Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals.

IFIT (interferon-induced with tetratricopeptide repeats) proteins are critical mediators of mammalian innate antiviral immunity. Mouse IFIT1 selectively inhibits viruses that lack 2'O-methylation of their mRNA 5' caps. Surprisingly, human IFIT1 does not share this antiviral specificity. Here, we resolve this discrepancy by demonstrating that human and mouse IFIT1 have evolved distinct functions using a combination of evolutionary, genetic and virological analyses. First, we show that human IFIT1 and mouse IFIT1 (renamed IFIT1B) are not orthologs, but are paralogs that diverged >100 mya. Second, using a yeast genetic assay, we show that IFIT1 and IFIT1B proteins differ in their ability to be suppressed by a cap 2'O-methyltransferase. Finally, we demonstrate that IFIT1 and IFIT1B have divergent antiviral specificities, including the discovery that only IFIT1 proteins inhibit a virus encoding a cap 2'O-methyltransferase. These functional data, combined with widespread turnover of mammalian IFIT genes, reveal dramatic species-specific differences in IFIT-mediated antiviral repertoires

Blue fluorescent proteins with enhanced brightness and photostability from a structurally targeted library

The utility of blue fluorescent protein (BFP) has been limited by its low quantum yield and rapid photobleaching. A library targeting residues neighboring the chromophore yielded a variant with enhanced quantum yield (0.55 versus 0.34), reduced pH sensitivity and a 40-fold increase in photobleaching half-life. This BFP, named Azurite, is well expressed in bacterial and mammalian cells and extends the palette of fluorescent proteins that can be used for imaging

Electron-Positron Jets from a Critically Magnetized Black Hole

The curved spacetime surrounding a rotating black hole dramatically alters the structure of nearby electromagnetic fields. The Wald field which is an asymptotically uniform magnetic field aligned with the angular momentum of the hole provides a convenient starting point to analyze the effects of radiative corrections on electrodynamics in curved spacetime. Since the curvature of the spacetime is small on the scale of the electron's Compton wavelength, the tools of quantum field theory in flat spacetime are reliable and show that a rotating black hole immersed in a magnetic field approaching the quantum critical value of $B_k=m^2 c^3/(e\hbar) \approx 4.4 \times 10^{13}$~G $\approx 1.3\times10^{-11}$ cm$^{-1}$ is unstable. Specifically, a maximally rotating three-solar-mass black hole immersed in a magnetic field of $2.3 \times 10^{12}$~G would be a copious producer of electron-positron pairs with a luminosity of $3 \times 10^{52}$ erg s$^{-1}$.Comment: 10 pages, 6 figures, submitted to Phys. Rev.

Subjective cognitive decline predicts lower cingulo-opercular network functional connectivity in individuals with lower neurite density in the forceps minor

Cognitive complaints of attention/concentration problems are highly frequent in older adults with subjective cognitive decline (SCD). Functional connectivity in the cingulo-opercular network (CON-FC) supports cognitive control, tonic alertness, and visual processing speed. Thus, those complaints in SCD may reflect a decrease in CON-FC. Frontal white-matter tracts such as the forceps minor exhibit age- and SCD-related alterations and, therefore, might influence the CON-FC decrease in SCD. Here, we aimed to determine whether SCD predicts an impairment in CON-FC and whether neurite density in the forceps minor modulates that effect. To do so, we integrated cross-sectional and longitudinal analyses of multimodal data in a latent growth curve modeling approach. Sixty-nine healthy older adults (13 males; 68.33 ± 7.95 years old) underwent resting-state functional and diffusion-weighted magnetic resonance imaging, and the degree of SCD was assessed at baseline with the memory functioning questionnaire (greater score indicating more SCD). Forty-nine of the participants were further enrolled in two follow-ups, each about 18 months apart. Baseline SCD did not predict CON-FC after three years or its rate of change (p-values > 0.092). Notably, however, the forceps minor neurite density did modulate the relation between SCD and CON-FC (intercept; b = 0.21, 95% confidence interval, CI, [0.03, 0.39], p = 0.021), so that SCD predicted a greater CON-FC decrease in older adults with relatively lower neurite density in the forceps minor. The neurite density of the forceps minor, in turn, negatively correlated with age. These results suggest that CON-FC alterations in SCD are dependent upon the forceps minor neurite density. Accordingly, these results imply modifiable age-related factors that could help delay or mitigate both age and SCD-related effects on brain connectivity

Very-high-energy gamma radiation associated with the unshocked wind of the Crab pulsar

We show that the relativistic wind in the Crab pulsar, which is commonly thought to be invisible in the region upstream of the termination shock at R < 0.1 pc, in fact could be directly observed through its inverse Compton gamm-ray emission. The search for such specific component of radiation in the gamma-ray spectrum of the Crab can provide unique information about the unshocked pulsar wind that is not accessible at other wavelengths.Comment: 11 pages, 11 figures, to appear in one of the April issues of MNRA

