Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway

<p>Abstract</p> <p>Background</p> <p>Regulatory T cells (Tregs) can employ a cell contact- and granzyme B-dependent mechanism to mediate suppression of bystander T and B cells. Murine studies indicate that granzyme B is involved in the Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment and in the Treg-mediated maintenance of allograft survival. In spite of its central importance, a detailed study of granzyme B expression patterns in human Tregs has not been performed.</p> <p>Results</p> <p>Our data demonstrated that natural Tregs freshly isolated from the peripheral blood of normal adults lacked granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, expressed high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone failed to induce granzyme B. Treatment of Tregs with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppressed granzyme B expression. However, neither rapamycin, as previously reported by others, nor LY294002 inhibited Treg proliferation or induced significant cell death in TCR/CD28/IL-2 stimulated cells. The proliferation rate of Tregs was markedly higher than that of CD4+ conventional T cells in the setting of rapamycin treatment. Tregs expanded by CD3/CD28/IL-2 stimulation without rapamycin demonstrated increased <it>in vitro </it>cytotoxic activity compared to Tregs expanded in the presence of rapamycin in both short term (6 hours) and long term (48 hours) cytotoxicity assays.</p> <p>Conclusion</p> <p>TCR/CD28 mediated activation of the PI3K-mTOR pathway is important for granyzme B expression but not proliferation in regulatory T cells. These findings may indicate that suppressive mechanisms other than granzyme B are utilized by rapamycin-expanded Tregs.</p

Differences between "geriatric" and "medical" patients aged 75 and over.

We analysed the characteristics of patients aged 75 and over admitted to the geriatric and general medical wards over a three month period in a teaching hospital. Patients admitted to the geriatric wards were slightly older, were more often female, more likely to be admitted during the day and during a week day, more likely to have been seen by their own general practitioner, had more chronic and multiple illness with non-specific presentations, and stayed longer in hospital. Referring doctors seem to discriminate between patients needing geriatric care and those more suitable for general medical care, but there is an overlap in the characteristics of the two groups

Statistical stability of equilibrium states for interval maps

We consider families of multimodal interval maps with polynomial growth of the derivative along the critical orbits. For these maps Bruin and Todd have shown the existence and uniqueness of equilibrium states for the potential $\phi_t:x\mapsto-t\log|Df(x)|$, for $t$ close to 1. We show that these equilibrium states vary continuously in the weak$^*$ topology within such families. Moreover, in the case $t=1$, when the equilibrium states are absolutely continuous with respect to Lebesgue, we show that the densities vary continuously within these families.Comment: More details given and the appendices now incorporated into the rest of the pape

Damped Lyman-alpha absorption from a nearby Low Surface Brightness galaxy

Ground-based & HST images of the nearby galaxy SBS 1543+593 (z=0.009) show it to be a Low Surface Brightness (LSB) galaxy with a central surface brightness of mu_B(0)=23.2 mag/arcsec-2 and scale length 0.9 h-1 kpc, values typical for the local LSB galaxy population. The galaxy lies directly in front of the QSO HS 1543+5921 (z=0.807); an HST STIS spectrum of the quasar reveals a damped Lyman-alpha (DLA) line at the redshift of the interloper with an HI column density of log N(HI) = 20.35, as well as several low-ionization metal lines with strengths similar to those found in the Milky Way interstellar medium. Our data show that LSB galaxies are certainly able to produce the DLA lines seen at higher redshift, and fuels the speculation that LSB galaxies are a major contributor to that population of absorbers.Comment: Submitted to A

Muon decay in a linearly polarized laser field

In a previous paper, we showed that the decay rate of a muon is only slightly affected by the presence of a circularly polarized laser and we gave an analytic expression for the correction. In this paper, we present the analytical result for the case of a linearly polarized laser. Again the effect of the laser is small.Comment: 6 pages, no figure

Random matrices, non-backtracking walks, and orthogonal polynomials

Several well-known results from the random matrix theory, such as Wigner's law and the Marchenko--Pastur law, can be interpreted (and proved) in terms of non-backtracking walks on a certain graph. Orthogonal polynomials with respect to the limiting spectral measure play a role in this approach.Comment: (more) minor change

Survival in pulmonary fibrosis combined with emphysema: likely defined by characteristics of specific patient subpopulations

Authors' Reply to letter from Cottin et al

The Discovery of XY Sex Chromosomes in a \u3cem\u3eBoa\u3c/em\u3e and \u3cem\u3ePython\u3c/em\u3e

For over 50 years, biologists have accepted that all extant snakes share the same ZW sex chromosomes derived from a common ancestor [1, 2, 3], with different species exhibiting sex chromosomes at varying stages of differentiation. Accordingly, snakes have been a well-studied model for sex chromosome evolution in animals [1, 4]. A review of the literature, however, reveals no compelling support that boas and pythons possess ZW sex chromosomes [2, 5]. Furthermore, phylogenetic patterns of facultative parthenogenesis in snakes and a sex-linked color mutation in the ball python (Python regius) are best explained by boas and pythons possessing an XY sex chromosome system [6, 7]. Here we demonstrate that a boa (Boa imperator) and python (Python bivittatus) indeed possess XY sex chromosomes, based on the discovery of male-specific genetic markers in both species. We use these markers, along with transcriptomic and genomic data, to identify distinct sex chromosomes in boas and pythons, demonstrating that XY systems evolved independently in each lineage. This discovery highlights the dynamic evolution of vertebrate sex chromosomes and further enhances the value of snakes as a model for studying sex chromosome evolution

Wave Optics Approach to Solar Cell BRDF Modeling with Experimental Results

Light curve analysis is often used to discern information about satellites in geosynchronous orbits. Solar panels, comprising a large part of the satellite’s body, contribute significantly to these light curves. Historically, theoretical bidirectional reflectance distribution functions (BRDFs) have failed to capture key features in the scattered light from solar panels. In recently published work, a new solar cell BRDF was developed by combining specular microfacet and “two-slit” diffraction terms to capture specular and periodic/array scattering, respectively. This BRDF was experimentally motivated and predicted many features of the solar cell scattered irradiance. However, the experiments that informed the BRDF were limited to a single laser wavelength, single beam size, and single solar cell sample. In addition, the BRDF was not physics based and therefore, physical insight into what causes certain features in the scattered irradiance was not evident. In this work, we examine solar cell scattering from first principles and derive a simple physics-based expression for the scattered irradiance. We analyze this expression and physically link terms to important scattering features, e.g., out-of-plane phenomena. In addition, we compare our model with experimental data and find good agreement in the locations and behaviors of these features. Our new model, being more predictive by nature, will allow for greater flexibility and accuracy when modeling reflection from solar cells in both real-world and experimental situations

A zeta function approach to the relation between the numbers of symmetry planes and axes of a polytope

A derivation of the Ces\`aro-Fedorov relation from the Selberg trace formula on an orbifolded 2-sphere is elaborated and extended to higher dimensions using the known heat-kernel coefficients for manifolds with piecewise-linear boundaries. Several results are obtained that relate the coefficients, $b_i$, in the Shephard-Todd polynomial to the geometry of the fundamental domain. For the 3-sphere we show that $b_4$ is given by the ratio of the volume of the fundamental tetrahedron to its Schl\"afli reciprocal.Comment: Plain TeX, 26 pages (eqn. (86) corrected