Pseudotype-based neutralization assays for influenza: a systematic analysis

The use of vaccination against the influenza virus remains the most effective method of mitigating the significant morbidity and mortality caused by this virus. Antibodies elicited by currently licensed influenza vaccines are predominantly hemagglutination-inhibition (HI)-competent antibodies that target the globular head of HA thus inhibiting influenza virus entry into target cells. These antibodies predominantly confer homosubtypic/strain specific protection and only rarely confer heterosubtypic protection. However, recent academia or pharma-led R&D towards the production of a "universal vaccine" has centered on the elicitation of antibodies directed against the stalk of the influenza HA that has been shown to confer broad protection across a range of different subtypes (H1 to H16). The accurate and sensitive measurement of antibody responses elicited by these "next-generation" influenza vaccines is however hampered by the lack of sensitivity of the traditional influenza serological assays hemagglutinin inhibition (HI), single radial hemolysis (SRH) and microneutralization (MN). Assays utilizing pseudotypes, chimeric viruses bearing influenza glycoproteins, have been shown to be highly efficient for the measurement of homosubtypic and heterosubtypic broadly-neutralizing antibodies, making them ideal serological tools for the study of cross-protective responses against multiple influenza subtypes with pandemic potential. In this review, we will analyze and compare literature involving the production of influenza pseudotypes with particular emphasis on their use in serum antibody neutralization assays. This will enable us to establish the parameters required for optimization and propose a consensus protocol to be employed for the further deployment of these assays in influenza vaccine immunogenicity studies

CGM2, a Member of the Carcinoembryonic Antigen Gene Family is Down- Regulated in Colorectal Carcinomas

We have determined the precise chromosomal location, the exon structure, and the expression pattern of CGM2, a member of the carcinoembryonic antigen (CEA) gene family. CGM2 cDNA was amplified by reverse transcription-polymerase chain reaction (RT/PCR) from the colon adenocarcinoma cell line, LS174T. A defective exon is missing from this cDNA clone, leading to a novel domain organization for the human CEA family with two immunoglobulin-like domains. The derived C-terminal domain predicts that the CGM2 protein is membrane-bound through a glycosyl phosphatidylinositol anchor. RT/PCR analyses identified CGM2 transcripts in mucinous ovarian and colonic adenocarcinomas as well as in adjacent colonic tissue, but not in other tumors including leukocytes from six chronic myeloid leukemia patients. Thus, unlike several other family members, CGM2 is not expressed in granulocytes but reveals a more CEA-like expression pattern. Northern blot analyses identified a 2.5-kilobase CGM2 mRNA that is strongly down-regulated in colonic adenocarcinomas compared with adjacent colonic mucosa, suggesting a possible tumor suppressor function. In addition, a 3.2- kilobase transcript was observed in a number of colon tumors that is not detectable in normal colonic tissue. This mRNA species could represent a tumor-specific CGM2 splice variant

Simulations to benchmark time-varying connectivity methods for fMRI

Published: May 29, 2018There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.WHT acknowledges support from the Knut och Alice Wallenbergs Stiftelse (SE) (grant no. 2016.0473, http://kaw.wallenberg.org). PR acknowledges support from the Swedish Research Council (Vetenskapsrådet) (grants no. 2016-03352 and 773 013-61X-08276-26-4) (http://vr.se) and the Swedish e-Science Research Center (http://e- science.se/). CGR acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the ªSevero Ochoaº Programme for Centres/Units of Excellence in R&Dº (SEV-2015-490, http://csic.es/)

The Pim kinases control rapamycin-resistant T cell survival and activation

Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics

Large Torque Variations in Two Soft Gamma Repeaters

We have monitored the pulse frequencies of the two soft gamma repeaters SGR 1806-20 and SGR 1900+14 through the beginning of year 2001 using primarily Rossi X-ray Timing Explorer Proportional Counter Array observations. In both sources, we observe large changes in the spin-down torque up to a factor of ~4, which persist for several months. Using long baseline phase-connected timing solutions as well as the overall frequency histories, we construct torque noise power spectra for each SGR. The power spectrum of each source is very red (power-law slope ~-3.5). The torque noise power levels are consistent with some accreting systems on time scales of ~1 year, yet the full power spectrum is much steeper in frequency than any known accreting source. To the best of our knowledge, torque noise power spectra with a comparably steep frequency dependence have only been seen in young, glitching radio pulsars (e.g. Vela). The observed changes in spin-down rate do not correlate with burst activity, therefore, the physical mechanisms behind each phenomenon are also likely unrelated. Within the context of the magnetar model, seismic activity cannot account for both the bursts and the long-term torque changes unless the seismically active regions are decoupled from one another.Comment: 26 pages, 11 figures included, accepted for publication in ApJ, analysis of torque noise power density spectra is revised from previous version and minor text changes were mad

