Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response

The balance between protective immunity and immunopathology often determines the fate of the virus-infected host. How rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. Here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (LCMV), how the race between virus replication and T cell responses can result in different disease outcomes. A low dose of LCMV generated efficient CD8 T effector cells, which cleared the virus with minimal lung and liver pathology. A high dose of LCMV resulted in clonal exhaustion of T cell responses, viral persistence, and little immunopathology. An intermediate dose only partially exhausted the T cell responses and resulted in significant mortality, and the surviving mice developed viral persistence and massive immunopathology, including necrosis of the lungs and liver. This suggests that for non-cytopathic viruses like LCMV, hepatitis C virus, and hepatitis B virus, clonal exhaustion may be a protective mechanism preventing severe immunopathology and death

Starbursting Nuclear CO Disks of Early-type Spiral Galaxies

We have initiated the first CO interferometer survey of early-type spiral galaxies (S0-Sab). We observed five early-type spiral galaxies with HII nuclei (indicating circumnuclear starburst activities). These observations indicate gas masses for the central kiloparsec of \sim 1-5% of the dynamical masses. Such low gas mass fractions suggest that large-scale gravitational instability in the gas is unlikely to be the driving cause for the starburst activities. The Toomre Q values were >1 (mostly >3) within the central kiloparsec, indicating that the gas disks are globally gravitationally stable. The area filling factor of the gas disks is estimated to be about 0.05. This small value indicates the existence of lumpy structure, i.e. molecular clouds, in the globally-gravitationally stable disks. The typical surface density of the molecular clouds is as high as \sim 3000 Msun pc^{-2}. We reconsider the nature of the Toomre Q criterion, and conclude that the Q derived from CO observations indicates neither star formation nor molecular cloud formation. This argument should be valid not only for the circumnuclear disks but also for any region in galactic disks. We tentatively explore an alternative model, i.e. cloud-cloud collisions, as an initiating mechanism of star formation.Comment: 7pages, including 2 figures ; A&A accepted (19 Oct. 2004

Members of the fatty acid binding protein family are differentiation factors for the mammary gland

Mammary gland development is controlled by systemic hormones and by growth factors that might complement or mediate hormonal action. Peptides that locally signal growth cessation and stimulate differentiation of the developing epithelium have not been described. Here, we report that recombinant and wild-type forms of mammary-derived growth inhibitor (MDGI) and heart-fatty acid binding protein (FABP), which belong to the FABP family, specifically inhibit growth of normal mouse mammary epithelial cells (MEC), while growth of stromal cells is not suppressed. In mammary gland organ culture, inhibition of ductal growth is associated with the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures. In parallel, MDGI stimulates its own expression and promotes milk protein synthesis. Selective inhibition of endogenous MDGI expression in MEC by antisense phosphorothioate oligonucleotides suppresses appearance of alveolar end buds and lowers the beta-casein level in organ cultures. Furthermore, MDGI suppresses the mitogenic effects of epidermal growth factor, and epidermal growth factor antagonizes the activities of MDGI. Finally, the regulatory properties of MDGI can be fully mimicked by an 11-amino acid sequence, represented in the COOH terminus of MDGI and a subfamily of structurally related FABPs. This peptide does not bind fatty acids. To our knowledge, this is the first report about a growth inhibitor promoting mammary gland differentiation

Ready ... Go: Amplitude of the fMRI Signal Encodes Expectation of Cue Arrival Time

What happens when the brain awaits a signal of uncertain arrival time, as when a sprinter waits for the starting pistol? And what happens just after the starting pistol fires? Using functional magnetic resonance imaging (fMRI), we have discovered a novel correlate of temporal expectations in several brain regions, most prominently in the supplementary motor area (SMA). Contrary to expectations, we found little fMRI activity during the waiting period; however, a large signal appears after the “go” signal, the amplitude of which reflects learned expectations about the distribution of possible waiting times. Specifically, the amplitude of the fMRI signal appears to encode a cumulative conditional probability, also known as the cumulative hazard function. The fMRI signal loses its dependence on waiting time in a “countdown” condition in which the arrival time of the go cue is known in advance, suggesting that the signal encodes temporal probabilities rather than simply elapsed time. The dependence of the signal on temporal expectation is present in “no-go” conditions, demonstrating that the effect is not a consequence of motor output. Finally, the encoding is not dependent on modality, operating in the same manner with auditory or visual signals. This finding extends our understanding of the relationship between temporal expectancy and measurable neural signals

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

First fabrication of full 3D-detectors at SINTEF

International audienceA knowledge of the mechanical properties of bacterial biofilms is required to more fully understand the processes of biofilm formation such as initial adhesion or detachment. The main contribution of this article is to demonstrate the use of homogenization techniques to compute mechanical parameters of Pseudomonas aeruginosa PAO1 biofilms. For this purpose, homogenization techniques are used to analyze freeze substitution electron micrographs of the biofilm cross-sections. The concept of a representative volume element and the study about his representativeness allows us to determine the optimal size in order to analyze these biofilm images. Results demonstrate significant heterogeneities with respect to stiffness and these can be explained by varying cell density distribution throughout the bacterial biofilms. These stiffness variations lead to different mechanical properties along the height of the biofilm. Moreover, a numerical shear stress test shows the impact of these heterogeneities on the detachment process. Several modes of detachment are highlighted according to the local strain energy in the different parts of the biofilm. Knowing where, and how, a biofilm may detach will allow better prediction of accumulation and biomass detachment

