Targeting lentiviral vectors to antigen-specific immunoglobulins

Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell Populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient rnethod to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and hi vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral Surface. This engineered vector could specifically bind to cells expressing Surface immunoglobulin recognizing CD20 (αCD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing αCD20. These results show the feasibility of engineering lentivectors to target immunoglobulin-specific cells to deliver a therapeutic effect. Such targeting lentivectors also Could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology

Abundance analysis, spectral variability, and search for the presence of a magnetic field in the typical PGa star HD 19400

The aim of this study is to carry out an abundance determination, to search for spectral variability and for the presence of a weak magnetic field in the typical PGa star HD 19400. High-resolution, high signal-to-noise High Accuracy Radial-velocity Planet Searcher (HARPS) spectropolarimetric observations of HD 19400 were obtained at three different epochs in 2011 and 2013. For the first time, we present abundances of various elements determined using an ATLAS12 model, including the abundances of a number of elements not analysed by previous studies, such as Ne I, Ga II, and Xe II. Several lines of As II are also present in the spectra of HD 19400. To study the variability, we compared the behaviour of the line profiles of various elements. We report on the first detection of anomalous shapes of line profiles belonging to Mn and Hg, and the variability of the line profiles belonging to the elements Hg, P, Mn, Fe, and Ga. We suggest that the variability of the line profiles of these elements is caused by their non-uniform surface distribution, similar to the presence of chemical spots detected in HgMn stars. The search for the presence of a magnetic field was carried out using the moment technique and the Singular Value Decomposition (SVD) method. Our measurements of the magnetic field with the moment technique using 22 Mn II lines indicate the potential existence of a weak variable longitudinal magnetic field on the first epoch. The SVD method applied to the Mn II lines indicates &lt;Bz&gt; = -76 &plusmn; 25 G on the first epoch, and at the same epoch the SVD analysis of the observations using the Fe II lines shows &lt;Bz&gt; = -91 &plusmn; 35 G. The calculated false alarm probability values, 0.008 and 0.003, respectively, are above the value 10-3, indicating no detection.</p

A Helicity-Based Method to Infer the CME Magnetic Field Magnitude in Sun and Geospace: Generalization and Extension to Sun-Like and M-Dwarf Stars and Implications for Exoplanet Habitability

Patsourakos et al. (Astrophys. J. 817, 14, 2016) and Patsourakos and Georgoulis (Astron. Astrophys. 595, A121, 2016) introduced a method to infer the axial magnetic field in flux-rope coronal mass ejections (CMEs) in the solar corona and farther away in the interplanetary medium. The method, based on the conservation principle of magnetic helicity, uses the relative magnetic helicity of the solar source region as input estimates, along with the radius and length of the corresponding CME flux rope. The method was initially applied to cylindrical force-free flux ropes, with encouraging results. We hereby extend our framework along two distinct lines. First, we generalize our formalism to several possible flux-rope configurations (linear and nonlinear force-free, non-force-free, spheromak, and torus) to investigate the dependence of the resulting CME axial magnetic field on input parameters and the employed flux-rope configuration. Second, we generalize our framework to both Sun-like and active M-dwarf stars hosting superflares. In a qualitative sense, we find that Earth may not experience severe atmosphere-eroding magnetospheric compression even for eruptive solar superflares with energies ~ 10^4 times higher than those of the largest Geostationary Operational Environmental Satellite (GOES) X-class flares currently observed. In addition, the two recently discovered exoplanets with the highest Earth-similarity index, Kepler 438b and Proxima b, seem to lie in the prohibitive zone of atmospheric erosion due to interplanetary CMEs (ICMEs), except when they possess planetary magnetic fields that are much higher than that of Earth.Comment: http://adsabs.harvard.edu/abs/2017SoPh..292...89

