---
abstract: 'We derive an exact solution to the problem of spin snake states induced in a nonhomogeneous magnetic field by a combined action of the Rashba spin-orbit and Zeeman fields. In an antisymmetric magnetic field the spin snake states are nonlocal composite particles, originating from spatially separated entangled spins. Adding an external homogeneous magnetic field breaks the spin-parity symmetry gapping out the spectral branches, which results in a regular beating pattern of the spin current. These new phenomena in a helical liquid of snake states are proposed for an experimental realization.'
author:
- 'Kh. Shakouri'
- 'S. M. Badalyan'
- 'F. M. Peeters'
title: Helical liquid of snake states
---

In a spatially nonhomogeneous magnetic field the alternating Lorenz force produces opposite rotations of electrons on both sides of the magnetic interface, resulting in a drift of carriers in snake-like classical trajectories. Gapless excitations of snake states are formed, leading to conduction along the magnetic interface. The snake states have been a subject of active theoretical [@Muller1992; @Peeters1993; @Peeters1999; @SMB2001] and experimental [@Carmona1995; @Ye1995; @Nogaret2000] investigations in two-dimensional electron systems (2DES) formed in semiconductor heterojunctions as well as in graphene [@Oroszl; @Ghosh2008; @Martino2011]. Snake states formed in homogeneous magnetic fields along the charge neutrality lines of electrons and holes play a key role in ambipolar transport of topological insulators [@Gusev2010; @Gusev2012] and graphene [@Marcus2011; @Sun201212].

Spin-orbit interaction (SOI) provides an effective tool for an electrical control of the spin behavior [@Fabian2007]. It enables physical separation of the spin of charge carriers [@Dyakonov1971; @SMB2009; @Glazov2011], permitting spin transport properties in a non-ohmic regime. Helical one-dimensional states with opposite spins moving in opposite directions can be effectively generated by a combined action of SOI and a homogeneous magnetic field in quantum wires [@Streda2003; @Debald2005; @Klinovaja2012] and at edges of 2DES [@Scharf2012; @SMB2010; @SMB200909]. Suppression of backscattering processes and a large inter-edge states equilibration length [@Komiyama1992; @SMB1991] make such spin edge states suitable for spintronics applications [@Ji2003; @Nakajima2012], particularly for quantum information processing purposes [@Bertoni2000; @Chirolli2012]. As a distinction from spin edge states, the helical system of snake states exhibits unidirectional motion, which emerges due to the spatially nonhomogeneous magnetic field, and which in a combination with SOI can produce additional spin transport channels with even richer physics.

Here we present an exact solution of the problem of spin snake states that emerge due to combined action of the Rashba spin-orbit and Zeeman fields in the presence of a magnetic interface. Our theory is equally applicable to the spin snakes formed along p-n junctions in a homogeneous magnetic field. We find that the energy dispersions are described by the main Landau number, the spin-parity and the spin-chirality quantum numbers. In an antisymmetric magnetic field the spin-split quasibulk Landau levels are degenerate with respect to the spin-parity. Close to the magnetic interface this degeneracy is lifted except the point where the even and odd spin-parity terms cross. We demonstrate that for such a magnetic field profile the electron spin vanishes for states located far from the magnetic interface. This implies that an electron in such a spin snake state is transformed into a composite particle, which experiences simultaneously positive and negative magnetic fields. Such a [*nonlocal*]{} composite particle executes semiclassical cyclotron orbits with opposite rotations on both sides of the magnetic interface, producing [*entangled*]{} spins separated in space. When an additional homogeneous magnetic field is applied, moving the total averaged magnetic field slightly away from zero, the spin-parity symmetry breaks down and we find that the electron spin makes a jump, acquiring a finite out-of-plane component. Towards the magnetic interface the in-plane x-component (perpendicular to the interface) of the electron spin becomes finite while the out-of-plane z-component decreases. Both spin projections show an oscillating behavior before the z-component will tend to zero and the x-component$-$to its quantized value. This is consistent with changes of the Rashba field in parallel to the transformation of the electron circular motion into an unidirectional one along the magnetic interface. Furthermore, at the energies corresponding to the crossings in the spectrum of the spin snake states, we find strong peaks in the spin current. Applying an external uniform magnetic field gaps out the electronic spectral branches and produces a helical liquid of spin snake states resulting in a regular [*beating*]{} patterns in the spin current. These predictions of the properties of spin snake states can be used in an experimental probe of this special class of helical liquid and be of practical relevance for quantum information processing and spintronic applications.

Consider a 2DES formed in a quantum well parallel to the (001) plane of a zinc-blende semiconductor heterostructure. A nonhomogeneous antisymmetric magnetic field, $\text{sign}(x) B_{0}$, together with an external uniform field, $B_u$, is applied perpendicular to the 2DES. In the presence of the Rashba spin-orbit and Zeeman fields, the effective Hamiltonian of the system can be written as $$\begin{aligned}
\label{H}
    H=&&\frac{\vec{\pi}^2}{2m^\ast}\openone +\alpha\left[\pi_x\hat\sigma_y-\pi_{y}\hat\sigma_x\right] -\frac{1}{2}g\mu_B B(x) \hat\sigma_z.\end{aligned}$$ Here $m^\ast$ is the electron effective mass, $\vec{\pi}$ the kinetic momentum, $\openone$ and $\hat\sigma_{x,y,z}$ the unit and Pauli matrices in spin space, $\mu_B$ the Bohr magneton, $\alpha$ and $g$ the strength of Rashba SOI and the Land$\grave{e}$ factor, respectively. In the Landau gauge with the vector potential $\vec{A}=(0, x B(x))$ where $B(x) =B_u+ \text{sign}(x) B_0$ is the total magnetic field, the Hamiltonian (\[H\]) is invariant under translations along the $y$ direction and we can reduce the two-dimensional Schr[ö]{}dinger equation into an effective one-dimensional problem making use of the ansatz $\Psi(x,y)=e^{i k_y y}\chi_{k_y}(x)$. Here $k_y$ is the electron wave vector and $ \chi_{k_y}(x)=\left| \chi_{1 k_y}(x), \chi_{2 k_y}(x) \right|^{T}$ the spinor wave function. We introduce dimensionless quantities for the x-coordinate, $x/l_B/\sqrt{2}$, and for the center of cyclotron orbit, $X(k_y)=\sqrt{2}k_yl_B$, in units of the magnetic length, $l_B=\sqrt{\hbar/e B}$, and for the electron energy, ${\varepsilon}/\hbar\omega_{B}=\nu+1/2$, in units of the cyclotron frequency, $\omega_{B}=e B/m^\ast$. Here $B=B_{u}+B_{0}$ and it is assumed that $B_{u}, B_{0}>0$. Then we can cast the Schr[ö]{}dinger equation for $\chi_{k_y}(x)$ in the following compact matrix form $$\label{compct}
\left(
\begin{array}
[c]{cc}
h_{\nu \pm \lambda} & \pm h_{\pm}\\
\pm h_{\mp} & h_{\nu \mp \lambda}\end{array}
\right)  \left(
\begin{array}
[c]{c}\chi_{1k_{y}}\left(  \xi\right) \\
\chi_{2k_{y}}\left(  \xi\right)
\end{array}
\right) =0$$ where $\xi=x \sqrt{\theta(x)} \mp X(k_{y})/\sqrt{\theta(x)}$ with the upper (lower) sign corresponding to $x>0$ ($x<0$). The step function $\theta(x)=1$ for $x>0$ and $\theta(x)=|B_{u}-B_{0}|/(B_u+B_0)$ for $x<0$. The operators in Eq. (\[compct\]) are defined as $$\begin{aligned}
\label{oper}
h_{\nu\pm\lambda}&=& \frac{d^{2}}{d\xi^{2}}+\frac{1}{\theta(x)}\left(\nu+\frac{1}{2}\right) \pm \lambda -\frac{\xi^{2}}{4}~,
\\
h_{\pm}  &=&-\frac{\gamma}{\sqrt{\theta(x)}}\left(  \frac{\xi}{2}\mp\frac{d}{d\xi}\right) \nonumber\end{aligned}$$ where the dimensionless parameters $\gamma=2\alpha/v_B$ ($v_{B}=\sqrt{2}l_{B}\omega_{B}$ is the cyclotron velocity) and $\lambda=g\mu_B m^\ast /2 e\hbar$ describe the spin-orbit and Zeeman fields, respectively, and $\gamma$ depends on the magnetic field strength.

In the absence of SOI, $h_{\pm}=0$, the solution of (\[compct\]) is given in terms of the scalar parabolic cylindrical functions, $D_{\nu}(x)$ [@SMB2001]. For $\nu\geqslant-1/2$ and $\nu\neq 0,1,2,...$ there exist two independent solutions, $D_{\nu}(x)$ and $D_{\nu}(-x)$ and $D_{\nu}(x) \rightarrow 0$ only for $x \rightarrow+\infty $. Making use of this behavior, we construct the solution of the matrix equation (\[compct\]) satisfying the boundary conditions at infinity in terms of the following spinors $$\label{bulk}
\chi_{\pm}^{L}(\xi)=\left(
\begin{array}
[c]{c}c^{L}_{\pm}D_{\mu^{L}_{\pm}-1}\left(-\xi^{L}\right) \\
D_{\mu^{L}_{\pm}}\left(-\xi^{L}\right)
\end{array}
\right),~
\chi_{\pm}^{R}(\xi)=\left(
\begin{array}
[c]{c}D_{\mu^{R}_{\pm}}\left(\xi^{R}\right) \\
c^{R}_{\pm}D_{\mu^{R}_{\pm}-1}\left(\xi^{R}\right)
\end{array}
\right)~,$$ which represent the bulk solutions of Eq. (\[compct\]) when $$\begin{aligned}
\label{indec}
\mu^{L,R}_{\pm}&=&\frac{1}{\theta(x)}\left(\nu+\frac{1}{2}+\frac{\gamma^{2}}{2} \pm \sqrt{\cal D}\right)~,
\\
c^{L,R}_{\pm}&  =&-\frac{\sqrt{\theta(x)}}{\gamma}\left(\frac{1}{2}-\lambda +\frac{1}{\theta(x)}\left(\frac{\gamma^{2}}{2} \pm \sqrt{\cal D}\right)\right)~. \nonumber\end{aligned}$$ Here ${\cal D}= \gamma^{2}\left(\nu+1/2+\gamma^{2}/4\right) +\theta^{2}(x)(1/2-\lambda)^{2}$ and the index $L$ ($R$) refers to the $x<0$ ($x>0$) values of respective quantities. To satisfy the boundary conditions at the magnetic interface and to obtain the spectrum of spin snake states, we form a linear combination of two independent bulk solutions (\[bulk\]) as $\psi(x)=a_{L,R} \chi_{+}^{L,R}(\xi) + b_{L,R} \chi_{-}^{L,R}(\xi)$ and obtain the coefficients $a_{L,R}$ and $b_{L,R}$ from the continuity of the new spinor wave function $\psi(x)$ and its derivative $\psi^{\prime}(x)$ at $x=0$. This $4\times4$ eigenvalue problem has a nontrivial solution if the respective determinant vanishes, which leads to the following [*exact dispersion equation*]{} for the spin snake states