Discovery of a New Transient Magnetar Candidate: XTE J1810-197

We report the discovery of a new X-ray pulsar, XTE J1810-197. The source was serendipitously discovered on 2003 July 15 by the Rossi X-ray Timing Explorer (RXTE) while observing the soft gamma repeater SGR 1806-20. The pulsar has a 5.54 s spin-period and a soft spectrum (photon index ~ 4). We detect the source in earlier RXTE observations back to 2003 January. These show that a transient outburst began between 2002 November 17 and 2003 January 23 and that the pulsar has been spinning down since then, with a high rate Pdot ~ 10^-11 s/s showing significant timing noise, but no evidence for Doppler shifts due to a binary companion. The rapid spin-down rate and slow spin-period imply a super-critical magnetic field B=3x10^14 G and a young characteristic age < 7600 yr. These properties are strikingly similar to those of anomalous X-ray pulsars and soft gamma repeaters, making the source a likely new magnetar. A follow-up Chandra observation provided a 2".5 radius error circle within which the 1.5 m Russian-Turkish Optical Telescope RTT150 found a limiting magnitude of R_c=21.5, in accord with other recently reported limits. The source is present in archival ASCA and ROSAT data as well, at a level 100 times fainter than the \~ 3 mCrab seen in 2003. This suggests that other X-ray sources that are currently in a state similar to the inactive phase of XTE J1810-197 may also be unidentified magnetars awaiting detection via a similar activity.Comment: Submitted to ApJL; 4 pages; 4 figure

Asymmetric Supernovae, Pulsars, Magnetars, and Gamma-Ray Bursts

We outline the possible physical processes, associated timescales, and energetics that could lead to the production of pulsars, jets, asymmetric supernovae, and weak gamma-ray bursts in routine circumstances and to a magnetar and perhaps stronger gamma-ray burst in more extreme circumstances in the collapse of the bare core of a massive star. The production of a LeBlanc-Wilson MHD jet could provide an asymmetric supernova and result in a weak gamma-ray burst when the jet accelerates down the stellar density gradient of a hydrogen-poor photosphere. The matter-dominated jet would be formed promptly, but requires 5 to 10 s to reach the surface of the progenitor of a Type Ib/c supernova. During this time, the newly-born neutron star could contract, spin up, and wind up field lines or turn on an alpha-Omega dynamo. In addition, the light cylinder will contract from a radius large compared to the Alfven radius to a size comparable to that of the neutron star. This will disrupt the structure of any organized dipole field and promote the generation of ultrarelativistic MHD waves (UMHDW) at high density and Large Amplitude Electromagnetic Waves (LAEMW) at low density. The generation of the these waves would be delayed by the cooling time of the neutron star about 5 to 10 seconds, but the propagation time is short so the UMHDW could arrive at the surface at about the same time as the matter jet. In the density gradient of the star and the matter jet, the intense flux of UMHDW and LAEMW could drive shocks, generate pions by proton-proton collision, or create electron/positron pairs depending on the circumstances. The UMHDW and LAEMW could influence the dynamics of the explosion and might also tend to flow out the rotation axis to produce a collimated gamma-ray burst.Comment: 31 pages, LaTeX, revised for referee comments, accepted for ApJ, July 10 issu

IMOS national reference stations: A continental-wide physical, chemical and biological coastal observing system

Sustained observations allow for the tracking of change in oceanography and ecosystems, however, these are rare, particularly for the Southern Hemisphere. To address this in part, the Australian Integrated Marine Observing System (IMOS) implemented a network of nine National Reference Stations (NRS). The network builds on one long-term location, where monthly water sampling has been sustained since the 1940s and two others that commenced in the 1950s. In-situ continuously moored sensors and an enhanced monthly water sampling regime now collect more than 50 data streams. Building on sampling for temperature, salinity and nutrients, the network now observes dissolved oxygen, carbon, turbidity, currents, chlorophyll a and both phytoplankton and zooplankton. Additional parameters for studies of ocean acidification and bio-optics are collected at a sub-set of sites and all data is made freely and publically available. Our preliminary results demonstrate increased utility to observe extreme events, such as marine heat waves and coastal flooding; rare events, such as plankton blooms; and have, for the first time, allowed for consistent continental scale sampling and analysis of coastal zooplankton and phytoplankton communities. Independent water sampling allows for cross validation of the deployed sensors for quality control of data that now continuously tracks daily, seasonal and annual variation. The NRS will provide multi-decadal time series, against which more spatially replicated short-term studies can be referenced, models and remote sensing products validated, and improvements made to our understanding of how large-scale, long-term change and variability in the global ocean are affecting Australia's coastal seas and ecosystems. The NRS network provides an example of how a continental scaled observing systems can be developed to collect observations that integrate across physics, chemistry and biology

