Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity

Osteosarcoma and Ewing’s sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-β. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcγRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment.     

Managing Insect Resistance to Plants Producing Bacillus thuringiensis Toxins

ABSTRACT:?

Insect-resistant transgenic plants have become an important tool for the protection of crops against insect pests. The acreage of insecticidal transgenic plants is expected to increase significantly in the near future. The bacterium Bacillus thuringiensis is currently the source of insecticidal proteins in commercial insect-resistant transgenic plants and will remain the most important source during the next decade. Insect resistance to B. thuringiensis Cry toxins is the main problem. Only one species, the diamondback moth, has evolved a resistance to B. thuringiensis-based formulations under field conditions. However, many other insect species were selected for resistance under laboratory conditions, indicating that there is a potential for evolution of resistance in most major pests. Many studies were conducted to elucidate the mode of action of the Cry toxins, the mechanisms and genetics of resistance, and the various factors influencing its development. This article reviews insect resistance to B. thuringiensis insecticidal proteins and related aspects, including the development of insect-resistant transgenic plants, B. thuringiensis toxins, their mode of action, mechanisms, stability, and genetics of resistance and management strategies for delaying resistance.     

Transmembrane Helix Packing of ErbB/Neu Receptor in Membrane Environment: A Molecular Dynamics Study

Abstract

Dimerization or oligomerization of the ErbB/Neu receptors are necessary but not sufficient for initiation of receptor signaling. The two intracellular domains must be properly oriented for the juxtaposition of the kinase domains allowing trans-phosphorylation. This suggests that the transmembrane (TM) domain acts as a guide for defining the proper orientation of the intracellular domains.

Two structural models, with the two helices either in left-handed or in right-handed coiling have been proposed as the TM domain structure of the active receptor. Because experimental data do not distinguish clearly helix-helix packing, molecular dynamics (MD) simulations are used to investigate the energetic factors that drive Neu TM-TM interactions of the wild and the oncogenic receptor (Val664/Glu mutation) in DMPC or in POPC environments. MD results indicate that helix-lipid interactions in the bilayer core are extremely similar in the two environments and raise the role of the juxtamembrane residues in helix insertion and helix-helix packing. The TM domain shows a greater propensity to adopt a left-handed structure in DMPC, with helices in optimal position for strong inter-helical Hbonds induced by the Glu mutation. In POPC, the right-handed structure is preferentially formed with the participation of water in inter-helical Hbonds. The two structural arrangements of the NeuTM helices both with GG4 residue motif in close contact at the interface are permissible in the membrane environment. According to the hypothesis of a monomer-dimer equilibrium of the proteins it is likely that the bilayer imposes structural constraints that favor dimerization- competent structure responsible of the proper topology necessary for receptor activation.     

Short-term temperature impact on soil heterotrophic respiration in limed agricultural soil samples

This study sought to investigate the hourly and daily timescale responses of soil CO₂ fluxes to temperature in a limed agricultural soil. Observations from different incubation experiments were compared with the results of a model combining biotic (heterotrophic respiration) and abiotic (carbonate weathering) components. Several samples were pre-incubated for 8–9 days at three temperatures (5, 15 and 25 °C) and then submitted to short-term temperature (STT) cycles (where the temperature was increased from 5 to 35 °C in 10 °C stages, with each stage being 3 h long). During the temperature cycles (hourly timescale), the soil CO₂ fluxes increased significantly with temperature under all pre-incubation temperature (PIT) treatments. A hysteresis effect and negative fluxes during cooling phases were also systematically observed. At a given hourly timescale temperature, there was a negative relationship of the CO₂ fluxes with the PIT. Using the combined model allowed the experimental results to be clearly described, including the negative fluxes and the hysteresis effect, showing the potentially large contribution of abiotic fluxes to total fluxes in limed soils, after STT changes. The fairly good agreement between the measured and simulated flux results also suggested that the biotic flux temperature sensitivity was probably unaffected by timescale (hourly or daily) or PIT. The negative relationship of the CO₂ fluxes with the PIT probably derived from very labile soil carbon depletion, as shown in the simulations. This was not, however, confirmed by soil carbon measurements, which leaves open the possibility of adaptation within the microbial community.     

Dating the “red beds” of the Eastern Moroccan High Plateaus: Evidence from late Late Cretaceous charophytes and dinosaur eggshells

A new locality in the poorly known “red beds” of Tendrara (High Plateaus, Morocco) has yielded four charophytes species (Feistiella anluensis, Lamprothamnium stipitatum, Peckisphaera portezueloensis, Platychara caudata) and dinosaur eggshells (Pseudomegaloolithus atlasi). These red beds, which overly the Cenomanian-Turonian marine deposits, generally assigned to “Senonian” based on geometric position, are directly dated by these fossils: the charophytes species and dinosaur oospecies association indicates a Campano-Maastrichtian or Maastrichtian age for these calm floodplain deposits.     

Modulation of adipose tissue inflammation by bioactive food compounds

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating the 5′ adenosine monophosphate-activated protein kinase (AMPK) pathway in adipose tissue. Dietary polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA) and monounsaturated fatty acids (MUFA), such as oleic acid, also impart anti-inflammatory effects through several mechanisms. These include activation of AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as suppression of toll-like receptors (TLRs) and NF-κB pathway. This review discusses the major molecular mechanisms of dietary polyphenols and fatty acids, alone or in combination, which are responsible for adipose tissue-associated anti-inflammatory effects.