$$\begin{aligned}
 \label{det}
     \text{det}\left\vert
     \begin{array}{c c c c}
           D_{\mu^{R}_{+}}(\xi^{R})  &  D_{\mu^{R}_{-}}(\xi^{R})  &  -c^{L}_{+} D_{\mu^{L}_{+}-1}(-\xi^{L})  &
           -c^{L}_{-} D_{\mu^{L}_{-}-1}(-\xi^{L}) \\
           c^{R}_{+} D_{\mu^{R}_{+}-1}(\xi^{R}) & c^{R}_{-} D_{\mu^{R}_{-}-1}(\xi^{R})  & -D_{\mu^{L}_{+}}(-\xi^{L}) &
           -D_{\mu^{L}_{-}}(-\xi^{L})\\
           D^{\prime}_{\mu^{R}_{+}}(\xi^{R})  &  D^{\prime}_{\mu^{R}_{-}}(\xi^{R}) &
           -c^{L}_{+} D^{\prime}_{\mu^{L}_{+}-1}(-\xi^{L})  &  -c^{L}_{-} D^{\prime}_{\mu^{L}_{-}-1}(-\xi^{L})\\
           c^{R}_{+} D^{\prime}_{\mu^{R}_{+}-1}(\xi^{R}) & c^{R}_{-} D^{\prime}_{\mu^{R}_{-}-1}(\xi^{R})  &
           -D^{\prime}_{\mu^{L}_{+}}(-\xi^{L}) & -D^{\prime}_{\mu^{L}_{-}}(-\xi^{L}) \\
     \end{array}\right\vert_{x=0}=0~.
  \end{aligned}$$

The energy dispersions ${\varepsilon}_{lpq}$ are described by the main Landau quantum number $l=0,1,2,\dots$ and [*the spin-parity*]{}, $p=\pm1$, and [*spin-chirality*]{}, $q=\pm1$, quantum numbers. In an antisymmetric magnetic field ($B_u=0$) the electron system coupled with SOI, possesses a spin-parity symmetry and the eigenvalue problem reduces to two $2\times2$ matrix equations. Then, for a given $l$ and $q$ the spectrum becomes degenerate in the bulk with respect to the spin-parity $p$ and exhibits a single crossing point near the magnetic interface. Introducing an additional homogeneous field brakes down the spin-parity, resulting in a lifting of the degeneracy in the bulk and in a [*crossing-anticrossing*]{} conversion near the magnetic interface.

Using Eq. (\[det\]) we carry out actual calculations of the spectrum of spin snake states in 2DES residing in InAs quantum wells with $\hbar\alpha=112.49$ meV [Å]{}, $g=-14.8$, and $m^\ast=0.026 m_e$ where $m_e$ is the free electron mass. Notice that both the Rashba and Zeeman fields can be significant in these structures, however, in relatively weak magnetic fields the SOI dominates, [*i.e.*]{} $\gamma\gg \lambda$.

![Energy dispersions of spin snake states as a function of the position of the cyclotron orbit center for: (a) $B_u=0$ and (b) $B_u=0.2B_0$. For given Landau number $l=0,1,2\dots$ the four energy branches are described by the spin-parity, $p=\pm1$, and the spin-chirality, $q=\pm1$, quantum numbers and are depicted, respectively, by solid, dashed, dotted, and dash-dotted curves. Insets are zooms of the open rectangles. In the main figure the arrows indicate the crossing points of the even and odd spin-parity energy terms while in the insets the arrows depict the electron average spin. The spin-orbit and Zeeman field parameters are $\gamma \approx 0.3$ (for $B_{u}=0$) and $\lambda \approx 0.1$.[]{data-label="disp"}](fig1a "fig:"){height="6cm"} ![Energy dispersions of spin snake states as a function of the position of the cyclotron orbit center for: (a) $B_u=0$ and (b) $B_u=0.2B_0$. For given Landau number $l=0,1,2\dots$ the four energy branches are described by the spin-parity, $p=\pm1$, and the spin-chirality, $q=\pm1$, quantum numbers and are depicted, respectively, by solid, dashed, dotted, and dash-dotted curves. Insets are zooms of the open rectangles. In the main figure the arrows indicate the crossing points of the even and odd spin-parity energy terms while in the insets the arrows depict the electron average spin. The spin-orbit and Zeeman field parameters are $\gamma \approx 0.3$ (for $B_{u}=0$) and $\lambda \approx 0.1$.[]{data-label="disp"}](fig1b "fig:"){height="6cm"}

Fig. \[disp\] shows the energy spectrum of snake states, ${\varepsilon}_{lpq}(k_{y})$, as a function of the cyclotron orbit center position $X(k_{y})$. Introducing the spin-orbit and the Zeeman fields in the presence of a magnetic interface removes the degeneracy of the usual Landau structure in a specific way. Groups of four different energy levels are formed as shown in the figure by the different dispersion curves, for different main Landau number $l$. In an antisymmetric magnetic field ([*cf.*]{} Fig. \[disp\](a)) the energy branches far from the magnetic interface represent the spin-split quasi-bulk Landau levels, which are described by the $q=\pm 1$ spin-chirality for given $l$. The splitting energy is determined by the strength of the spin-orbit and Zeeman fields. Each quasi-bulk Landau level remains partially degenerate due to the spin-parity symmetry. Usually, a magnetic field breaks the spin-parity [@Debald2005], here, however, the combined action of the magnetic interface and the SOI preserves the spin-parity in the bulk. Close to the magnetic interface, snake orbits with even ($p=1$) and odd ($p=-1$) spin-parities start to hybridize, which removes the degeneracy of the spin snake states except in one singular point where the even and odd terms cross. It is seen that the application of an external uniform magnetic field ([*cf.*]{} Fig. \[disp\](b)) brakes the spin-parity symmetry$-$the singular crossing points are converted into anticrossings and the branches of the spectrum become fully spin-resolved. In this case, the energy of the quasi-bulk Landau levels is additionally determined by the two different cyclotron frequencies and this is an extra source of asymmetry in the spectrum. Notice that for given $l$ the electron Larmor radius of classical orbits depends on the $p$ and $q$ quantum numbers of the snake states.

![The $S_{z}$ and $S_{x}$ spin projections of the snake states for the lowest $l=0$ Landau band as a function of the position of the cyclotron orbit center. (a) and (c) are for $B_u=0$ and (b) and (d) are for $B_u=0.2B_0$. The other parameters and the type of curves corresponding to the $p=\pm1$ and $q=\pm1$ states are the same as in Fig. \[disp\]](fig2){width="\columnwidth"}

. \[spin\]

![image](fig3a){width=".9\columnwidth"} ![image](fig3b){width=".9\columnwidth"}

As seen in Fig. \[spin\] the combined action of the magnetic interface and the spin interactions has critical consequences for the behavior of the electron average spin projections, $S_{x,z}(k_{y})=\int dx \psi^{+}(x)\hat\sigma_{x,z}\psi(x)$, which are calculated using the energy dispersions ${\varepsilon}_{lpq}(k_{y})$. We observe that in an antisymmetric magnetic field ($B_{u}=0$) the average spin vanishes in the bulk for any values of the spin-parity and the spin-chirality quantum numbers. The $S_x$ projection of the spin vanishes in the limit of $X(k_{y})\rightarrow +\infty$ because of the electron circular motion perpendicular to the magnetic field. We find that the $S_z$ component of the average spin also vanishes independently of the electron position with respect to the magnetic interface ([*cf.*]{} Fig. \[spin\](a)). This implies that an electron becomes a nonlocal composite particle, which captures simultaneously the spatially separated negative and positive magnetic flux quanta and manifests itself as a particle with zero spin. The nonlocality originates from the cyclotron rotations in the opposite directions of the composite particle on both sides of the magnetic interface, respectively, with the up and down entangled projections of the spin. The application of an external homogeneous magnetic field destroys this spin-parity symmetry and the $S_{z}$ projection of the spin jumps from zero to its quantized value. This jump is strongly pronounced at the crossing points, $X_{c}$, of the energy branches with the even and odd spin-parity ([*cf.*]{} the peaked behavior of $S_{z}$ at $X_{c}\approx 0.71$ for the solid and dashed curves in Fig. \[spin\](b)). In the opposite limit of $X(k_{y})\rightarrow -\infty$ the snake states exhibit an unilateral motion along the magnetic interface and $S_{z}$ vanishes. As seen in Fig. \[spin\](c), being zero in the bulk the $S_{x}$ spin projection becomes finite when the electron moves towards the interface. This behavior is modified in a finite external homogeneous field ([*cf.*]{} Fig. \[spin\](d)). It is seen that close to the interface $S_{x}$ starts to oscillate before reaching its quantized value. Notice also that the orientation of $S_{x}$ is independent of the direction of the total averaged magnetic field, which determines, however, the orientation of the $S_{z}$ projection.