Resonant Cyclotron Radiation Transfer Model Fits to Spectra from Gamma-Ray Burst GRB870303

We demonstrate that models of resonant cyclotron radiation transfer in a strong field (i.e. cyclotron scattering) can account for spectral lines seen at two epochs, denoted S1 and S2, in the Ginga data for GRB870303. Using a generalized version of the Monte Carlo code of Wang et al. (1988,1989b), we model line formation by injecting continuum photons into a static plane-parallel slab of electrons threaded by a strong neutron star magnetic field (~ 10^12 G) which may be oriented at an arbitrary angle relative to the slab normal. We examine two source geometries, which we denote "1-0" and "1-1," with the numbers representing the relative electron column densities above and below the continuum photon source plane. We compare azimuthally symmetric models, i.e. models in which the magnetic field is parallel to the slab normal, with models having more general magnetic field orientations. If the bursting source has a simple dipole field, these two model classes represent line formation at the magnetic pole, or elsewhere on the stellar surface. We find that the data of S1 and S2, considered individually, are consistent with both geometries, and with all magnetic field orientations, with the exception that the S1 data clearly favor line formation away from a polar cap in the 1-1 geometry, with the best-fit model placing the line-forming region at the magnetic equator. Within both geometries, fits to the combined (S1+S2) data marginally favor models which feature equatorial line formation, and in which the observer's orientation with respect to the slab changes between the two epochs. We interpret this change as being due to neutron star rotation, and we place limits on the rotation period.Comment: LaTeX2e (aastex.cls included); 45 pages text, 17 figures (on 21 pages); accepted by ApJ (to be published 1 Nov 1999, v. 525

Synergistic drug combinations from electronic health records and gene expression.

ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing

APPLICATION OF POLYURETHANE FOAM FOR IMPACT ABSORPTION AND THERMAL INSULATION FOR GENERAL PURPOSE RADIOACTIVE MATERIALS PACKAGINGS

Polyurethane foam has been employed in impact limiters for large radioactive materials packagings since the early 1980's. Its consistent crush response, controllable structural properties and excellent thermal insulating characteristics have made it attractive as replacement for the widely used cane fiberboard for smaller, drum size packagings. Accordingly, polyurethane foam was chosen for the overpack material for the 9977 and 9978 packagings. The study reported here was undertaken to provide data to support the analyses performed as part of the development of the 9977 and 9978, and compared property values reported in the literature with published property values and test results for foam specimens taken from a prototype 9977 packaging. The study confirmed that, polyurethane foam behaves in a predictable and consistent manner and fully satisfies the functional requirements for impact absorption and thermal insulation

Activated Magnetospheres of Magnetars

Like the solar corona, the external magnetic field of magnetars is twisted by surface motions of the star. The twist energy is dissipated over time. We discuss the theory of this activity and its observational status. (1) Theory predicts that the magnetosphere tends to untwist in a peculiar way: a bundle of electric currents (the "j-bundle") is formed with a sharp boundary, which shrinks toward the magnetic dipole axis. Recent observations of shrinking hot spots on magnetars are consistent with this behavior. (2) Continual discharge fills the j-bundle with electron-positron plasma, maintaining a nonthermal corona around the neutron star. The corona outside a few stellar radii strongly interacts with the stellar radiation and forms a "radiatively locked" outflow with a high e+- multiplicity. The locked plasma annihilates near the apexes of the closed magnetic field lines. (3) New radiative-transfer simulations suggest a simple mechanism that shapes the observed X-ray spectrum from 0.1 keV to 1 MeV: part of the thermal X-rays emitted by the neutron star are reflected from the outer corona and then upscattered by the inner relativistic outflow in the j-bundle, producing a beam of hard X-rays.Comment: 23 pages, 7 figures; review chapter in the proceedings of ICREA Workshop on the High-Energy Emission from Pulsars and Their Systems, Sant Cugat, Spain, April 201

APPLICATION OF POLYURETHANE FOAM FOR IMPACT ABSORPTION AND THERMAL INSULATION FOR RADIOACTIVE MATERIALS PACKAGINGS.

Polyurethane foam has been widely used as an impact absorbing and thermal insulating material for large radioactive materials packages, since the 1980's. With the adoption of the regulatory crush test requirement, for smaller packages, polyurethane foam has been adopted as a replacement for cane fiberboard, because of its ability to withstand the crush test. Polyurethane foam is an engineered material whose composition is much more closely controlled than that of cane fiberboard. In addition, the properties of the foam can be controlled by controlling the density of the foam. The conditions under which the foam is formed, whether confined or unconfined have an affect on foam properties. The study reported here reviewed the application of polyurethane foam in RAM packagings and compared property values reported in the literature with published property values and test results for foam specimens taken from a prototype 9977 packaging. The study confirmed that, polyurethane foam behaves in a predictable and consistent manner and fully satisfies the functional requirements for impact absorption and thermal insulation