of the deletion endpoints defining dep was described by Smyth et al [@pgen.1000748-Smyth1]. Palmitoylation assay {#s3d} -------------------- cDNA encoding wild type and mutant Zdhhc21 were transfected into HEK293 cells, along with candidate palmitoylation substrates. Cells were labelled with \[^3^H\]palmitate for 4 hours as previously described [@pgen.1000748-Fukata1],[@pgen.1000748-Fukata2]. After metabolic labeling, palmitoylated proteins were analysed by SDS-PAGE. Transfection efficiency and translation of substrates was assessed by Western blotting. Preparation of mammalian expression plasmids and cell culture {#s3e} ------------------------------------------------------------- The mammalian expression vector of wild-type Zdhhc21, pEFBos-HA-Zdhhc-21 (with EF1-alpha promoter), was provided by Masaki Fukata. It was then modified by using the QuikChange® Site-Directed Mutagenesis Kit (Stratagene), to introduce single nucleotide changes for the following Zdhhc21 alleles: L91F, C95S and C106S. For the dep mutation, del-233F, was modified from pEFBos-HA-Zdhhc-21 by subcloning dep cDNA (Access RT-PCR System, Promega) into the BamHI sites flanking the insert. Full-length mouse Wnt cDNAs (kindly provided by Jeremy Nathans (Wnt3a), Wnt5a (Yingzi Yang) and Wnt10a (Takano Yamamoto)) were introduced into a pCMX2GFPFLAGSTOP vector (kindly provided by Nick Gilbert) to express double FLAG-tagged full-length proteins. Constructs were verified by direct DNA sequencing, using primers: 5′-CAAATGGGCGGTAGGCGTGT-3′ (Pcmxgfp2fg-seqF) 5′-TTGTCCAATTATGTCACACCA-3′ (Pcmxgfp2fg-seqR) The Myc-tagged full length Wls cDNA used in these studies has accension number BC018381 (Catalog No: MR207034: Origene, MD). Human foreskin keratinocytes [@pgen.1000748-DiColandrea1] and NIH 3T3 cells (ATCC) were maintained as described. DNA plasmids were transfected into cells using Lipofectamine 2000 (Invitrogen) as per manufacturer\'s specifications. Zdhhc21 RNA in situ probe and antibody generation {#s3f} --------------------------------------------------- Zdhhc21 cDNA product was generated using Access RT-PCR kit (Promega) and cloned into p-GEM-T. The RT-PCR primers used were: 5′-CATGGGCTTGATTGTCTTTGT-3′ and 5′-ACGTGATTGGCAAAGTGGTAG-3′. DIG-labeled RNA section in situ protocol was performed, details available on request. Custom rabbit polyclonal antibodies to Zdhhc21 were generated using a peptide comprising residues 73--87 (GRLPENPKIPHAERE+C)(Eurogentec). Pre-incubation of the Zdhhc21 antibody with its immunizing peptide blocked all signal in immunohistochemistry ([Figure S2L](#pgen.1000748.s002){ref-type="supplementary-material"}). Histological and marker gene analysis {#s3g} ------------------------------------- ### Tail epidermis wholemount preparations {#s3g1} Whole tail skin was peeled off connective tissue and bone, then incubated in 5mM EDTA/PBS for 4 hours at 37°C. Forceps were used to separate epidermis from dermis which was then fixed in 4% paraformaldehyde/PBS. ### Alkaline phosphatase staining of dermal papilla and staging hair cycle {#s3g2} Paraffin embedded sections of 6µm thickness were dewaxed and rehydrated, and rinsed in PBS. Sections were incubated 15 minutes in APB (100mM NaCl, 100mM Tris pH9.5, 50mM MgCl2, 0.3% Tween-20), then either BM Purple (Roche) or Vector Red Alkaline Phosphatase kit (Vector Labs) color substrate was added. Slides were incubated at room temperature in the dark until staining developed. Sections were rinsed in water and counterstained with eosin (in the case of BM Purple), then dehydrated and mounted in DePex mounting media (BDH). Staging of hair follicles in hair cycle was done according to characteristics described in [@pgen.1000748-MullerRover1]. ### Oil-Red-O staining for lipids {#s3g3} Cryosections of P24 skin of 10µm thickness were rinsed in water, followed by 50% EtOH and stained with Oil-Red-O (60% stock in water). Slides were rinsed in 50% EtOH, followed by water and counterstained with haematoxylin. Samples were blued and washed in water and mounted in Aquamount (BDH). Oil-Red-O stock solution was prepared by dissolving 