An external homogeneous magnetic field brakes the spin-parity symmetry, removing not only the degeneracy of the quasi-bulk $p=\pm1$ Landau levels with a vanishing velocity but, what is more important for transport, gapping out spectral branches of the extended snake states at the crossing points $X_{c}$ close to the magnetic interface ([*cf.*]{} the inset of Fig. \[SPC\](b)). Thus, the combined effect of the magnetic interface and the spin interactions induces a helical liquid of spin snake orbits with additional channels for carrying an uncompensated spin current. The overall spin current is calculated from $J^{x,z}_y=\sum \left. S_{x,z}(k_y) v_y(k_y) \right|_{{\varepsilon}_{lpq}(k_{y})={\varepsilon}_{F}}$ where the sum is over the quantum numbers of current carrying spin snake channels at the Fermi energy, ${\varepsilon}_{F}$, and the electron group velocity along the magnetic interface is $v_y(k_y)=\partial{\varepsilon}_{lpq}(k_{y})/\partial k_{y}$. In Fig. \[SPC\] we observe that the application of an external uniform magnetic field induces local peaks and beatings, respectively, in the current of the $S_{x}$ and $S_{z}$ spin projections versus the Fermi energy (compare the curves corresponding to $B_u=0$ and $B_u=0.01 B_0$), which appear precisely at the crossing points of the energy levels with even and odd spin-parity. Notice that the charge current ([*cf.*]{} inset in Fig. \[SPC\](a)) does not exhibit such beatings or peaks instead a small oscillatory structure is not visible on the scale of its variation. When increasing the applied uniform field the shape of the energy dispersion changes and the beatings and peaks are broadened. As seen in Fig. \[SPC\](a), for $0<B_{u}<B_{0}$ the overall magnitude of the $J^{x}_{y}$ spin current increases monotonically with $B_{u}$. For $B_{u}=0.8B_{0}$ it shows almost a linear dependence on the Fermi energy because the velocity of extended snake orbits is linear in ${\varepsilon}_{F}$ while the x-component of the average spin, $S_{x}$, is approximately directed along the $x$ axis. However, this monotonic tendency in the dependence of $J^{x}_{y}$ versus $B_{u}$ ceases to exist at $B_{u}=B_{0}$. For $B_u>B_0$ the magnetic field does not change its sign at the magnetic interface, the extended snake orbits are transformed into the spiral orbit states with a smaller velocity and this results in a suppression of the spin current, which is observed in Fig. \[SPC\](a) for $B_{u}=1.2 B_{0}$.

In conclusion, we demonstrated that in an antisymmetric magnetic field carriers in the spin snake states are rendered into nonlocal composite particles, originating from the spatially separated entangled spins. Applying an external uniform magnetic field destroys the spin-parity symmetry gapping out the spectral branches of the spin snake states with finite velocities. This leads to new structures in the behavior of the spin current. The predicted effects are of experimental relevance for exploring the helical liquid of snake states in quantum entanglement and spin transport phenomena to generate novel information processing and spintronic applications.

This work was supported by the Methusalem program of the Flemish government and the Flemish Science Foundation (FWO-Vl).

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Liberal frontbencher Christopher Pyne has thrown his support behind Barnaby Joyce becoming the next leader of the Nationals.

Mr Joyce has again declared he will be a candidate if current leader and Deputy Prime Minister Warren Truss decided to stand down.

Mr Truss is expected to make an announcement on his political future in the coming weeks, with Prime Minister Malcolm Turnbull holding off a frontbench reshuffle until then.

Mr Pyne today joined a number of Coalition members in backing Mr Joyce, describing the outspoken MP as "focused".

But he told Channel Nine the decision will ultimately come down to the Nationals party room and Mr Truss.

"If he does stand down, the National Party if they choose Barnaby Joyce — which I seem to think they will, given the publicity recently — he will be an excellent Deputy Prime Minister," he said.

"He has a focused view on creating jobs, particularly in rural and regional Australia.

"In terms of his handling of the agricultural portfolio, it is booming."

But Nationals senator Bridget McKenzie dismissed the leadership talk as "media speculation".

Speaking to the ABC, she refused to name who she would be backing for the role and described the current leader as "fabulous".

She said the Nationals had a "sensible and stable, traditional approach to leadership transition".

"I think Australia is very, very well served by Deputy Prime Minister Warren Truss at the moment," she said.

Acting Opposition Leader Penny Wong yesterday questioned Mr Joyce's suitability as the potential leader, while Labor frontbencher Anthony Albanese today said that the prospect of Acting Prime Minister Barnaby Joyce was "scary".

"Australia would get a lot more attention internationally, given his propensity for gaffes," he said.


(Editor’ s Note: We’d like to thank fellow backyard astronomer Clay M. Davis with giving us the “Nuclear Physics 101″ help embedded in this post!)

Amidst the impending decade of transition for the United States space program, a quiet fact is slowly rearing its ugly head, one that will have wide implications for the future of manned & unmanned space exploration. Specifically, NASA is running out of juice to explore the solar system. And that’s not a figurative or political metaphor, but we mean “juice” in terms of real, honest-to-goodness fuel in the form of plutonium-238. But first, a little background/history of this often maligned substance and its role in space;

When leaving our fair planet, mass is everything. Space being a harsh place, you must bring nearly everything you need, including fuel, with you. And yes, more fuel means more mass, means more fuel, means… well, you get the idea. One way around this is to use available solar energy for power generation, but this only works well in the inner solar system. Take a look at the solar panels on the Juno spacecraft bound for Jupiter next month… those things have to be huge in order to take advantage of the relatively feeble solar wattage available to it… this is all because of our friend the inverse square law which governs all things electromagnetic, light included.

To operate in the environs of deep space, you need a dependable power source. To compound problems, any prospective surface operations on the Moon or Mars must be able to utilize energy for long periods of sun-less operation; a lunar outpost would face nights that are about two Earth weeks long, for example. To this end, NASA has historically used Radioisotope Thermal Generators (RTGs) as an electric “power plant” for long term space missions. These provide a lightweight, long-term source of fuel, generating from 20-300 watts of electricity. Most are about the size of a small person, and the first prototypes flew on the Transit-4A & 5BN1/2 spacecraft in the early 60’s. The Pioneer, Voyager, New Horizons, Galileo and Cassini spacecraft all sport Pu238 powered RTGs. The Viking 1 and 2 spacecraft also had RTGs, as did the long term Apollo Lunar Surface Experiments Package (ALSEP) experiments that Apollo astronauts placed on the Moon. An ambitious sample return mission to the planet Pluto was even proposed in 2003 that would have utilized a small nuclear engine.

New Horizons in the laboratory with the RTG (on left) attached. (Credit: NASA).

This is not without risks; for example, the aborted Apollo 13 mission had to ditch their Lunar Module Aquarius in the Pacific Ocean near Fuji along with its nuclear fueled payload on return to Earth reentry (which by the way survived intact as intended and is somewhere in the deep ocean where it can do no harm). Pu238 has a half life of 87.7 years and a 55 kg mass can power a spacecraft like the Pluto-bound New Horizons mission for decades. The next spacecraft headed for Mars, the SUV sized Mars Science Laboratory, will also contain an RTG as it explores the environs of Gale crater, and doubtless this launch slated for late 2011 will draw a scattering of protesters as did the Galileo, New Horizons, and Cassini missions…

Yes, plutonium is nasty stuff. It is a strong alpha-emitter and a highly toxic metal. If inhaled, it exposes lung tissue to a very high local radiation dose with the attending risk of cancer. If ingested, some forms of plutonium accumulate in our bones where it can damage the body’s blood-forming mechanism and wreck havoc with DNA. NASA had historically pegged a chance of a launch failure of the New Horizons spacecraft at 350-to-1 against, which even then wouldn’t necessarily rupture the RTG and release the contained 11 kilograms of plutonium dioxide into the environment. Sampling conducted around the South Pacific resting place of the aforementioned Apollo 13 LM re-entry of the ascent stage of the Lunar Module, for example, suggests that the reentry of the RTG did NOT rupture the container, as no plutonium contamination has ever been found. The same went for another failure, that of the nuclear powered Nimbus B-1 weather satellite in 1968, in which case the RTG was recovered intact. Yes, the Soviets have had a few release failures historically (see below), but NASA knows its business and has a long standing track record of safely handling nuclear material. RTG’s are designed to withstand intact uncontrolled re-entry, spacecraft explosion, booster explosion, and a host of other high energy events without releasing the contents of the fuel package. Of course, all stats are highly speculative. The black swan events such as Three Mile Island, Chernobyl and Fukushima have served to demonize all things nuclear, much like the view that 19th century citizens had of electricity. Never mind that coal-fired plants put many times the equivalent of radioactive contamination into the atmosphere in the form of lead210, polonium214, thorium and radon gases, every day. Safety detectors at nuclear plants are often triggered during temperature inversions due to nearby coal plant emissions… radiation was part of our environment even before the Cold War and is here to stay. To quote Carl Sagan, “Space travel is one of the best uses of nuclear weapons that I can think of…” Whether it is as use as a thermal electric power plant, a nuclear propulsion engine, or even an Orion style bomb-propelled spacecraft, nuclear fission and the energy it produces provides us a way to get out into the solar system, now. Ideas such as fusion engines and Bussard ramjets are all well and good and should be researched, but for now are on the drawing board only. The joke is that contained fusion capability is always “20 years down the road” and may remain there for some time.

Any science fiction “space ark’ will likely include an RTG or two…(Amazing Stories cover/In the Public Domain).

And therein, as they say, lies the rub. But first let’s look at some basic nuclear physics. We promise, it will only hurt for a little bit…

Plutonium is an artificial element that does not occur in nature. First produced by Glen Seaborg and friends in 1940, plutonium is created in the modern day laboratory by the beta decay process which occurs when uranium238 is bombarded with neutrons and decays into unstable neptunium and then plutonium239, the “weapons grade” isotope of the stuff. If neptunium-237 is used as target (fertile material) instead of U238 in a “fast” reactor the product is plutonium238. Likewise, bombard uranium-238 with deuterium (2x hydrogen nuclei) in an accelerator and the decay result is Plutonium-238 Pu-238 produces 560 watts per kg of decay heat, 280x times that of Pu239. The United States ceased production of plutonium in 1989 as the Cold War ground to an end, (more on the political aspect in a moment) and starting that production train back up would be no easy process. The United States and Russia have tiny dwindling reserves, and at best NASA has enough for one more Cassini-style mission and perhaps a small scout style mission like New Horizons past the launch of the Mars Science Laboratory. And as you can see, utilizing the pre-existing weaponized Pu239/240 would do little good beyond perhaps as part of an Orion-style propulsion system, as the energy of decay or the specific power yielded is just too low. Reading the writing on the cosmic wall, things look pretty grim for the recent Planetary Exploration Decadal Survey published earlier this year; a Uranus probe, Titan blimp, and Enceladus or Europa orbiter plus lander would all require RTGs, as would the shelved Jupiter Icy Moons Mission. Contrast the problems the spunky Mars Rovers had with “dusty solar panels,” as well as the eventual lack of solar power that did the Mars Phoenix polar lander in…

One of the RTGs that flew on the Voyager spacecraft. (Credit: NASA).