The first ultracompact Roche lobe-filling hot subdwarf binary

We report the discovery of the first short period binary in which a hot subdwarf star (sdOB) fills its Roche lobe and started mass transfer to its companion. The object was discovered as part of a dedicated high-cadence survey of the Galactic Plane named the Zwicky Transient Facility and exhibits a period of Porb=39.3401(1) min, making it the most compact hot subdwarf binary currently known. Spectroscopic observations are consistent with an intermediate He-sdOB star with an effective temperature of Teff=42,400±300 K and a surface gravity of log(g)=5.77±0.05. A high-signal-to noise GTC+HiPERCAM light curve is dominated by the ellipsoidal deformation of the sdOB star and an eclipse of the sdOB by an accretion disk. We infer a low-mass hot subdwarf donor with a mass MsdOB=0.337±0.015 M⊙ and a white dwarf accretor with a mass MWD=0.545±0.020 M⊙. Theoretical binary modeling indicates the hot subdwarf formed during a common envelope phase when a 2.5−2.8 M⊙ star lost its envelope when crossing the Hertzsprung Gap. To match its current Porb, Teff, log(g), and masses, we estimate a post-common envelope period of Porb≈150 min, and find the sdOB star is currently undergoing hydrogen shell burning. We estimate that the hot subdwarf will become a white dwarf with a thick helium layer of ≈0.1 M⊙ and will merge with its carbon/oxygen white dwarf companion after ≈17 Myr and presumably explode as a thermonuclear supernova or form an R CrB star

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

DNA Encoding an HIV-1 Gag/Human Lysosome-Associated Membrane Protein-1 Chimera Elicits a Broad Cellular and Humoral Immune Response in Rhesus Macaques

Previous studies of HIV-1 p55Gag immunization of mice have demonstrated the usefulness of targeting antigens to the cellular compartment containing the major histocompatibility complex type II (MHC II) complex molecules by use of a DNA antigen formulation encoding Gag as a chimera with the mouse lysosome-associated membrane protein (mLAMP/gag). In the present study, we have analyzed the magnitude and breadth of Gag-specific T-lymphocyte and antibody responses elicited in Rhesus macaques after immunization with DNA encoding a human LAMP/gag (hLAMP/gag) chimera. ELISPOT analyses indicated that the average Gag-specific IFN-γ response elicited by the hLAMP/gag chimera was detectable after only two or three naked DNA immunizations in all five immunized macaques and reached an average of 1000 spot-forming cells (SFC)/10(6) PBMCs. High IFN-γ ELISPOT responses were detected in CD8(+)-depleted cells, indicating that CD4(+) T-cells play a major role in these responses. The T-cell responses of four of the macaques were also tested by use of ELISPOT to 12 overlapping 15-amino acids (aa) peptide pools containing ten peptides each, encompassing the complete Gag protein sequence. The two Mamu 08 immunized macaques responded to eight and twelve of the pools, the Mamu B01 to six, and the other macaque to five pools indicating that the hLAMP/gag DNA antigen formulation elicits a broad T-cell response against Gag. Additionally, there was a strong HIV-1-specific IgG response. The IgG antibody titers increased after each DNA injection, indicating a strong amnestic B-cell response, and were highly elevated in all the macaques after three immunizations. Moreover, the serum of each macaque recognized 13 of the 49 peptides of a 20-aa peptide library covering the complete Gag amino acid sequence. In addition, HIV-1-specific IgA antibodies were present in the plasma and external secretions, including nasal washes. These data support the findings of increased immunogenicity of genetic vaccines encoded as LAMP chimeras, including the response to DNA vaccines by non-human primates

A dense 0.1-solar-mass star in a 51-minute-orbital-period eclipsing binary

Of more than a thousand known cataclysmic variables (CVs), where a white dwarf is accreting from a hydrogen-rich star, only a dozen have orbital periods below 75 minutes1,2,3,4,5,6,7,8,9. One way to achieve these short periods requires the donor star to have undergone substantial nuclear evolution before interacting with the white dwarf10,11,12,13,14, and it is expected that these objects will transition to helium accretion. These transitional CVs have been proposed as progenitors of helium CVs13,14,15,16,17,18. However, no known transitional CV is expected to reach an orbital period short enough to account for most of the helium CV population, leaving the role of this evolutionary pathway unclear. Here we report observations of ZTF J1813+4251, a 51-minute-orbital-period, fully eclipsing binary system consisting of a star with a temperature comparable to that of the Sun but a density 100 times greater owing to its helium-rich composition, accreting onto a white dwarf. Phase-resolved spectra, multi-band light curves and the broadband spectral energy distribution allow us to obtain precise and robust constraints on the masses, radii and temperatures of both components. Evolutionary modelling shows that ZTF J1813+4251 is destined to become a helium CV binary, reaching an orbital period under 20 minutes, rendering ZTF J1813+4251 a previously missing link between helium CV binaries and hydrogen-rich CVs

