ALPS: the Arbitrary Linear Plasma Solver

The Arbitrary Linear Plasma Solver (ALPS) is a parallelised numerical code that solves the dispersion relation in a hot (even relativistic) magnetised plasma with an arbitrary number of particle species with arbitrary gyrotropic equilibrium distribution functions for any direction of wave propagation with respect to the background field. ALPS reads the background momentum distributions as tables of values on a (p⊥, pk) grid, where p⊥ and pk are the momentum coordinates in the directions perpendicular and parallel to the background magnetic field, respectively. We present the mathematical and numerical approach used by ALPS and introduce our algorithms for the handling of poles and the analytic continuation for the Landau contour integral. We then show test calculations of dispersion relations for a selection of stable and unstable configurations in Maxwellian, bi-Maxwellian, κ-distributed and Jüttner-distributed plasmas. These tests demonstrate that ALPS derives reliable plasma dispersion relations. ALPS will make it possible to determine the properties of waves and instabilities in the non-equilibrium plasmas that are frequently found in space, laboratory experiments and numerical simulations

Identifying Tightly Regulated and Variably Expressed Networks by Differential Rank Conservation (DIRAC)

A powerful way to separate signal from noise in biology is to convert the molecular data from individual genes or proteins into an analysis of comparative biological network behaviors. One of the limitations of previous network analyses is that they do not take into account the combinatorial nature of gene interactions within the network. We report here a new technique, Differential Rank Conservation (DIRAC), which permits one to assess these combinatorial interactions to quantify various biological pathways or networks in a comparative sense, and to determine how they change in different individuals experiencing the same disease process. This approach is based on the relative expression values of participating genes—i.e., the ordering of expression within network profiles. DIRAC provides quantitative measures of how network rankings differ either among networks for a selected phenotype or among phenotypes for a selected network. We examined disease phenotypes including cancer subtypes and neurological disorders and identified networks that are tightly regulated, as defined by high conservation of transcript ordering. Interestingly, we observed a strong trend to looser network regulation in more malignant phenotypes and later stages of disease. At a sample level, DIRAC can detect a change in ranking between phenotypes for any selected network. Variably expressed networks represent statistically robust differences between disease states and serve as signatures for accurate molecular classification, validating the information about expression patterns captured by DIRAC. Importantly, DIRAC can be applied not only to transcriptomic data, but to any ordinal data type

Independent Regulation of Reovirus Membrane Penetration and Apoptosis by the μ1 ϕ Domain

Apoptosis plays an important role in the pathogenesis of reovirus encephalitis. Reovirus outer-capsid protein μ1, which functions to penetrate host cell membranes during viral entry, is the primary regulator of apoptosis following reovirus infection. Ectopic expression of full-length and truncated forms of μ1 indicates that the μ1 ϕ domain is sufficient to elicit a cell death response. To evaluate the contribution of the μ1 ϕ domain to the induction of apoptosis following reovirus infection, ϕ mutant viruses were generated by reverse genetics and analyzed for the capacity to penetrate cell membranes and elicit apoptosis. We found that mutations in ϕ diminish reovirus membrane penetration efficiency by preventing conformational changes that lead to generation of key reovirus entry intermediates. Independent of effects on membrane penetration, amino acid substitutions in ϕ affect the apoptotic potential of reovirus, suggesting that ϕ initiates apoptosis subsequent to cytosolic delivery. In comparison to wild-type virus, apoptosis-defective ϕ mutant viruses display diminished neurovirulence following intracranial inoculation of newborn mice. These results indicate that the ϕ domain of μ1 plays an important regulatory role in reovirus-induced apoptosis and disease

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.Published versionThe authors thank the UK MS Society for financial support (grant number: C008-16.1). DRO was funded by an MRC Clinician Scientist Award (MR/N008219/1). P.M.M. acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Senior Investigator programme and the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. P.M.M. and D.R.O. thank the Imperial College Healthcare Trust-NIHR Biomedical Research Centre for infrastructure support and the Medical Research Council for support of TSPO studies (MR/N016343/1). E.A. was supported by the ALS Stichting (grant “The Dutch ALS Tissue Bank”). P.M. and B.B.T. are funded by the Swiss National Science Foundation (projects 320030_184713 and 310030_212322, respectively). S.T. was supported by an “Early Postdoc.Mobility” scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a “Clinical Medicine Plus” scholarship from the Prof Dr. Max Cloëtta Foundation (Zurich, Switzerland), from the Jean et Madeleine Vachoux Foundation (Geneva, Switzerland) and from the University Hospitals of Geneva. This work was funded by NIH grants U01AG061356 (De Jager/Bennett), RF1AG057473 (De Jager/Bennett), and U01AG046152 (De Jager/Bennett) as part of the AMP-AD consortium, as well as NIH grants R01AG066831 (Menon) and U01AG072572 (De Jager/St George-Hyslop)

Infection of XC Cells by MLVs and Ebola Virus Is Endosome-Dependent but Acidification-Independent

Inhibitors of endosome acidification or cathepsin proteases attenuated infections mediated by envelope proteins of xenotropic murine leukemia virus-related virus (XMRV) and Ebola virus, as well as ecotropic, amphotropic, polytropic, and xenotropic murine leukemia viruses (MLVs), indicating that infections by these viruses occur through acidic endosomes and require cathepsin proteases in the susceptible cells such as TE671 cells. However, as previously shown, the endosome acidification inhibitors did not inhibit these viral infections in XC cells. It is generally accepted that the ecotropic MLV infection in XC cells occurs at the plasma membrane. Because cathepsin proteases are activated by low pH in acidic endosomes, the acidification inhibitors may inhibit the viral infections by suppressing cathepsin protease activation. The acidification inhibitors attenuated the activities of cathepsin proteases B and L in TE671 cells, but not in XC cells. Processing of cathepsin protease L was suppressed by the acidification inhibitor in NIH3T3 cells, but again not in XC cells. These results indicate that cathepsin proteases are activated without endosome acidification in XC cells. Treatment with an endocytosis inhibitor or knockdown of dynamin 2 expression by siRNAs suppressed MLV infections in all examined cells including XC cells. Furthermore, endosomal cathepsin proteases were required for these viral infections in XC cells as other susceptible cells. These results suggest that infections of XC cells by the MLVs and Ebola virus occur through endosomes and pH-independent cathepsin activation induces pH-independent infection in XC cells

Zfp488 promotes oligodendrocyte differentiation of neural progenitor cells in adult mice after demyelination

Basic helix-loop-helix transcription factors Olig1 and Olig2 critically regulate oligodendrocyte development. Initially identified as a downstream effector of Olig1, an oligodendrocyte-specific zinc finger transcription repressor, Zfp488, cooperates with Olig2 function. Although Zfp488 is required for oligodendrocyte precursor formation and differentiation during embryonic development, its role in oligodendrogenesis of adult neural progenitor cells is not known. In this study, we tested whether Zfp488 could promote an oligodendrogenic fate in adult subventricular zone (SVZ) neural stem/progenitor cells (NSPCs). Using a cuprizone-induced demyelination model in mice, we examined the effect of retrovirus-mediated Zfp488 overexpression in SVZ NSPCs. Our results showed that Zfp488 efficiently promoted the differentiation of the SVZ NSPCs into mature oligodendrocytes in vivo. After cuprizone-induced demyelination injury, Zfp488-transduced mice also showed significant restoration of motor function to levels comparable to control mice. Together, these findings identify a previously unreported role for Zfp488 in adult oligodendrogenesis and functional remyelination after injury