Are there alternatives in the nuclear area? Yes, but not without cost; for example, there are difficulties with the use of thorium isotopes. Relatively abundant in the Earth’s crust compared to uranium, the preferable thorium232 & thorium230 isotopes have a low abundance and a relatively low specific power in comparison to plutonium, again, making it a very poor heat source. In addition, thorium232 is bread to uranium233, which is nasty stuff and emits a very penetrating dose of gamma radiation as it decays further to thallium208. (Remember the Hulk?) Weaponized plutonium 239/240 also has too low a specific power, creating a huge mass penalty for outgoing spacecraft with its very short 30 year half-life. Strontium90 can be used as a RTG, but also at a great mass penalty. Same goes for any prospects of a pulsed fission reactor. In the 50’s through 70’s, NASA and the Department of Energy looked into the possibility of building a nuclear engine via Project Rover. This phases included Kiwi, Phoebus, and Pewee engines which were tested at the Nevada Test Site Area 25 desert complex facility… several extreme high altitude nuclear detonations where also conducted, most notably the Starfish Prime project in 1962. The Limited Test Ban Treaty of 1967 put the lid on further weapons testing in space, along with the prospects for a development of a nuclear propulsion engine.

Small high power solid core fission reactors have been used in space as the heat source for turbo-electric high power applications (primarily Soviet radar-satellites for intelligence purposes). One accidently returned to Earth landing in Canada in the 1970’s causing much political uproar and very little environmental damage. Solid core propulsion reactors have been designed and tested in both the United States (NERVA) and Russia and have a solid theoretical and practical engineering foundation. None have been tested in space. This concept still stands as our best bet to get humans quickly to Mars.

Currently, NASA faces a dilemma that will put a severe damper on outer solar system exploration in the coming decade. As mentioned, current plutonium reserves stand at about enough for the Mars Science LaboratoryCuriosity, which will contain 4.8kilograms of plutonium dioxide, and one last large & and perhaps one small outer solar system mission. MSL utilizes a new generation MMRTG (the “MM” stands for Multi-Mission) designed by Boeing that will produce 125 watts for up to 14 years. But the production of new plutonium would be difficult. Restart of the plutonium supply-line would be a lengthy process, and take perhaps a decade. Other nuclear based alternatives do indeed exist, but not without a penalty either in low thermal activity, volatility, expense in production, or short half life.

The implications of this factor may be grim for both manned and unmanned space travel to the outer solar system. Juxtaposed against at what the recent 2011 Decadal Survey for Planetary Exploration proposes, we’ll be lucky to see many of those ambitious “Battlestar Galactica” –style outer solar system missions come to pass. A mission like Juno headed to the environs around Jupiter gets around this somewhat by utilizing huge solar panels; Juno is scheduled to leave the pad at Cape Canaveral next month on August 5th and this will mark the first non-nuclear powered mission to the outer solar system. This will occur, however, at a huge cost; Juno must drag its panels along for the ride and will only operate in a wide 11-day Jovian orbit. This is necessary to keep Juno exposed to the Sun and will preclude exploration of the Jovian moons during its projected 32-orbit life span. The three solar arrays on Juno also equal an area of 650 sq ft, a large target for any debris in the Jovian system that makes engineers cringe. Solar cells are also sensitive to high radiation fields such as those encountered in Jupiter space. This is one of the factors behind Juno’s short mission life.

Landers, blimps and submersibles on Europa, Titan, and Enceladus will all operate well out of the Sun’s domain and will need said nuclear power plants to get the job done… contrast this with the European Space Agency’s Huygens probe, which landed on Titan after being released from NASA’s Cassini spacecraft in 2004, which operated for scant hours on battery power before succumbing to the -179.5 C° temps that represent a nice balmy day on the Saturnian moon.

One of the “other” uses for plutonium; Fat Man on Tinian. (Credit: US Govt image in the Public Domain).

Part of what has always complicated matters is what is known as the Outer Space Treaty, or in its long-form, The Treaty on Principles Governing Activities of States in the Exploration and the Use of Space. Signed and ratified by the U.S., U.K. and the Soviet Union on January 1967, this treaty seeks to curb the militarization of space and specifically the use of space-based nuclear weapons as well as nuclear detonations in space. This has formed the basis of a broad amalgam of what been termed over the years as “Space Law” which covers such things as the international use of space, salvage rights and claims, and the non-recognition of any territorial claims on a celestial body. And while “Space Court” hasn’t become filler for afternoon or late-night cable TV, the Treaty did largely keep nuclear weapons out of space during the Cold War. Some of the ideas for an “EMP shield” over the US from the 50’s are slightly frightening to read about today, as we would be now reaping the environmental consequences. While said treaties never specifically limited the use of fissile material for deep space exploration, the very concept and stigma of “Nukes in Space” made it suffer by extension. Whenever a launch with an RTG occurs, a small band of protesters gather outside the gates and grab the media spotlight until the payload has cleared Earth orbit. Modern day fears of all things nuclear can be likened to the 19th century suspicion of electricity, which to date has taken far more victims than the peaceful use of radioactive isotopes in space.

So, what’s a space-faring civilization to do? Certainly, the “not going into space” option is not one we want on the table, and warp or Faster-Than-Light drives ala every bad science fiction flick are nowhere in the immediate future. In our highly opinionated view, NASA has the following options;

3. Exploit other RTG sources at penalty. As mentioned previous, other nuclear sources in the form of Plutonium, Thorium, and Curium isotopes do exist and could be conceivably incorporated into RTGs; all, however, have problems. Some have unfavorable half-lives; others release too little energy or hazardous penetrating gamma-rays. Plutonium238 has high energy output throughout an appreciable life span, and its alpha particle emissions can be easily contained.

MER’s curium-containing spectrometer. (Credit: NASA/JPL).

2. Design innovative new technologies. Solar cell technology has come a long way in recent years, making perhaps exploration out to the orbit of Jupiter is do-able with enough collection area. The plucky Spirit and Opportunity Mars rovers (which did contain Curium isotopes in their spectrometers!) made do well past their respective warranty dates using solar cells, and NASA’s Dawn spacecraft currently orbiting the asteroid Vesta sports an innovative ion-drive technology. Solar sails have made their debut on JAXA’s IKAROS spacecraft in the inner solar system, and perhaps a technology employing the use of space-based lasers could do double duty propelling spacecraft through the outer solar system like something out of a Larry Niven novel. Fusion of deuterium or helium3 resources could also provide a powerful light weight energy source, but of course this is all strictly drawing board stuff… the standing joke is that controlled fusion stated above is that its always “20 years away,” which leads us to option #3;

1. Push to restart plutonium production. Again, it is not that likely or even feasible that this will come to pass in today’s financially strapped post-Cold War environment. Other countries, such as India and China are looking to “go nuclear” to break their dependence on oil, but it would take some time for any trickle-down plutonium to reach the launch pad. Also, power reactors are not good producers of Pu238. The dedicated production of Pu238 requires either high neutron flux reactors or specialized “fast” reactors specifically designed for the production of trans-uranium isotopes. Going along with such specialized reactors are adequate safe facilities for the separation, concentration, and preparation of the final product. Since the end of the Cold War, the United States and Russia have closed and decommissioned the vast majority of their plutonium production facilities and reactors. The reconstitution of these cold war process plants is as of this writing beyond reasonable consideration. The huge plants at Hanford Washington and Savanna River South Carolina made sense during the Cold War, where Pu238 was a minor byproduct in the production of many tons of weapons grade plutonium. Practically, specialized research reactors at Oak Ridge Tennesse and Idaho National Laboratory can breed Pu238 and special separation and processing facilities there could produce gram per cycle quantities. However about 5kg/yr would be required to meet anticipated needs requiring a retool of currently available reactors and processing labs. Such a mission deviates critical research facilities from their primary missions that are themselves vital to understanding materials for spacecraft. Construction of new reactors and facilities for the production and processing of fissile materials is also fraught with significant funding, environmental, treaty, and local / national opposition hurdles. This can lead to very significant increases in cost over initial estimates and multi-decade delays prior to construction or production. Based on the realities of nuclear materials production the levels of funding for Pu238 production restart are frighteningly small. NASA must rely on the DOE for the infrastructure and knowledge necessary and solutions to the problem must fit the realities within both agencies.

And that’s the grim reality of a brave new plutonium-free world that faces NASA; perhaps the solution will come as a combination of some or all of the above. The next decade will be fraught with crisis and opportunity… plutonium gives us a kind of Promethean bargain with its use; we can either build weapons and kill ourselves with it, or we can inherit the stars.

Astro Documentaries

Pictured is a Delta IV rocket launch from Cape Canaveral on November 21st, 2010. The image is a 20 second exposure taken at dusk, shot from about 100 miles west of the launch site. The launch placed a classified payload in orbit for the United States Air Force.

DIY Astronomy

Difficult but not impossible to catch against the dawn or dusk sky, spotting an extreme crescent moon can be a challenge. The slender crescent pictured was shot 30 minutes before sunrise when the Moon was less than 20 hours away from New. A true feat of visual athletics to catch, a good pair of binoculars or a well aimed wide field telescopic view can help with the hunt.

The Sun is our nearest star, and goes through an 11-year cycle of activity. This image was taken via a properly filtered telescope, and shows the Sun as it appeared during its last maximum peak in 2003. This was during solar cycle #23, a period during which the Sun hurled several large flares Earthward. The next solar cycle is due to peak around 2013-14.

Astronomy Gear Reviews

Located in the belt of the constellation Orion, Messier 42, also known as the Orion Nebula is one of the finest deep sky objects in the northern hemisphere sky. Just visible as a faint smudge to the naked eye on a clear dark night, the Orion Nebula is a sure star party favorite, as it shows tendrils of gas contrasted with bright stars. M42 is a large stellar nursery, a star forming region about 1,000 light years distant.

Astronomical Observing Targets

Orbiting the planet in Low Earth Orbit (LEO) every 90 minutes, many people fail to realize that you can see the International Space Station (ISS) from most of the planet on a near-weekly basis. In fact, the ISS has been known to make up to four visible passes over the same location in one night. The image pictured is from the Fourth of July, 2011 and is a 20 second exposure of a bright ISS pass.

