Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4 + cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4 + T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4 + T cells and inhibit the migration of CD4 + CD25 + T cells in vitro. Recognition of the importance of CCR4 + Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4 + Treg cells on the host immune response to tumor cells. (Cancer Res 2006; 66(11): 5716-22)
Abstract. In this paper, we describe the PALM model system 6.0. PALM (formerly an abbreviation for Parallelized Large-eddy Simulation Model and now an independent name) is a Fortran-based code and has been applied for studying a variety of atmospheric and oceanic boundary layers for about 20 years. The model is optimized for use on massively parallel computer architectures. This is a follow-up paper to the PALM 4.0 model description in Maronga et al. (2015). During the last years, PALM has been significantly improved and now offers a variety of new components. In particular, much effort was made to enhance the model with components needed for applications in urban environments, like fully interactive land surface and radiation schemes, chemistry, and an indoor model. This paper serves as an overview paper of the PALM 6.0 model system and we describe its current model core. The individual components for urban applications, case studies, validation runs, and issues with suitable input data are presented and discussed in a series of companion papers in this special issue.
A large-eddy simulation (LES) study is presented that investigates the spatial variability of temporal eddy covariance fluxes and the systematic underestimation of representative fluxes linked to them. It extends a prior numerical study by performing high resolution simulations that allow for virtual measurements down to 20 m in a convective boundary layer, so that conditions for small tower measurement sites can be analysed. It accounts for different convective regimes as the wind speed and the near-surface heat flux are varied. Moreover, it is the first LES imbalance study that extends to the stable boundary layer. It reveals shortcomings of single site measurements and the necessity of using horizontally-distributed observation networks. The imbalances in the convective case are attributed to a locally non-vanishing mean vertical advection due to turbulent organised structures (TOS). The strength of the TOS and thus the imbalance magnitude depends on height, the horizontal mean wind and the convection type. Contrary to the results of a prior study, TOS cannot generally be responsible for large energy imbalances: at low observation heights (corresponding to small towers and near-surface energy balance stations) the TOS related imbalances are generally about one order of magnitude smaller than those in field experiments. However, TOS may cause large imbalances at large towers not only in the case of cellular convection and low wind speeds, as found in the previous study, but also in the case of roll convection at large wind speeds.In the stably stratified boundary layer for all observation heights neither TOS nor significant imbalances are observed. Boundary-Layer Meteorol (2007) 123:77-98 Attempting to reduce imbalances in convective situations by applying the conventional linear detrending method increases the systematic flux underestimation. Thus, a new filter method is proposed.
CaBPs are a family of Ca(2+)-binding proteins related to calmodulin and are localized in the brain and sensory organs, including the retina and cochlea. Although their physiological roles are not yet fully elucidated, CaBPs modulate Ca(2+) signaling through effectors such as voltage-gated Ca(v) Ca(2+) channels. In this study, we identified a splice-site mutation (c.637+1G>T) in Ca(2+)-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss. This mutation, most likely a founder mutation, probably leads to skipping of exon 6 and premature truncation of the protein (p.Phe164Serfs(∗)4). Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca(2+) binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca(2+) channels. We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment. The mutation might cause a hypofunctional CaBP2 defective in Ca(2+) sensing and effector regulation in the inner ear.
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