0.5g Oil-Red-O in 100ml 99% Isopropyl Alcohol. ### Barrier function assay {#s3g4} Dye penetration assays were performed on late E16.5 litters as previously described [@pgen.1000748-Hardman1] with the following modifications. Embryos were dissected out in cold PBS and permeabilized by taking them up and down a methanol/PBS series (25%, 50%, 75%, 100%) with 5 minute washes. Embryos were stained in 0.1% toludine blue solution for 3 minutes, then rinsed through 4 rapid PBS washes. Embryos were immediately photographed on a Nikon AZ100 macroscope using a Nikon APO 0.5× lens in PBS on 2% agarose plates. Immunohistochemistry and immunocytochemistry {#s3h} -------------------------------------------- Paraffin sections were dewaxed and rehydrated, followed by washes in TBST +0.5% Tx-100). Microwave antigen retrieval was carried out using 1mM EDTA (pH8) or citrate buffer (1.8mM citric acid, 8.2mM sodium citrate, pH6) for 20--30 minutes depending on the antigen at 900W. Cryosections samples were allowed to come to room temperature and post-fixed in acetone (−20'C for 10 minutes) followed by rinsing in water. No antigen retrieval step was required for cryosections. Slides were cooled to room temperature and washed in TBST. Slides were blocked in 10% donkey serum/TBST, followed by TBST washes. Primary antibodies were diluted in 1% donkey serum/TBST incubated on slides overnight at 4°C ([Table 1](#pgen-1000748-t001){ref-type="table"}). After TBST washes, secondary antibodies were diluted in 1% donkey serum/TBST and added to the slides for 60 minute incubation ([Table 2](#pgen-1000748-t002){ref-type="table"}). Following stringent TBST washes, nuclei were stained with DAPI (Sigma) or TOTO-3 (Molecular Probes). In the case of TOTO-3, slides were pre-incubated with RNAse A during primary antibody incubation. Slides were mounted with Vectashield (Vector) or Prolong Gold (Molecular Probes) antifade media and coverslips. Brightfield and fluorescent images were acquired using a Coolsnap HQ CCD camera (Photometrics Ltd, Tucson, AZ) Zeiss Axioplan II fluorescence microscope with Plan-neofluar objectives. Image capture and analysis were performed using in-house scripts written for IPLab Spectrum (Scanalytics Corp, Fairfax, VA). For colocalization studies, 0.5--1 µm optical slice images in Z-stacks were acquired with a Zeiss LSM510 confocal microscope and Zeiss Plan Apochromat lenses (Carl Zeiss, Welwyn Garden City, UK). LSM software was used for analysis (Carl Zeiss, Welwyn Garden City, UK). 10.1371/journal.pgen.1000748.t001 ###### Details of primary antibodies used in this study. ![](pgen.1000748.t001){#pgen-1000748-t001-1} Antigen Clone Name Host Species Dilution Source Notes -------------------------------- -------------- -------------- ------------ ---------------------- --------------- AE13 N/A Mouse 1∶10 T.T. Sun P-IHC AE15 N/A Mouse 1∶2 T.T. Sun P-IHC β-catenin 15B8 Mouse IgG1 1∶500 Sigma P-IHC β-catenin C2206 Rabbit 1∶2000 Sigma P-IHC β-galactosidase CR7001RP2 Mouse IgG1 1∶1000 Cortex P-IHC BrDU B44 Mouse IgG1 1∶50 BD Biosciences P-IHC Cleaved Caspase3 (Asp175) 9661 Rabbit 1∶400 Cell Signaling P-IHC Filaggrin PRB-417P Rabbit 1∶1000 Covance P-IHC Foxn1 G-20 Goat 1∶100 Santa Cruz P-IHC Fyn Y303 Rabbit IgG 1∶50 Abcam P-IHC Gata3 HG3-31 Mouse 1∶75 Santa Cruz P-IHC GM130 35 Mouse IgG1 1∶200 BD Biosciences IF, P-IHC HA 05-904 Mouse IgG3 1∶200--400 Upstate IF, WB HA HA-7 Mouse IgG1 1∶25 Sigma IF Hoxc13 10D4 Mouse IgG1 1∶50 abnova P-IHC Keratin 5 PRB-160 Rabbit 1∶1000 Covance P-IHC Keratin 6 PRB-169 Rabbit 1∶500 Covance P-IHC Keratin 10 PRB-159 Rabbit 1∶500 Covance P-IHC Keratin 14 AF64 Rabbit 1∶500 Covance IF Keratin 15 sc-56520 Mouse IgG2a 01∶50 Santa Cruz P-IHC Ki67 TEC-3 Rat 1∶50 DakoCytomation P-IHC Lck 3A5 Mouse IgG2bk 1∶600 Chemicon WB Lef1 N/A Rabbit 1∶500 R. Grosschedl P-IHC Lef1 C12A5 Rabbit 1∶1000 Cell Signaling P-IHC Loricrin PRB-145 Rabbit 1∶500 Covance P-IHC p63 BC4A4 Mouse IgG2a 1∶100 Abcam P-IHC PDI RL90 Mouse IgG2a 1∶100 Abcam IF phospho-p38 (Thr180/Tyr182) 12F8 (4631) Rabbit IgG 1∶50 Cell Signaling P-IHC phospho-p42/44 (Thr202/Tyr204) E10 (9106) Mouse IgG1 1∶400 Cell Signaling P-IHC phospho-p42/44 (Thr202/Tyr204) 20G11 (9106) Rabbit IgG 1∶100 Cell Signaling P-IHC phospho-histone H3 (Ser10) 9701 Rabbit 1∶100 Cell Signaling P-IHC phospho-Smad1/5/8 9511 Rabbit 1∶50 Cell Signaling P-IHC phospho-Smad2 3101 Rabbit 1∶50 Cell Signaling P-IHC phospho-Src Family (Tyr416) 2101 Rabbit 1∶25 Cell Signaling P-IHC Tgn138 2F7.1 Mouse IgG1 1∶50 Affinity Bioreagents IF Zdhhc21 299 Rabbit 1∶100--500 Custom Eurogentec P-IHC, IF, WB 10.1371/journal.pgen.1000748.t002 ###### Details of secondary antibodies used in this study. ![](pgen.1000748.t002){#pgen-1000748-t002-2} Antigen Host Species Dilution Source Notes ---------------------------------- -------------- ---------- ------------------------ ----------- ECL α-Mouse IgG, HRP-conjugated Sheep 1∶10000 GE Healthcare UK Ltd WB ECL α-Rabbit IgG, HRP-conjugated Sheep 1∶10000 GE Healthcare UK Ltd WB TRITC-conjugated α-Rabbit IgG Donkey 1∶250 Jackson Immunoresearch P-IHC, IF FITC-conjugated α-Rabbit IgG Donkey 1∶250 Jackson Immunoresearch P-IHC, IF Alexa 488-conjugated-α-Mouse Donkey 1∶500 Molecular Probes P-IHC, IF Alexa 594-conjugated-α-Mouse Donkey 1∶500 Molecular Probes P-IHC, IF Alexa 594-conjugated-α-Rabbit Donkey 1∶500 Molecular Probes P-IHC, IF Alexa 488-conjugated-α-Rat Donkey 1∶500 Molecular Probes P-IHC, IF Biotin-conjugated-α-Rabbit Donkey 1∶400 Jackson Immunoresearch P-IHC, IF BrdU labeling {#s3i} ------------- For BrdU labeling experiments, 2 age- and gender-matched mice of each genotype were injected with 50 µg BrdU/g body weight and sacrificed after 2 hrs. Skin sections were dewaxed, subjected to proteinase K antigen retrieval, followed by HCl denaturation and neutralization, before incubation with anti-BrdU antibody (BD). For indirect colorimetric visualization, a biotinylated donkey anti-mouse secondary antibody (Jackson Labs) and Vectastain Universal Elite ABC Kit (Vector Laboratories) were used, followed by NovaRed substrate (Vector Laboratories) according to manufacturer\'s protocol. A proliferative index was calculated by counting the number of positive cells divided by the total number of nuclei within the epidermal compartment, in each of ten fields at 10× magnification, and the average index per field was calculated. Statistical significance was calculated using a two-tailed Student\'s t-test. Supporting Information {#s4} ====================== ###### Localization and function of Zdhhc21 is altered by mutations of cysteines within DHHC consensus core. (A) Schematic of mutations in Zdhhc21. In addition to the dep deletion in C-terminal intracellular tail, several point mutations were generated by disrupting key cysteine residues within the DHHC domain. Another mutation, L91F, close to the DHHC domain was identified from an archive of ENU-mutagenised sperm from Harwell. However unlike mutations in the critical cysteines, this mutant protein was correctly localized and exhibited normal PAT activity. Mice homozygous for this mutation had normal hair. (B--G) Localization of HA-tagged Zdhhc21 cDNAs transfected into NIH-3T3 cells (anti-HA red) compared to cis-Golgi marker GM130 (green). Wild type and L91F strongly co-localize with GM130, whereas mutations within DHHC domain disrupt localization similar to dep. (H) Zdhhc21 protein variants which disrupt localization abrogate autopalmitoylation responses using ABE chemistry and pulled down by streptavidin agarose beads and resolved by SDS-PAGE [@pgen.1000748-Merrill1]. Portions not pulled down were also resolved by SDS-PAGE as loading control (I). (1.66 MB TIF) ###### Click here for additional data file. ###### Characterization of Zdhhc21 expression in skin. Expression of Zdhhc21 mRNA (B,D,E,G,J) and protein (A,C,F,H,I,K,). (A) E16.5 vibrissae follicle (Zdhhc21: green, p63: red). (B,C) P24 dorsal control skin. (D--F) P35 dorsal follicles of dep (D) and wild type (E), show similar levels and patterns of transcript, as observed with Zdhhc21 antibody (F). (G--I) While Zdhhc21 mRNA and protein expression is similar in the lower portions of P63 dorsal follicles (G,H), only