Next to the Sun, the two brightest objects in the sky are the Moon and the planet Venus. In fact, when Venus is favorably placed next to the Moon, it might just be possible to spot the two in the daytime. Another intriguing effect known as earthshine or ashen light is also seen in the image on the night side of the Moon; this is caused by sunlight reflected back off of the Earth towards our only satellite.

A mosaic of three images taken during the total lunar eclipse of December 21st, 2010. The eclipse occurred the same day as the winter solstice. The curve and size of the Earth’s shadow is apparent in the image.


Q:

GSON to Ormlite foreign collection

My model object has simple datatypes as well as other types of model objects
@SerializedName("account")
Account account;`

I serialize these model objects from a network api call using GSON.  GSON needs my model objects to be their respective types. I want to then write my model objects to a database using Ormlite and batch tasks, but Ormlite requires ForeignCollection<T> even if I only have one foreign object (instead of a list of foreign objects) in my model.
How do I get from one serialized element of T  into ForeignCollection<T> in my model file?
The real question of course is how to serialize and store models in my database which contain references to other models.

A:

It's not very clear what you are asking here, but maybe this can be useful:
assignEmptyForeignCollection
void assignEmptyForeignCollection(T parent,
                                  String fieldName)
                                  throws SQLException

Creates an empty collection and assigns it to the appropriate field in the parent object. This allows you to add things to the collection from the start. For example let's say you have an Account which has the field:
 @ForeignCollectionField(columnName = "orders")
 Collection<Order> orders;

You would then call: (In this case)
accoundDao.assignEmptyForeignCollection(account, "orders");
Order order1= new Gson().fromJson(someMethodThatCallsYourNetworkApi(),Order.class);

 // this would add it the collection and the internal DAO
 account.orders.add(order1);


Rainbows of brightly colored computer cases were a common sight at this
year's Comdex.

I am on my way to my first Comdex show, and this is my first trip
to Las Vegas.
I have been an assistant editor at
Macworld
for three months. And here
I am, minutes from the show floor, arguing with my cab driver, defending the
fact that colored computers are not girly. I suddenly become painfully aware
of the fact that I am wearing an iMac-blueberry blue dress. I match
my G3 desktop
perfectly. This is not on purpose, and I'm about to tell him so, but I stop
myself.

"Men, they don't care about that kind of stuff," he says. "I
mean, a pink computer?! You've got to be kidding." He shakes his
head.

"Actually, a lot of men seem to like the iMac," I say. I shut my
mouth about the iBook.

"Yeah, right," he grumbles, but I detect a note of uncertainty.

"Really," I say. "They even came out with a computer that's
transparent. The men seem to love it."

"A clear computer, shit," he says. "I mean, it's not like it
works any different, right? Who cares what it looks like?" He throws his
shoulders back in a little manly-man gesture. But at this point, I can tell
he's intrigued.

Eupa's angel and devil speakers are sooooo cuuuuute!

I arrive at the show. The floor is filled with manly men. Manly men typing
on transparent keyboards; manly men handling blue, green, purple, and orange
mice; manly men getting visibly excited by yellow, blue, and even
pink computer
cases. But these computers aren't Macs, so it's okay.

"This is a PC company, sweetheart," a manly booth man tells me when
I inquire whether his translucent mauve USB mouse is
Mac-compatible. He emphasizes
"PC," as in "PC, a real computer." This is a phrase I'll
here often at Comdex. "We make PC products," he repeats. "But
aren't they pretty?"

"I call them iMac-alikes," the man says with a wink. Personally,
I call them cease-and-desist orders, but I return his wink with a chuckle and
shuffle on down the aisle.

I am at the Sands Convention Center, where the OEMs (Original
Equipment Manufacturers
to the uninitiated) show their stuff. And this year, it's all about color and
fun. Intel has a booth right outside the floor, and it's filled
with space-age
inspired computers. A Taiwanese company called Eupa has a pair of
speakers designed
to look like an angel and a devil. Cute. But most of the designs
seem to spring
directly from the Apple lineage, even using the exact same colors (see "
Separated at Birth." The strange thing is, while men complain
about girly iMac colors and iBooks they say look like purses, it seems okay
for them to like a colored PC, and they're all acting like this is the latest
thing. And here I thought color was last year's news.

All of a sudden I'm reminded of the days before Windows, the days
when PC-heads
mocked the Mac OS. "Aw, how cute," they'd say mockingly, "the
little files actually look like little file folders." They'd turn back
to their PCs, secure with the notion that typing obscure lines of code like
"

C:>dir /s /w | more

" made them worthy of The Machine.
And then Windows came out, and suddenly little file folders actually made the
computer easier to use and that was okay. And now colored PCs are here, and
it's okay to touch a purple mouse.


# Generated by Django 3.0.4 on 2020-04-18 14:27

from django.db import migrations, models

class Migration(migrations.Migration):

    dependencies = [
        ('posts', '0001_initial'),
    ]

    operations = [
        migrations.AlterField(
            model_name='historicalpost',
            name='type',
            field=models.CharField(choices=[('post', 'Текст'), ('intro', '#intro'), ('link', 'Ссылка'), ('question', 'Вопрос'), ('pain', 'Расскажи где болит'), ('project', 'Проект'), ('referral', 'Рефералка'), ('battle', 'Батл'), ('weekly_digest', 'Еженедельный дайджест')], db_index=True, default='post', max_length=32),
        ),
        migrations.AlterField(
            model_name='post',
            name='type',
            field=models.CharField(choices=[('post', 'Текст'), ('intro', '#intro'), ('link', 'Ссылка'), ('question', 'Вопрос'), ('pain', 'Расскажи где болит'), ('project', 'Проект'), ('referral', 'Рефералка'), ('battle', 'Батл'), ('weekly_digest', 'Еженедельный дайджест')], db_index=True, default='post', max_length=32),
        ),
    ]


Multiscale modeling and mechanics of filamentous actin cytoskeleton.
The adaptive structure and functional changes of the actin cytoskeleton are induced by its mechanical behavior at various temporal and spatial scales. In particular, the mechanical behaviors at different scales play important roles in the mechanical functions of various cells, and these multiscale phenomena require clarification. To establish a milestone toward achieving multiscale modeling and simulation, this paper reviews mathematical analyses and simulation methods applied to the mechanics of the filamentous actin cytoskeleton. The actin cytoskeleton demonstrates characteristic behaviors at every temporal and spatial scale, and mathematical models and simulation methods can be applied to each level of actin cytoskeletal structure ranging from the molecular to the network level. This paper considers studies on mathematical models and simulation methods based on the molecular dynamics, coarse-graining, and continuum dynamics approaches. Every temporal and spatial scale of actin cytoskeletal structure is considered, and it is expected that discrete and continuum dynamics ranging from functional expression at the molecular level to macroscopic functional expression at the whole cell level will be developed and applied to multiscale modeling and simulation.


Background {#Sec1}
==========

The development of ureteral calculi after Yang-Monti ileal ureter reconstruction has not been reported. The treatment of ureteral stones is technically challenging, especially for surgeons with minimal experience in such procedures. We used ureteroscopy combined with laser lithotripsy to successfully treat a patient with ipsilateral distal ureteral calculi and ipsilateral lower calyceal calculi after Yang-Monti ileal ureter reconstruction due to long-segment ureteral stenosis.

Case presentation {#Sec2}
=================

The patient was a 48-year-old man with a 4-year history of ureteral calculi and a 2-year history of ureteral stenosis for which he had undergone multiple surgeries. Ureteral calculi recurred many times, resulting in repeated ureteral stricture that was treated three times by ureteroscopic holmium laser lithotripsy, and twice by ureteroscopic balloon dilation. He had been admitted to our hospital for left ureteral stenosis in June 2015. Examination at that time revealed a 20-cm stenosis in the middle and lower segments of the ureter. Noncontrast computed tomography showed inflammation and adhesion around the kidney as a result of multiple ureteral surgeries, making the patient unsuitable for autologous kidney transplantation. Yang-Monti ileal ureter reconstruction was performed, and the 6-month postoperative examination revealed left ureteral patency (Fig. [1](#Fig1){ref-type="fig"}), stable renal function, normal electrolyte levels, and no obvious mucus-like flocculation in the urine.Fig. 1Left ureteral patency at 6 months after Yang-Monti ileal ureter reconstruction

Ten months after the Yang-Monti ileal ureter reconstruction, the patient developed left lumbar pain and discomfort. Noncontrast computed tomography showed that the left kidney had a slightly smaller volume than the right, and that the left renal pelvis and renal calices were slightly expanded and hydronephrotic. Two nodule-shaped high-density shadows were present in the lower renal calyx; the diameter of the larger shadow was 4 to 5 mm. A liquid-density shadow was seen in the ileal lumen of the left ureter, with a small nodule-shaped high-density shadow (3-mm diameter) at its end. Corticomedullary development was good. During excretion, accumulation of contrast agent could be seen in the left renal pelvis, renal calices, and ureter (Figs. [2](#Fig2){ref-type="fig"}, [3](#Fig3){ref-type="fig"} and [4](#Fig4){ref-type="fig"}). The serum creatinine concentration was normal.Fig. 2Two nodule-shaped high-density shadows in the lower renal calyx (indicated by the arrows)Fig. 3A nodule-shaped high-density shadow in the ileal lumen of the left ureter (indicated by the arrow)Fig. 4A nodule-shaped high-density shadow in the ileal lumen of the left ureter (indicated by the arrow)

