The interferon-stimulated gene IFITM3 restricts West Nile virus infection and pathogenesis

The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(−/−) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this, Ifitm3(−/−) fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected Ifitm3(−/−) mice showed decreases in the total number of B cells, CD4(+) T cells, and antigen-specific CD8(+) T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells. IMPORTANCE As part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of IFITM genes on viral pathogenesis in vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of Ifitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types

Monoclonal antibodies in neuro-oncology: Getting past the blood-brain barrier

Monoclonal antibodies (mAbs) are used with increasing success against many tumors, but for brain tumors the blood-brain barrier (BBB) is a special concern. The BBB prevents antibody entry to the normal brain; however, its role in brain tumor therapy is more complex. The BBB is closest to normal at micro-tumor sites; its properties and importance change as the tumor grows. In this review, evolving insight into the role of the BBB is balanced against other factors that affect efficacy or interpretation when mAbs are used against brain tumor targets. As specific examples, glioblastoma multiforme (GBM), primary central nervous system lymphoma (PCNSL) and blood-borne metastases from breast cancer are discussed in the context of treatment, respectively, with the mAbs bevacizumab, rituximab and trastuzumab, each of which is already widely used against tumors outside the brain. It is suggested that success against brain tumors will require getting past the BBB in two senses: physically, to better attack brain tumor targets, and conceptually, to give equal attention to problems that are shared with other tumor sites

Explosion Mechanisms of Core-Collapse Supernovae

Supernova theory, numerical and analytic, has made remarkable progress in the past decade. This progress was made possible by more sophisticated simulation tools, especially for neutrino transport, improved microphysics, and deeper insights into the role of hydrodynamic instabilities. Violent, large-scale nonradial mass motions are generic in supernova cores. The neutrino-heating mechanism, aided by nonradial flows, drives explosions, albeit low-energy ones, of ONeMg-core and some Fe-core progenitors. The characteristics of the neutrino emission from new-born neutron stars were revised, new features of the gravitational-wave signals were discovered, our notion of supernova nucleosynthesis was shattered, and our understanding of pulsar kicks and explosion asymmetries was significantly improved. But simulations also suggest that neutrino-powered explosions might not explain the most energetic supernovae and hypernovae, which seem to demand magnetorotational driving. Now that modeling is being advanced from two to three dimensions, more realism, new perspectives, and hopefully answers to long-standing questions are coming into reach.Comment: 35 pages, 11 figures (29 eps files; high-quality versions can be obtained upon request); accepted by Annual Review of Nuclear and Particle Scienc

A picogram and nanometer scale photonic crystal opto-mechanical cavity

We describe the design, fabrication, and measurement of a cavity opto-mechanical system consisting of two nanobeams of silicon nitride in the near-field of each other, forming a so-called "zipper" cavity. A photonic crystal patterning is applied to the nanobeams to localize optical and mechanical energy to the same cubic-micron-scale volume. The picrogram-scale mass of the structure, along with the strong per-photon optical gradient force, results in a giant optical spring effect. In addition, a novel damping regime is explored in which the small heat capacity of the zipper cavity results in blue-detuned opto-mechanical damping.Comment: 15 pages, 4 figure

Unbalanced Holographic Superconductors and Spintronics

We present a minimal holographic model for s-wave superconductivity with unbalanced Fermi mixtures, in 2+1 dimensions at strong coupling. The breaking of a U(1)_A "charge" symmetry is driven by a non-trivial profile for a charged scalar field in a charged asymptotically AdS_4 black hole. The chemical potential imbalance is implemented by turning on the temporal component of a U(1)_B "spin" field under which the scalar field is uncharged. We study the phase diagram of the model and comment on the eventual (non) occurrence of LOFF-like inhomogeneous superconducting phases. Moreover, we study "charge" and "spin" transport, implementing a holographic realization (and a generalization thereof to superconducting setups) of Mott's two-current model which provides the theoretical basis of modern spintronics. Finally we comment on possible string or M-theory embeddings of our model and its higher dimensional generalizations, within consistent Kaluza-Klein truncations and brane-anti brane setups.Comment: 45 pages, 15 figures; v2: two paragraphs below eq. (3.1) slightly modified, figure 5 (left) replaced, references added; v3: typos corrected, comments added, figure 12 replace

Long-Range Rapidity Correlations in Heavy Ion Collisions at Strong Coupling from AdS/CFT

We use AdS/CFT correspondence to study two-particle correlations in heavy ion collisions at strong coupling. Modeling the colliding heavy ions by shock waves on the gravity side, we observe that at early times after the collision there are long-range rapidity correlations present in the two-point functions for the glueball and the energy-momentum tensor operators. We estimate rapidity correlations at later times by assuming that the evolution of the system is governed by ideal Bjorken hydrodynamics, and find that glueball correlations in this state are suppressed at large rapidity intervals, suggesting that late-time medium dynamics can not "wash out" the long-range rapidity correlations that were formed at early times. These results may provide an insight on the nature of the "ridge" correlations observed in heavy ion collision experiments at RHIC and LHC, and in proton-proton collisions at LHC.Comment: 32 pages, 2 figures; v2: typos corrected, references adde

Holographic Lovelock Gravities and Black Holes

We study holographic implications of Lovelock gravities in AdS spacetimes. For a generic Lovelock gravity in arbitrary spacetime dimensions we formulate the existence condition for asymptotically AdS black holes. We consider small fluctuations around these black holes and determine the constraint on Lovelock parameters by demanding causality of the boundary theory. For the case of cubic Lovelock gravity in seven spacetime dimensions we compute the holographic Weyl anomaly and determine the three point functions of the stress energy tensor in the boundary CFT. Remarkably, these correlators happen to satisfy the same relation as the one imposed by supersymmetry. We then compute the energy flux; requiring it to be positive is shown to be completely equivalent to requiring causality of the finite temperature CFT dual to the black hole. These constraints are not stringent enough to place any positive lower bound on the value of viscosity. Finally, we conjecture an expression for the energy flux valid for any Lovelock theory in arbitrary dimensions.Comment: 31 pages, 1 figure, harvmac, references added, calculation of viscosity/entropy ratio include