Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach towards combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression presents novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic

Negative Energy and Angular Momentum Modes of Thin Accretion Disks

This work derives the linearized equations of motion, the Lagrangian density, the Hamiltonian density, and the canonical angular momentum density for general perturbations [$\propto \exp(im\phi)$ with $m=0,\pm 1,..$] of a geometrically thin self-gravitating, homentropic fluid disk including the pressure. The theory is applied to ``eccentric,'' $m=\pm 1$ perturbations of a geometrically thin Keplerian disk. We find $m=1$ modes at low frequencies relative to the Keplerian frequency. Further, it shown that these modes can have negative energy and negative angular momentum. The radial propagation of these low frequency $m=1$ modes can transport angular momentum away from the inner region of a disk and thus increase the rate of mass accretion. Depending on the radial boundary conditions there can be discrete low-frequency, negative-energy, $m=1$ modes.Comment: 24 pages, 8 figure

Critical aspects of the random-field Ising model

We investigate the critical behavior of the three-dimensional random-field Ising model (RFIM) with a Gaussian field distribution at zero temperature. By implementing a computational approach that maps the ground-state of the RFIM to the maximum-flow optimization problem of a network, we simulate large ensembles of disorder realizations of the model for a broad range of values of the disorder strength h and system sizes  = L3, with L ≤ 156. Our averaging procedure outcomes previous studies of the model, increasing the sampling of ground states by a factor of 103. Using well-established finite-size scaling schemes, the fourth-order’s Binder cumulant, and the sample-to-sample fluctuations of various thermodynamic quantities, we provide high-accuracy estimates for the critical field hc, as well as the critical exponents ν, β/ν, and γ̅/ν of the correlation length, order parameter, and disconnected susceptibility, respectively. Moreover, using properly defined noise to signal ratios, we depict the variation of the self-averaging property of the model, by crossing the phase boundary into the ordered phase. Finally, we discuss the controversial issue of the specific heat based on a scaling analysis of the bond energy, providing evidence that its critical exponent α ≈ 0−

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure

D* Production in Deep Inelastic Scattering at HERA

This paper presents measurements of D^{*\pm} production in deep inelastic scattering from collisions between 27.5 GeV positrons and 820 GeV protons. The data have been taken with the ZEUS detector at HERA. The decay channel $D^{*+}\to (D^0 \to K^- \pi^+) \pi^+$ (+ c.c.) has been used in the study. The $e^+p$ cross section for inclusive D^{*\pm} production with $5<Q^2<100 GeV^2$ and $y<0.7$ is 5.3 \pms 1.0 \pms 0.8 nb in the kinematic region {$1.3<p_T(D^{*\pm})<9.0$ GeV and $| \eta(D^{*\pm}) |<1.5$}. Differential cross sections as functions of p_T(D^{*\pm}), $\eta(D^{*\pm}), W$ and $Q^2$ are compared with next-to-leading order QCD calculations based on the photon-gluon fusion production mechanism. After an extrapolation of the cross section to the full kinematic region in p_T(D^{*\pm}) and $\eta$(D^{*\pm}), the charm contribution $F_2^{c\bar{c}}(x,Q^2)$ to the proton structure function is determined for Bjorken $x$ between 2 $\cdot$ 10$^{-4}$ and 5 $\cdot$ 10$^{-3}$.Comment: 17 pages including 4 figure

Observation of Scaling Violations in Scaled Momentum Distributions at HERA

Charged particle production has been measured in deep inelastic scattering (DIS) events over a large range of $x$ and $Q^2$ using the ZEUS detector. The evolution of the scaled momentum, $x_p$, with $Q^2,$ in the range 10 to 1280 $GeV^2$, has been investigated in the current fragmentation region of the Breit frame. The results show clear evidence, in a single experiment, for scaling violations in scaled momenta as a function of $Q^2$.Comment: 21 pages including 4 figures, to be published in Physics Letters B. Two references adde