The patient was placed in the lithotomy position under general anesthesia. The ileal ureterovesical reimplantation opening was smoothly entered under direct vision using a 9.5-Fr semirigid ureteroscope (Richard Wolf Medical Instruments, Knittlingen, Germany). Ureteroscopic examination revealed that the calculi were attached to surgical sutures located from 1 cm from the inner end of the ileal ureter to the ureteral opening, and that the sutures were embedded under the ileal ureteral mucosa in a ring shape (Fig. [5](#Fig5){ref-type="fig"}). A basket extractor \[NGage Nitinol Stone Extractor (NGE-017115), 1.7 Fr × 115 cm; Cook Medical, Bloomington, IN, USA\] was used to hold the calculi and sutures, which were then broken up with a holmium laser (0.6 J, 30 Hz, 200-μm fiber; 60-W LISA Sphinx Holmium:Yttrium-Aluminium-Garnet Laser System, LISA Laser Products, Katlenburg-Lindau, Germany) and completely removed (Figs. [6](#Fig6){ref-type="fig"}, [7](#Fig7){ref-type="fig"}). Ureteroscopy revealed that the Yang-Monti ileal ureter had a thick and straight lumen, smooth mucosa, and no obvious folds or anastomoses between sections (Fig. [8](#Fig8){ref-type="fig"}). Using a Zebra guidewire (Boston Scientific, Marlborough, MA, USA) for guidance, a flexible ureteroscope working sheath (12/14 Fr × 115 cm, M006250226; Boston Scientific) was imbedded and inserted into the left renal pelvis under direct vision using a digital flexible ureteroscope (8.5 Fr, 11278VS; Karl Storz, Tuttlingen, Germany). Using a filling pump (26331020--1; Storz Medical, Tägerwilen, Switzerland) with an infusion pressure of 80 mmHg, the two lower calyceal calculi were identified, broken up, and removed. As a preoperative urine culture had revealed a urinary tract infection, antibiotics were administered postoperatively. Additionally, a 5-Fr ureteral catheter (Kangge Medical Instruments, Shanghai, China) and a urinary catheter were left indwelling, and were removed on postoperative day 3.Fig. 5The calculi were attached to surgical sutures, and the sutures were embedded under the ileal ureteral mucosaFig. 6A basket extractor was used to hold the calculi and suturesFig. 7The calculi and sutures were broken up with a holmium laserFig. 8The Yang-Monti ileal ureter had a thick and straight lumen and smooth mucosa

Discussion and conclusion {#Sec3}
=========================

A previous study investigating minimally invasive treatment of ureteral calculi following ileal neobladder surgery reported that the cause of calculi development may be related to the presence of foreign bodies (e.g., ureteral stents and sutures) \[[@CR1]\]. Furthermore, the generation of ileal ureteral calculi also has a very close relationship with intestinal mucous \[[@CR2]\]; when the ileal anastomosis is bulky, the intestinal mucous secreted in the ileal segment near the kidney during bowel movements is more likely to enter the kidney, accumulate in the renal pelvis within the calyx, and become a matrix or core of stone formation, along with urine salt deposition and stone formation \[[@CR2]\]. If the ileal replacement ureter is too long and the postoperative replacement urine becomes stored in the ileum, this urine combines with the large amount of mucus secreted by the intestinal tract to form calculi, and ureteral calculi in the ureteral diversion may be formed by renal calculi falling through the urine drainage \[[@CR3]\]. In the present case, the absorbable suture in the lower ileal ureteral segment from the previous ureteral reconstruction had not degraded or fallen off, and so served as a matrix or core for calculi formation; its long-term contact with urine resulted in urinary salt being continuously deposited to form calculi \[[@CR4], [@CR5]\]. The lower ileal ureteral calculi were successfully removed using a rigid ureteroscope combined with holmium laser lithotripsy to remove the sutures and attached calculi.

During the holmium laser removal of sutures, it is important to determine the shape and direction of the suture, cut the suture from its root near the ileal ureteral mucosa, and check the integrity of the suture to prevent leaving residual suture that will again enable calculi to form. Suture removal must be performed under direct vision. As the suture moves along with the movement of the perfusate, the suture must be fixed with a basket extractor to create adequate tension and thus prevent the suture from moving; this improves the success rate of suture removal, and reduces the risk of ileal ureteral injury.

A digital flexible ureteroscope was entered into the left renal collection system. As the calculi were small (maximum diameter of 5 mm) and oval-shaped with smooth surfaces, we were able to use a basket extractor to cover and remove the calculi. During removal, we discovered that the calculi had diameters that were larger than that of the working sheath for the flexible ureteroscope; hence, we covered each calculus and removed it together with the working sheath of the flexible ureteroscope. Using intraoperative ureteroscopic guidance, a 5-Fr double-J stent was placed upon completion of the surgery.

The key points gained from our experience are as follows. (1) The thinnest holmium laser fiber with the appropriate energy for cutting should be selected, so that the laser fiber can pass through the gap between the basket extractor and the ureteroscopic operation channel. It is best to conduct an in vitro analysis of suture materials, and then choose the best energy setting for cutting. The appropriate energy setting is that which can cut the suture while preventing damage to the ureter. (2) Good intraoperative control of the perfusion pressure must be maintained. Excessive pressure causes dilatation of the reconstructed ureteral lumen, increased pressure in the renal pelvis and renal calices, and an increased risk of postoperative infection. (3) The ileal ureter has a large lumen diameter. Even if the diameter of the intestinal canal is cut using the Yang-Monti method, the reconstructed ureteral lumen still has a large diameter, and thus the rigid ureteroscope, flexible ureteroscope, and working sheath of the flexible ureteroscope can be successfully retrograded to the renal pelvis. When the diameters of the calculi are smaller than the diameter of the ureteral lumen, a basket extractor can be used.

In summary, ureteroscopy combined with laser lithotripsy seems to be a valuable option for the management of urinary calculi following Yang-Monti ileal ureter reconstruction.

We thank Kelly Zammit, BVSc, and Angela Morben, DVM, ELS, from Liwen Bianji, Edanz Editing China (<http://www.liwenbianji.cn/ac>), for editing the English text of a draft of this manuscript.

Funding {#FPar1}
=======

This study was supported by the Guizhou Province Science and Technology Fund.

Availability of data and materials {#FPar2}
==================================

Not applicable.

Declarations {#FPar3}
============

No conflict of interest exits in the submission of this manuscript, and the manuscript has been approved by all authors for publication. The work described herein is original research that has not been published previously and is not under consideration for publication elsewhere, in whole or in part. All authors of the manuscript have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria, and all agree to the terms of the BioMed Central License Agreement and Open Data Policy.

ZW wrote the first draft of the manuscript. ZS, GL, YT, and XY reviewed the manuscript and were involved in its critical revision before submission. All authors read and approved the final manuscript.

Ethics approval and consent to participate {#FPar4}
==========================================

Not applicable.

Consent for publication {#FPar5}
=======================

Written informed consent for publication was obtained from the patient.

Competing interests {#FPar6}
===================

The authors declare that they have no competing interests.

Publisher's Note {#FPar7}
================

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Background
==========

Skeletal muscle displays a remarkable ability to remodel in response to pathologic and physiologic stimuli (\[[@B1]-[@B3]\] and reviewed in \[[@B4]\]). How changes in gene expression mediate these processes by post-transcriptional regulation has been heavily studied in the context of diseased, hypertrophic, and regenerating skeletal muscle \[[@B5]-[@B7]\]. While recent studies have greatly enhanced our understanding of these dynamic processes, measuring post-transcriptional changes that occur *in vivo* is challenging and this has limited the experimental avenues available. Additionally, the discovery of post-transcriptional regulation by microRNAs (miRNAs) in skeletal muscle has increased the complexity of these processes.

miRNAs are a type of short, non-coding RNA that post-transcriptionally regulate gene expression. miRNAs function by guiding the RNA-induced silencing complex (RISC) to target mRNAs, dictated by base pairing to target sites primarily in their 3′-untranslated regions (UTRs). miRNAs can downregulate the expression of several to hundreds of target genes by repressing translation and/or destabilizing target mRNAs \[[@B8],[@B9]\]. miRNAs are required for normal skeletal muscle development in mice \[[@B10]\], and several miRNAs have been shown to be dynamically regulated during hypertrophy \[[@B11]\], acute exercise \[[@B12]\], regeneration after injury \[[@B13]\], and in the remodeling that occurs in response to genetic muscle disease \[[@B14]-[@B17]\]. In particular, miR-206 is expressed specifically in skeletal muscle, and is highly expressed in regenerating fibers \[[@B13]\]. miR-206 has been shown to promote terminal differentiation of myoblasts by regulating the expression of genes including connexin43 \[[@B18]\], utrophin \[[@B19]\], pax3 \[[@B20]\], pax7 \[[@B21]\] and DNA polymerase α \[[@B22]\]. Many of these studies rely on data obtained from transgenic mouse studies, and *ex vivo* sample analysis - both currently invaluable to the study of miRNAs. The study of miRNA regulation in skeletal muscle, however, would benefit from a system that enabled rapid, reproducible, longitudinal *in vivo* reporter assays, at a fraction of the cost of transgenic mouse production and analysis, and with fewer animals needed than for *ex vivo* studies.

Several studies have shown that stable gene expression can be achieved in post-mitotic myofibers *in vivo* by the introduction of plasmid DNA (pDNA) \[[@B23]-[@B26]\]. Unlike viral DNA vectors, pDNA is non-immunogenic \[[@B23]\], easily manipulated, and relatively inexpensive to produce. Methods for introducing naked pDNA into myofibers include intramuscular injection \[[@B24]\], electroporation \[[@B26],[@B27]\], and more recently, hydrodynamic limb vein (HLV) injection \[[@B28],[@B29]\]. While these methods all result in efficient myofiber transduction, only HLV injection is minimally damaging to the muscle \[[@B30]\], enabling studies of muscle remodeling to take place in the absence of widespread myofiber regeneration. Moreover, HLV injection results in more widespread pDNA distribution than intramuscular injection or electroporation, which are limited to the site of injection, or single muscle groups, respectively \[[@B24],[@B26]\].

*In vivo* bioluminescent and fluorescent imaging (BLI) of genetically encoded reporters has been a useful tool in murine xenograft studies including cancer \[[@B31]\], chondrogenic differentiation \[[@B32]\], viral infection \[[@B33]\], and even in studies of miRNA biogenesis and post-transcriptional regulation \[[@B34],[@B35]\]. All of these studies, however, have relied on the expression of reporter genes in cells cultured *in vitro*, and none have demonstrated the ability to quantify skeletal muscle reporter gene expression *in situ.* We therefore developed a novel system using HLV injection of reporter pDNA into skeletal muscle in combination with *in vivo* BLI in order to quantify miRNA activity. Before testing, we anticipated that animal-to-animal variation in injection efficiency would confound true changes in reporter expression. While several groups have reported the utility of *Renilla* luciferases as a normalizer in *in vivo* reporter studies \[[@B32],[@B36]\], we found that the fast kinetics and requirement for intravenous substrate delivery made this approach technically challenging. To solve this problem, we employed a dual-reporter approach consisting of a high-efficiency click-beetle luciferase from *Pyrophorus plagiophthalamus* (CBG99) \[[@B37]\], and the far-red fluorescent protein mKATE \[[@B38]\] for signal normalization. mKATE has been shown to have a maximum emission wavelength (635 nm) that is optimal for tissue penetration, and to have high pH and photostability, making this an ideal protein for *in vivo* BLI.