X-ray Bursts from the Transient Magnetar Candidate XTE J1810-197

We have discovered four X-ray bursts, recorded with the Rossi X-ray Timing Explorer Proportional Counter Array between 2003 September and 2004 April, that we show to originate from the transient magnetar candidate XTE J1810-197. The burst morphologies consist of a short spike or multiple spikes lasting ~1 s each followed by extended tails of emission where the pulsed flux from XTE J1810-197 is significantly higher. The burst spikes are likely correlated with the pulse maxima, having a chance probability of a random phase distribution of 0.4%. The burst spectra are best fit to a blackbody with temperatures 4-8 keV, considerably harder than the persistent X-ray emission. During the X-ray tails following these bursts, the temperature rapidly cools as the flux declines, maintaining a constant emitting radius after the initial burst peak. During the brightest X-ray tail, we detect a narrow emission line at 12.6 keV with an equivalent width of 1.4 keV and a probability of chance occurrence less than 4 x 10^-6. The temporal and spectral characteristics of these bursts closely resemble the bursts seen from 1E 1048.1-5937 and a subset of the bursts detected from 1E 2259+586, thus establishing XTE J1810-197 as a magnetar candidate. The bursts detected from these three objects are sufficiently similar to one another, yet significantly different from those seen from soft gamma repeaters, that they likely represent a new class of bursts from magnetar candidates exclusive (thus far) to the anomalous X-ray pulsar-like sources.Comment: Accepted for publication in ApJ. 26 pages and 11 figure

Birds of a feather eat plastic together: high levels of plastic ingestion in Great Shearwater adults and juveniles across their annual migratory cycle

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Robuck, A. R., Hudak, C. A., Agvent, L., Emery, G., Ryan, P. G., Perold, V., Powers, K. D., Pedersen, J., Thompson, M. A., Suca, J. J., Moore, M. J., Harms, C. A., Bugoni, L., Shield, G., Glass, T., Wiley, D. N., & Lohmann, R. Birds of a feather eat plastic together: high levels of plastic ingestion in Great Shearwater adults and juveniles across their annual migratory cycle. Frontiers in Marine Science, 8, (2022): 719721, https://doi.org/10.3389/fmars.2021.719721.Limited work to date has examined plastic ingestion in highly migratory seabirds like Great Shearwaters (Ardenna gravis) across their entire migratory range. We examined 217 Great Shearwaters obtained from 2008–2019 at multiple locations spanning their yearly migration cycle across the Northwest and South Atlantic to assess accumulation of ingested plastic as well as trends over time and between locations. A total of 2328 plastic fragments were documented in the ventriculus portion of the gastrointestinal tract, with an average of 9 plastic fragments per bird. The mass, count, and frequency of plastic occurrence (FO) varied by location, with higher plastic burdens but lower FO in South Atlantic adults and chicks from the breeding colonies. No fragments of the same size or morphology were found in the primary forage fish prey, the Sand Lance (Ammodytes spp., n = 202) that supports Great Shearwaters in Massachusetts Bay, United States, suggesting the birds directly ingest the bulk of their plastic loads rather than accumulating via trophic transfer. Fourier-transform infrared spectroscopy indicated that low- and high-density polyethylene were the most common polymers ingested, within all years and locations. Individuals from the South Atlantic contained a higher proportion of larger plastic items and fragments compared to analogous life stages in the NW Atlantic, possibly due to increased use of remote, pelagic areas subject to reduced inputs of smaller, more diverse, and potentially less buoyant plastics found adjacent to coastal margins. Different signatures of polymer type, size, and category between similar life stages at different locations suggests rapid turnover of ingested plastics commensurate with migratory stage and location, though more empirical evidence is needed to ground-truth this hypothesis. This work is the first to comprehensively measure the accumulation of ingested plastics by Great Shearwaters over the last decade and across multiple locations spanning their yearly trans-equatorial migration cycle and underscores their utility as sentinels of plastic pollution in Atlantic ecosystems.This project was supported by the NOAA Fisheries National Seabird Program and the Volgenau Foundation. AR acknowledges support from the National Oceanic and Atmospheric Administration Dr. Nancy Foster Scholarship Program (NOAA Award Number NA17NOS4290028), the Robert and Patricia Switzer Foundation, the STEEP Superfund Research Program (NIEHS Award Number P42ES027706), and the Oak Ridge Institute for Science and Education (ORISE) program. LB was funded by INCT-Mar COI and PQ Grant No. 311409/2018-0, both by the Brazilian National Research Council (CNPq). JS was funded by the National Science Foundation Graduate Research Fellowship program