protein can be detected in the upper (I) portions of the isthmus (I) but not in the bulge, sebaceous glands or IFE. (J--L) In telogen, (P21) wild-type dorsal skin shows no expression of Zdhhc21 mRNA (J) while some antibody staining is detected in the isthmus (K), which is specifically blocked by pre-incubating the antibody with the blocking peptide (L). (4.99 MB TIF) ###### Click here for additional data file. ###### Cyclic expression of Zdhhc21 during postnatal hair cycle in wild-type and dep mutant follicles. Expression of Zdhhc21 (red) and Gata3 (green) during catagen (P14 A,B), telogen (P21 C,D), initiation of anagen (P24 E,F), early anagen (P28 G,H) and late anagen (P35 I,J) in wild-type (A,C,E,G,I) and dep follicles (B,D,F,H,J). Expression of Zdhhc21 is limited to the post-mitotic lineages of IRS and cuticle of both control and dep anagen and catagen follicles. (6.63 MB TIF) ###### Click here for additional data file. ###### Aberrant epidermal proliferation during anagen contributes to dep hyperplastic interfollicular epidermis and sebaceous glands. Hematoxylin and eosin (A--D). Phosphohistone H3 (red, E--J) with Ki67 (green; I,J,). Significant differences in proliferation were not readily detectable at telogen (P21; A,B,E,F), or early (P28; C,D,G--J) anagen. However, quantitative BrDU labelling studies during anagen (P32) revealed a small but significant increase in proliferation in dep sebaceous glands and IFE (L), with a parallel decrease in proliferation in dep hair follicles (K). (\\p\<0.005, \p\<0.05) (4.18 MB TIF) ###### Click here for additional data file. ###### Aberrant epidermal differentiation in dep* mutant skin. Wild-type (A--F) and dep (G--,L) P28 dorsal follicles. Expression of terminal differentiation markers (loricrin (red), p63 (green) (A,G); filaggrin (red) (B,H) is delayed in dep mutant skin. Ectopic Keratin 6 expression (K6 (red), Ki67 (green) (C,I) is not observed in dep interfollicular epidermis, but expression remains restricted to the infundibulum and inner root sheath of the hair follicle. Imbalance of proliferative and differentiation signals in dep basal IFE where increased nuclear phospho-ERK (phospho-P42/44 (red), Gata3 (green), (D,--D′,J--J′) is observed with reduced expression of Gata3, in contrast to wild type skin where high suprabasal phospho-ERK is associated with strong Gata3 expressing cells (D--D′, arrowheads). Aberrant elevated basal p42/44 signalling was confirmed with a second antibody (I--I′,K--K′). Despite expanded bulge region below the dilated infundibulum and overgrown sebaceous glands, the expression of K15 (green) remains restricted to the bulge (F,L). Nuclei were labelled with DAPI (blue:C,I) or TOTO-3 (blue:D--F,J--L). (4.65 MB TIF) ###### Click here for additional data file. ###### Loss of Zdhhc21 function does not result in delays in selective barrier acquisition or keratinocyte terminal differentiation defects in embryonic dep epidermis. Wild-type (A--E) and dep mutant (F--J) late E16.5 embryos and E18.5 embryonic skins (C--E, H--J). (A,B,F,G) Dye exclusion assay showing similar range of barrier acquisition in a litter with wild-type and dep littermates from less advanced (A,F) to more established stages of barrier development (B,G). No difference in expression of terminal differentiation markers loricrin (C,H) and filaggrin (D,I) is detected between wild type and dep neonatal skin. Comparable Gata3 expression is observed in developing hair follicles and IFE of wild-type and dep neonatal skin (E--J). (2.42 MB TIF) ###### Click here for additional data file. ###### Initiation of Wnt-dependent anagen responses is normal in dep mice but subsequent propagation is affected. Alkaline phosphatase staining (A,C,E,G) marks dermal papillae. Induction of first anagen at P24 (A--D) with strong dermal papilla Lef1 staining (red) (B,D) and few adjacent positive cells in epidermal hair germ is observed in both wild-type (A,B) and mutant (C,D) skin. Subsequent propagation of anagen responses is defective at P28 (E--L) where retarded dep follicles show little Lef1 signal in matrix (F,H) as