Microflares and the Statistics of X-ray Flares

This review surveys the statistics of solar X-ray flares, emphasising the new views that RHESSI has given us of the weaker events (the microflares). The new data reveal that these microflares strongly resemble more energetic events in most respects; they occur solely within active regions and exhibit high-temperature/nonthermal emissions in approximately the same proportion as major events. We discuss the distributions of flare parameters (e.g., peak flux) and how these parameters correlate, for instance via the Neupert effect. We also highlight the systematic biases involved in intercomparing data representing many decades of event magnitude. The intermittency of the flare/microflare occurrence, both in space and in time, argues that these discrete events do not explain general coronal heating, either in active regions or in the quiet Sun.Comment: To be published in Space Science Reviews (2011

A new class of Roche lobe–filling hot subdwarf binaries

We present the discovery of the second binary with a Roche lobe–filling hot subdwarf transferring mass to a white dwarf (WD) companion. This 56 minute binary was discovered using data from the Zwicky Transient Facility. Spectroscopic observations reveal an He-sdOB star with an effective temperature of T eff = 33,700 ± 1000 K and a surface gravity of log(g) = 5.54 ± 0.11. The GTC+HiPERCAM light curve is dominated by the ellipsoidal deformation of the He-sdOB star and shows an eclipse of the He-sdOB by an accretion disk as well as a weak eclipse of the WD. We infer a He-sdOB mass of M sdOB = 0.41 ± 0.04 M ⊙ and a WD mass of M WD = 0.68 ± 0.05 M ⊙. The weak eclipses imply a WD blackbody temperature of 63,000 ± 10,000 K and a radius R WD = 0.0148 ± 0.0020 R ⊙ as expected for a WD of such high temperature. The He-sdOB star is likely undergoing hydrogen shell burning and will continue transferring mass for ≈1 Myr at a rate of 10−9 M ⊙ yr−1, which is consistent with the high WD temperature. The hot subdwarf will then turn into a WD and the system will merge in ≈30 Myr. We suggest that Galactic reddening could bias discoveries toward preferentially finding Roche lobe–filling systems during the short-lived shell-burning phase. Studies using reddening-corrected samples should reveal a large population of helium core–burning hot subdwarfs with T eff ≈ 25,000 K in binaries of 60–90 minutes with WDs. Though not yet in contact, these binaries would eventually come into contact through gravitational-wave emission and explode as a subluminous thermonuclear supernova or evolve into a massive single WD

A 62-minute orbital period black widow binary in a wide hierarchical triple

Over a dozen millisecond pulsars are ablating low-mass companions in close binary systems. In the original ‘black widow’, the eight-hour orbital period eclipsing pulsar PSR J1959+2048 (PSR B1957+20)1, high-energy emission originating from the pulsar2 is irradiating and may eventually destroy3 a low-mass companion. These systems are not only physical laboratories that reveal the interesting results of exposing a close companion star to the relativistic energy output of a pulsar, but are also believed to harbour some of the most massive neutron stars4, allowing for robust tests of the neutron star equation of state. Here we report observations of ZTF J1406+1222, a wide hierarchical triple hosting a 62-minute orbital period black widow candidate, the optical flux of which varies by a factor of more than ten. ZTF J1406+1222 pushes the boundaries of evolutionary models5, falling below the 80-minute minimum orbital period of hydrogen-rich systems. The wide tertiary companion is a rare low-metallicity cool subdwarf star, and the system has a Galactic halo orbit consistent with passing near the Galactic Centre, making it a probe of formation channels, neutron star kick physics6 and binary evolution