As a proof of principle, we measured miR-206 activity and show that the activity measured using this technique reproduces the levels obtained from quantitative reverse transcription PCR (qRT-PCR) measurements. We believe this technique will prove useful not only in the quantification of real-time miRNA activity, but also in studies of transcriptional and post-transcriptional regulation.

Methods
=======

Plasmid construction
--------------------

Two perfectly complementary miR-206 \[NCBI:NR_029593\] binding sites were inserted between the Xba1 and Fse1 restriction sites downstream of the CBG99 stop codon in pCBG99-Control (Promega, Madison, WI, USA) using the following oligonucleotide sequences: 5′-CTAGACCACACACTTCCTTACATTCCAAAACCACACACTTCCTTACATTCCAGGCCGG, and 5′-CCTGGAATGTAAGGAAGTGTGTGGTTTTGGAATGTAAGGAAGT GTGTGGT. pcDNA-mKATE was a kind gift from Amy Palmer (University of Colorado at Boulder, Boulder, CO, USA), and pCMV-eGFP from Stephen Langer (University of Colorado at Boulder, Boulder, CO, USA).

Hydrodynamic limb vein injection
--------------------------------

All animal experiments were performed using protocols approved by University of Colorado and Colorado State University Institutional Animal Care and Use Committees (IACUC). Mice were injected according to a protocol modified from Hagstrom, *et al*. \[[@B29]\]. Briefly, after sedation with 1 to 4% inhaled isoflurane, a tourniquet was secured around the upper hindlimb to restrict blood flow for 1 to 2 minutes prior to injection, and 2 minutes after injection. The hindlimb was first cleaned with 70% ethanol, and an incision was made with surgical scissors on the medial surface of the leg to expose the great saphenous vein. A ½ inch 30-gauge needle connected by catheter to a syringe was then inserted in an anterograde direction into the vein. Endotoxin-free pDNA isolated using Endofree® Plasmid Maxi Kit (Qiagen, Hilden, Germany) and diluted in sterile saline solution (volume determined according to the formula: 1 + (((body weight in grams − 25)/25) × 1/2)mL), was delivered at a rate of 7 mL/minute by a programmable syringe pump (KD Scientific, Holliston, MA, USA). Two minutes after the injection was completed, the tourniquet was released and the incision was closed with nonabsorbable 6--0 silk suture (Davis-Geck, Brooklyn, NY, USA). Mice recovered on a 37°C heat block and were monitored for adverse effects.

Barium chloride injury
----------------------

To induce muscle degeneration, mice were first anesthetized with 1 to 4% inhaled isoflurane, and the right hindlimb was shaved. After cleaning the area with 70% ethanol, the right gastrocnemius was injected with 50 μL of a 1.2% barium chloride solution in normal saline using a 27-gauge insulin syringe. Mice recovered on a 37°C heat block and were monitored for adverse effects.

*In vivo* bioluminescent and fluorescent imaging
------------------------------------------------

Animals were anesthetized using 1 to 4% isoflurane prior to imaging and placed in the chamber of an IVIS 100 *in vivo* imaging system (Caliper Biosciences, Hopkinton, MA, USA) housed at Colorado State University's Animal Cancer Center (Fort Collins, CO, USA). The mKATE fluorescent signal was then collected using sequential mode with a 1-s exposure time and the Cy5.5 excitation/emission filter set. Animals were then removed from the imaging chamber and injected intraperitoneally with 200 μL of 30 mg/mL D-luciferin. Ten minutes after substrate injection, bioluminescent signal was collected for 1 minute using the open filter mode. Images were analyzed using LivingImage software (Caliper Biosciences) and photons/sec/cm^2^/steradian were quantified using region-of-interest (ROI) analysis. Mice recovered from anesthesia on a 37°C heat block.

Immunofluorescence
------------------

Muscles for immunofluorescence were frozen in liquid nitrogen-cooled isopentane and mounted in optimal cutting temperature (OCT) medium (Sakura Finetek, Torrance, CA, USA). Cryosections (12 μm thick) were fixed in 4% paraformaldehyde for 10 minutes at room temperature, then blocked for 1 hour with 5% goat serum in PBS and 0.1% Triton X-100. Following blocking, sections were stained with anti-laminin at 1:500 (L-9393, Sigma, St. Louis, MO, USA) or anti-desmin at 1:20 (D-8281, Sigma) overnight at 4°C. After washing several times in PBS with 0.1% Triton X-100, anti-rabbit Texas red secondary antibody was applied at 1:100 dilution for 1 hour at 37°C (711-075-152, Jackson, West Grove, PA, USA). After washing again in PBS with 0.1% Triton X-100, sections were counterstained with 300 nM 4′,6-diamidino-2-phenylindole (DAPI) for 5 minutes at room temperature (Sigma D-9542), and mounted using Fluoromount G (Southern Biotech, Birmingham, AL, USA).

Quantification of injection efficiency
--------------------------------------

To determine HLV injection efficiency, percentages of GFP-positive fibers were quantified using immunofluorescence on lower hindlimb sections from pCMV-eGFP-injected animals. Following imaging on an inverted epifluorescent microscope (Eclipse TE2000, Nikon, Melville, NY, USA), GFP, laminin, and DAPI images were merged to produce a composite (ImageJ software, National Institutes of Health, Bethesda, MD, USA). GFP-positive fibers were counted when GFP signal across a myofiber was greater than background levels. Total fiber number was counted using laminin staining to demarcate fiber boundaries. Percentages are reported as an average of GFP-positive fibers for ten fields of view for the gastrocnemius, and five fields each for the soleus and tibialis anterior (TA).

qRT-PCR
-------

To measure miRNA expression, total RNA was first isolated from snap-frozen skeletal muscles using TRI reagent (Molecular Research Center, Cincinnati, OH, USA). Then, 7 ng of total RNA per reaction was reverse-transcribed and PCR-amplified on a CFX96 thermocycler (Bio-Rad, Hercules, CA, USA) using Taqman miRNA assays (Invitrogen, Grand Island, NY, USA). Relative miRNA expression was determined using the 2^-ΔΔCt^ method \[[@B39]\], using sno202 as a reference gene.

Statistical analysis
--------------------

For qRT-PCR experiments, relative miR-206 expression values were compared to controls (for assessment of muscle damage, controls were uninjured/uninjected contralateral limbs for each time point, and for miR-206 reporter measurements, controls were C57Bl/6 animals) using the unpaired Student's *t-*test. For BLI measurements, statistics were performed by comparing mean normalized photons/s/cm^2^/steradian (CBG99/mKATE) of pCBG99-2x-miR-206-injected hindlimbs, to mean normalized photons/s/cm^2^/steradian of pCBG99-Control-injected hindlimbs for *mdx4cv* and C57Bl/6 animals using the unpaired Student's *t*-test.

Results
=======

HLV injection does not induce myofiber regeneration
---------------------------------------------------

Prior to employing HLV to deliver miRNA reporters for miR-206 activity, it was important to determine whether the injection technique itself would induce muscle regeneration and consequently increase the levels of miR-206. To test this, we performed HLV injection (Figure [1](#F1){ref-type="fig"}A) on wild-type C57Bl/6 mice using saline only and compared miR-206 expression to that in animals injured with BaCl~2~. miR-206 levels decreased slightly (*P* =0.02) on the third day after saline injection, likely due to residual edema from the high-volume injection, but remained unchanged (day 7 animals trended towards a 1.7-fold increase, *P* = 0.051) on subsequent days (Figure [1](#F1){ref-type="fig"}B). Conversely, barium chloride injury strongly induced miR-206 approximately 11-fold (*P* = 0.0003) as previously reported \[[@B13]\], suggesting that HLV injection does not activate a widespread program of muscle regeneration.

![**miR-206 levels after hydrodynamic limb vein injection. (A)** Schematic depiction of hydrodynamic limb vein injection (HLV) of plasmid DNA followed by *in vivo* bioluminescent and fluorescent imaging (BLI). **(B)** miR-206 expression in 3 to 4 month-old C57Bl/6 mice receiving either HLV injection of saline solution or BaCl~2~ injury, sacrificed at the indicated time points, normalized to sno202. Relative levels measured in the right (treated) gastrocnemius are displayed as mean values normalized to contralateral controls; n= 3 or 4 animals/group, Error bars = standard error of the mean. ^*\**^*P ≤*0.05, ^*\*\**^*P ≤*0.001.](2044-5040-3-19-1){#F1}

Reporter expression is well distributed and is quantifiable using *in vivo* imaging
-----------------------------------------------------------------------------------

To test the muscle distribution of reporter pDNA, we next injected C57Bl/6 mice with 100 μg/animal of pCMV-eGFP. After 7 days, we performed immunofluorescence on fixed cryosections and found that GFP expression was visible in the sarcoplasm of myofibers in the gastrocnemius, soleus, and TA muscles (Figure [2](#F2){ref-type="fig"}). To determine injection efficiency, we quantified GFP-positive myofibers and found that 7.7%, 15.9% and 6.1% of fibers in the soleus, gastrocnemius, and TA, respectively, expressed the reporter. We also observed an absence of centrally located nuclei in GFP-positive myofibers, further supporting the finding that HLV injection itself causes minimal muscle injury. Next, we tested whether reporter gene expression can be quantified from both bioluminescent and fluorescent reporters using *in vivo* imaging. To this end, we injected either 100 μg each of pCBG99-Luc-Control and pcDNA-mKATE, or pcDNA-mKATE alone into the right hindlimbs of C57Bl/6 mice and collected images 7 days later using BLI. The signal was easily visible and localized to the hindlimb skeletal muscle for both reporters, although mKATE background signal was frequently observed from the ventilation nosepiece and/or the distal parts of the hindlimb (Figure [3](#F3){ref-type="fig"}). We also found that mKATE fluorescence did not bleed into the luciferase channel, making it ideal for *in vivo* use in combination with CBG99-luciferase.