Angular Momentum and the Formation of Stars and Black Holes

The formation of compact objects like stars and black holes is strongly constrained by the requirement that nearly all of the initial angular momentum of the diffuse material from which they form must be removed or redistributed during the formation process. The mechanisms that may be involved and their implications are discussed for (1) low-mass stars, most of which probably form in binary or multiple systems; (2) massive stars, which typically form in clusters; and (3) supermassive black holes that form in galactic nuclei. It is suggested that in all cases, gravitational interactions with other stars or mass concentrations in a forming system play an important role in redistributing angular momentum and thereby enabling the formation of a compact object. If this is true, the formation of stars and black holes must be a more complex, dynamic, and chaotic process than in standard models. The gravitational interactions that redistribute angular momentum tend to couple the mass of a forming object to the mass of the system, and this may have important implications for mass ratios in binaries, the upper stellar IMF in clusters, and the masses of supermassive black holes in galaxies.Comment: Accepted by Reports on Progress in Physic

Hemispherical power asymmetry: parameter estimation from CMB WMAP5 data

We reexamine the evidence of the hemispherical power asymmetry, detected in the CMB WMAP data using a new method. At first, we analyze the hemispherical variance ratios and compare these with simulated distributions. Secondly, working within a previously-proposed CMB bipolar modulation model, we constrain model parameters: the amplitude and the orientation of the modulation field as a function of various multipole bins. Finally, we select three ranges of multipoles leading to the most anomalous signals, and we process corresponding 100 Gaussian, random field (GRF) simulations, treated as observational data, to further test the statistical significance and robustness of the hemispherical power asymmetry. For our analysis we use the Internally-Linearly-Coadded (ILC) full sky map, and KQ75 cut-sky V channel, foregrounds reduced map of the WMAP five year data (V5). We constrain the modulation parameters using a generic maximum a posteriori method. In particular, we find differences in hemispherical power distribution, which when described in terms of a model with bipolar modulation field, exclude the field amplitude value of the isotropic model A=0 at confidence level of ~99.5% (~99.4%) in the multipole range l=[7,19] (l=[7,79]) in the V5 data, and at the confidence level ~99.9% in the multipole range l=[7,39] in the ILC5 data, with the best fit (modal PDF) values in these particular multipole ranges of A=0.21 (A=0.21) and A=0.15 respectively. However, we also point out that similar or larger significances (in terms of rejecting the isotropic model), and large best-fit modulation amplitudes are obtained in GRF simulations as well, which reduces the overall significance of the CMB power asymmetry down to only about 94% (95%) in the V5 data, in the range l=[7,19] (l=[7,79]).Comment: 24 pages, 10 figures; few typos corrected; published in JCA

The Effect of Epstein-Barr Virus Latent Membrane Protein 2 Expression on the Kinetics of Early B Cell Infection

Infection of human B cells with wild-type Epstein-Barr virus (EBV) in vitro leads to activation and proliferation that result in efficient production of lymphoblastoid cell lines (LCLs). Latent Membrane Protein 2 (LMP2) is expressed early after infection and previous research has suggested a possible role in this process. Therefore, we generated recombinant EBV with knockouts of either or both protein isoforms, LMP2A and LMP2B (Δ2A, Δ2B, Δ2A/Δ2B) to study the effect of LMP2 in early B cell infection. Infection of B cells with Δ2A and Δ2A/Δ2B viruses led to a marked decrease in activation and proliferation relative to wild-type (wt) viruses, and resulted in higher percentages of apoptotic B cells. Δ2B virus infection showed activation levels comparable to wt, but fewer numbers of proliferating B cells. Early B cell infection with wt, Δ2A and Δ2B viruses did not result in changes in latent gene expression, with the exception of elevated LMP2B transcript in Δ2A virus infection. Infection with Δ2A and Δ2B viruses did not affect viral latency, determined by changes in LMP1/Zebra expression following BCR stimulation. However, BCR stimulation of Δ2A/Δ2B cells resulted in decreased LMP1 expression, which suggests loss of stability in viral latency. Long-term outgrowth assays revealed that LMP2A, but not LMP2B, is critical for efficient long-term growth of B cells in vitro. The lowest levels of activation, proliferation, and LCL formation were observed when both isoforms were deleted. These results suggest that LMP2A appears to be critical for efficient activation, proliferation and survival of EBV-infected B cells at early times after infection, which impacts the efficient long-term growth of B cells in culture. In contrast, LMP2B did not appear to play a significant role in these processes, and long-term growth of infected B cells was not affected by the absence of this protein. © 2013 Wasil et al