well as reduced or absent Foxn1 (green,Zdhhc21 red; J,K) and AE13 (green, Zdhhc21 red; J,L) in hair shaft precursors. By P35 (M--P), although misshapen and misoriented, many dep follicles (O,P) are similar to control littermates (M,N) as shown by AE13 (green, Zdhhc21 red; M,O) and beta-catenin (green, K5 red; N,P). (5.73 MB TIF) ###### Click here for additional data file. ###### Effective membrane targeting of Fyn during keratinocyte differentiation is compromised in dep mutant skin. Fyn localization in P32 anagen follicles (A--B′) and IFE (E--F′) with localization of active Src family kinases (including Src, Fyn, Yes and Lck) (C--D′,G--H′). Fyn expression is detected diffusely in the wild type bulb and becomes restricted to the membrane of differentiating IRS cuticle and some Henle\'s layers at the junction of the hair bulb and shaft. High levels of membrane associated active SFKs are seen throughout anagen hair follicle including dermal papilla, proliferative matrix, ORS and IRS lineages. In dep mutants, this membrane association of Fyn is greatly reduced/absent whilst active Src family kinase expression is largely unchanged. Fyn expression in the control IFE and IF becomes membrane restricted in suprabasal, differentiating keratinocytes, whilst membrane associated active Src family kinases can be seen throughout the basal and suprabasal IFE. Membrane associated Fyn and active SFKs is delayed in dep mutants. Arrowheads indicated areas of interest in merge and single channels. (4.72 MB TIF) ###### Click here for additional data file. We thank A. Weiss (Lck cDNA), W. Sessa (eNOS cDNA), Jeremy Nathans (Wnt3a cDNA), Yingzi Yang (Wnt5a cDNA), Takano Yamamoto (Wnt10a cDNA), Nick Gilbert (pCMX2GFPFLAGSTOP vector), T.T.Sun (AE13 and AE15 antibodies), and R. Grosschedl (Lef1 antibody) for sharing reagents. We are grateful to Paul Perry and Brendan Doe for technical assistance and to Tilo Kunath and Richard Mort for critical comments and discussions. The authors have declared that no competing interests exist. This work was funded by the Medical Research Council (UK), a National Sciences and Engineering Research Council of Canada Fellowship to PM, a Caledonian Research Foundation Fellowship to PM, a Wellcome Trust Travelling Fellowship to IS, an R. Douglas Wright Fellowship to IS, an Australian Research Council grant to IS, and a Human Frontiers Science Program grant to YF and MF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript [^1]: ¤: Current address: (AWSL) Medical Research Council, Mammalian Genetics Unit, Harwell Science and Innovation Campus, London, United Kingdom [^2]: Conceived and designed the experiments: PM AWSL MF IS IJJ. Performed the experiments: PM AWSL YF RT MK LM IS. Analyzed the data: PM AWSL MF RMP IS. Wrote the paper: PM IJJ. [^3]: ¶ These authors are joint senior authors on this work.
High risk human papillomavirus testing: guidelines for use in screening, triage, and follow-up for the prevention and early detection of cervical cancer. The changes in cervical cytology characterization agreed on by the Bethesda committee meeting in 2001 created a category of atypical findings that has caused some management confusion. By description, the characterization of cervical cytology as only atypical implies a less worrisome prognosis. However, more than 40% of high-grade (CIN II or III or cancer) will be discovered within this category. The development and Food and Drug Administration approval of the Hybrid Capture 2 (HC-2; Digene Corporation, Gaithersburg, MD) for detecting high-risk human papillomavirus (HR-HPV) subtypes and the subsequent level I evidence supporting use of this test in the triage of women with atypical cytology has revolutionized the management of this cytology. With this success has come numerous additional uses for HR-HPV testing in the treatment and follow-up of women with a variety of cytologic abnormalities. This article reviews the literature on uses of HR-HPV testing in this population, with reference to currently accepted guidelines.

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