![**Reporter distribution.** Reporter expression after hydrodynamic limb vein injection. Left column: green fluorescent protein (GFP) epifluorescent signal displayed as inverted grayscale image, percentages are an average of GFP-positive fibers for indicated muscles. Right column: immunostaining for laminin (red) and epifluorescence for GFP (green) and 4′,6-diamidino-2-phenylindole (DAPI) (blue) to show distribution of GFP-positive myofibers in indicated muscles; n=1 animal. Scale bars = 100 μm. TA, tibialis anterior.](2044-5040-3-19-2){#F2}

![**Reporter detection using*in vivo*bioluminescent imaging.** Mice were injected with pcDNA-mKATE (top) or pcDNA-mKATE and pCBG99-Luc-Control (bottom). Data collected using Cy5.5 excitation/emission filters is shown in the left column, and after D-luciferin injection in the right column.](2044-5040-3-19-3){#F3}

miRNA activity measurements are consistent with miRNA qRT-PCR measurements
--------------------------------------------------------------------------

In order to measure miRNA activity *in vivo,* we inserted two perfectly complementary miRNA binding sites downstream of the CBG99 luciferase coding sequence, creating pCBG99-2x-miR-206. We next co-injected 100 μg of pcDNA-mKATE along with either pCBG99-2x-miR-206 (left hindlimbs) or pCBG99-Luc-Control (right hindlimbs) into C57Bl/6 or dystrophic *mdx4cv* mice. Seven days later, we measured the signal using *in vivo* BLI followed by ROI analysis (Figure [4](#F4){ref-type="fig"}B). To ensure that we minimized the effect of differential plasmid distribution and injection efficiency, the same region size was used for quantification in all animals, and the luciferase signal was normalized to mKATE. After normalizing, the CBG99:mKATE ratio from left hindlimbs was compared to control right hindlimbs. In agreement with a 5-fold increase in miR-206 expression in *mdx4cv* animals by qRT-PCR (*P* = 0.0001) (Figure [4](#F4){ref-type="fig"}A), the normalized bioluminescent signal in the left hindlimbs of *mdx4cv* mice was reduced 3.3-fold (*P* = 0.02) (Figure [2](#F2){ref-type="fig"}C). While the decreased average signal in C57Bl/6 did not reach significance *(P =* 0.15), the downward trend is likely due to the high abundance of miR-206 in skeletal muscle, and the decreased miR-206 reporter signal in *mdx4cv* animals is due to increased miR-206 expression. Given that miR-206 is highly expressed in the regenerating fibers of dystrophic mice \[[@B13]\], this result suggests that pDNA injected using HLV is also expressed in these fibers. To test this, we injected *mdx4cv* animals with 100 μg of pCMV-eGFP and collected tissues for immunofluorescence 7 days later. As expected, we found GFP expression in small, desmin-positive, regenerating myofibers with centrally located nuclei (Figure [5](#F5){ref-type="fig"}, arrowheads), indicating that the decrease in luciferase signal measured using BLI likely corresponds to a loss of luciferase activity in these fibers.

![**Quantification of miR-206 reporter activity in*mdx4cv*mice.(A)** miR-206 expression measured in the gastrocnemius muscles of 3 month-old *mdx4cv* animals in comparison to C57Bl/6. miR-206 expression is normalized to sno202 ( n = 4 animals/group), mean values are displayed; error bars *=* standard error of the mean (SEM), ^\*^*P* ≤0.05. **(B)** Bioluminescent imaging of *mdx4cv* animals showing CBG99 luciferase and mKATE expression. Left hindlimbs were co-injected with pCBG99-2x-miR-206 and pcDNA-mKATE, and right hindlimbs were co-injected with pCBG99-Control and pcDNA-mKATE. **(C)** Region of interest (ROI) analysis of **(B)**. The same region size was used for all animals (n= 4 animals/group; mean values are displayed; error bars = SEM, *\*P≤*0.05.](2044-5040-3-19-4){#F4}

![**Reporter expression in regenerating*mdx4cv*fibers.** pCMV-eGFP-injected *mdx4cv* (left column) and C57Bl/6 (right column) gastrocnemius sections showing desmin immunostaining (red), green fluorescent protein (GFP) epifluorescence (green), and 4′,6-diamidino-2-phenylindole (DAPI) (blue) demonstrate GFP expression in regenerating fibers. Upper row images were taken using 10× objective lens, lower row with 20× objective. Scale bars = 100 μm.](2044-5040-3-19-5){#F5}

Discussion
==========

Several groups have reported the safety and efficacy of pDNA injections using HLV for gene therapy approaches \[[@B23],[@B28],[@B29]\]. We found this technique also to be useful in studies requiring minimally damaging introduction of genetically encoded reporters into skeletal muscle and have used it in combination with BLI and ROI analysis to analyze *Myh7b* promoter activity *in vivo*\[[@B40]\]. We also found that this technique induces minimal muscle regeneration as assessed by miR-206 induction, and to our knowledge this is the first report of using an *in vivo* transfection method that does not induce myofiber regeneration for luciferase reporter studies.

The distribution of GFP-positive myofibers after HLV injection that we have seen is similar to that reported by Wooddell, *et al*. \[[@B41]\] although the percentage of transfected fibers we report is lower. This may be due to decreased sensitivity of detecting a fluorescent reporter (GFP) versus a colorimetric stain (β-galactosidase). Similar to this report, we find the highest percentage (15.9%) of transfected myofibers in the posterior lower leg (gastrocnemius) muscles and the lowest percentage (6.1%) in the anterior lower leg (TA) muscles (Figure [3](#F3){ref-type="fig"}). Additionally, others have observed reporter gene expression up to 49 weeks after HLV injection \[[@B41]\], suggesting that this method could be used for longer-term regulatory studies, provided that the luciferase and mKATE signals follow similar expression profiles.

Conclusion
==========

In summary, HLV injection of pDNA reporters into skeletal muscle followed by BLI is a useful technique for studies of gene regulation. Here, we show that it is possible to measure miRNA activity in myofibers *in situ,* without activation of a regeneration response. This technique has the added benefit of reducing the cost associated with producing transgenic animals for skeletal muscle studies, and will likely allow reduced animal numbers and decreased variability in future experiments by enabling longitudinal studies of the same animal cohort.

Abbreviations
=============

BLI: Bioluminescent and fluorescent imaging; DAPI: 4′,6-diamidino-2-phenylindole; GFP: Green fluorescent protein HLV: hydrodynamic limb vein; miRNA: microRNA; OCT: Optimum cutting temperature; PBS: Phosphate-buffered saline; pDNA: Plasmid DNA; qRT-PCR: Quantitative reverse transcription polymerase chain reaction; RISC: RNA-induced silencing complex; ROI: Region of interest; UTR: Untranslated region; TA: Tibialis anterior.

Competing interests
===================

The authors have no competing interests to declare.

Authors' contributions
======================

MG designed the experiments, wrote the paper, and carried out the qRT-PCR, injections, imaging, and molecular cloning. KB played a key role in the project's conception and provided useful discussion and critical reading of the manuscript. EP provided assistance with *in vivo* BLI and assembling figures. LL provided mentoring and discussion about all experiments and data. All authors have read and approved the manuscript.

Acknowledgements
================

We would like to thank Mark Noble for assistance with HLV injection, Adam Chicco for assistance with animal protocols, and Margaret Isenhart for animal care. This work was funded by NIH R01GM029090 to LL and NIH 5T32GM007135-36 to MG.


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A:

Had the same problem after updating Glimpse this morning (v1.3.0). Here's what I did to solve this.
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Turn on tracking for Asp.net
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Discover the use of martialness in the following bibliographical selection. Books relating to martialness and brief extracts from same to provide context of its use in English literature.

1

Imagination and fancy; or Selections from the English poets, ...

And as, when smoke goes heaven- ward from a town, In some far island which its
foes besiege, Who all day long with dreadful martialness Have pour'd from their
own town ; soon as the sun Has set, thick lifted fires are visible. Which, rushing ...

Leigh Hunt, 1845

2

The Poetical Works of Leigh Hunt

And as when smoke goes heavenward from a town In some far island, which its
foes besiege, Who all day long with dreadful martialness Have poured from their
own town ; — soon as the sun Has set, thick lifted fires are visible, Which, rushing
...

Thornton Leigh Hunt, 1860

3

The Indicator

A compound of Mary and Anne. Mafia", 3 gemle alld sprightly word, became in
request as the name of the real or fancied mistress of RobiniHood. Mark,
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Akenside.

Leigh Hunt, 1822

4

Selections from the English poets ...

In some far island which its foes besiege, Who all day long with dreadful
martialness Have pour'd from their own town ; soon as the sun Has set, thick lifted
fires are visible, Which, rushing upward, make a light in the sky. And let the
neighbors ...

Leigh Hunt, 1859

5

Imagination and Fancy; or Selections from the English Poets

And as, when smoke goes heaven-ward from a town, In some far island which its
foes besiege, Who all day long with dreadful martialness Have pour'd from their
own town ; soon as the sun Has set, thick lifted fires are visible, Which, rushing ...

1845

6

Poetical Works

And as when smoke goes heavenward from a town In some far island, which its
foes besiege, Who all day long with dreadful martialness Have poured from their
own town ; — soon as the sun Has set, thick lifted fires are visible, And let the ...

Leigh Hunt, 1863

7

Leigh Hunt's Works: Selections from the English poets

And as, when smoke goes heaven-ward from a town In some far island which its
foes besiege, Who all day long with dreadful martialness Have pour'd from their
own town ; soon as the sun Has set, thick lifted 6res are visible, Which, rushing ...

Leigh Hunt, 1859

8

The Poetical Works of Leigh Hunt

And as when smoke goes heavenward from a town In some far island, which its
foes besiege, Who all day long with dreadful martialness Have poured from their
own town ; — soon as the sun Has set, thick lifted fires are visible, Which, rushing
...

Narratives of Brahman martialness in India changed, which helped both to fill the
material gap in the numbers of the Indian Army in World War II and to fill the gap
in the psyche of the colonial military establishment that was searching for new ...


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Thank you!

A:

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The Chi-square goodness of fit test is used to test if your data follows a particular distribution. It's more useful for testing model assumptions rather than comparing models."
sounds like Chi-square is more useful if you have a function you are trying to test (or a model you are trying to fit to your data) as opposed to the R^2 which tells you how much variability there is in your data, and therefore how much the best model fits.


Krzysztof Kaczmarek

Krzysztof Kaczmarek (born October 28, 1988 in Wrocław) is a former Polish footballer.

Career

Club
In January 2011, he moved to MKS Kluczbork.

References

External links

Category:1988 births
Category:Polish footballers
Category:Czarni Żagań players
Category:Śląsk Wrocław players
Category:Stilon Gorzów Wielkopolski players
Category:MKS Kluczbork players
Category:Living people
Category:Sportspeople from Wrocław

Category:Association football midfielders