Cytoskeletal dynamics of Cytotoxic T cells during migration in the tumour microenvironment

Typically, migrating T cells display an elongated polarized shape with a very dynamic leading edge and a uropod in the rear. This ‘amoeboid’ movement guarantees a fast migration driven by the formation of polarized protrusions at the front. The actomyosin cytoskeleton is responsible for the generation of the forces that are involved in this process. This thesis aims to determine what is the effect of T cell migration when different components of the actomyosin cortex were inhibited using a pharmacological approach. We found that the inhibition of each component of the actomyosin cortex, T cells display different conformation of the actin filaments and produce different type of protrusion. Furthermore, T cell migration is an important feature for the killing and clearance of canner cells. It has been reported that T cells can migrate efficiently in any kind of tissue whilst scanning for cognate antigen. On the other hand, it is known that the tumor microenvironment secretes immunosuppressive cytokines such as TGF-β impairing the antitumor activity of T cells. Therefore, we aim to determine how TGF-β affects the migration behavior of T cells and its consequences in the scanning strategy to search their cognate antigen

Constraining the neutrino emission of gravitationally lensed Flat-Spectrum Radio Quasars with ANTARES data

This paper proposes to exploit gravitational lensing effects to improve the sensitivity of neutrino telescopes to the intrinsic neutrino emission of distant blazar populations. This strategy is illustrated with a search for cosmic neutrinos in the direction of four distant and gravitationally lensed Flat-Spectrum Radio Quasars. The magnification factor is estimated for each system assuming a singular isothermal profile for the lens. Based on data collected from 2007 to 2012 by the ANTARES neutrino telescope, the strongest constraint is obtained from the lensed quasar B0218+357, providing a limit on the total neutrino luminosity of this source of 1.08 x 10(46) erg s(-1) This limit is about one order of magnitude lower than those previously obtained in the ANTARES standard point source searches with non-lensed Flat-Spectrum Radio Quasars

Phosphatidic acid: an electrostatic/hydrogen-bond switch?

Phosphatidic acid (PA) has been shown to be an important bioactive lipid that is specifically recognized by various proteins. As such, it plays a crucial role in cellular signaling in all eukaryotes. An important determinant for PA's role in its diverse functions is its anionic headgroup that resides very close to the hydrophobic interior of the lipid bilayer. In this chapter, we describe a new model, the electrostatic/ hydrogen-bond switch that describes PA's ionization properties and its specific interaction with proteins. Furthermore, we will allude to the broader implications of the model for all phosphomonoester moieties found in biological compounds. Recent data in support of the model, as well as biological predictions arising from it, are also discussed

Phosphatidic acid: an electrostatic/hydrogen-bond switch?

Phosphatidic acid (PA) has been shown to be an important bioactive lipid that is specifically recognized by various proteins. As such, it plays a crucial role in cellular signaling in all eukaryotes. An important determinant for PA’s role in its diverse functions is its anionic headgroup that resides very close to the hydrophobic interior of the lipid bilayer. In this chapter, we describe a new model, the electrostatic/hydrogen-bond switch that describes PA’s ionization properties and its specific interaction with proteins. Furthermore, we will allude to the broader implications of the model for all phosphomonoester moieties found in biological compounds. Recent data in support of the model, as well as biological predictions arising from it, are also discussed

Provenance and exhumation of an exotic eclogite-bearing nappe in the Caledonides: a U–Pb and Rb–Sr study of the Jæren nappe, SW Norway

<p>The provenance and exhumation history of paragneisses that enclose the 471–458 Ma eclogites in the Caledonian Jæren nappe, SW Norway, were constrained by performing U–Pb analysis on detrital zircon and Rb–Sr dating of mica. Zircon grains from four samples were analysed by laser ablation inductively coupled plasma mass spectrometry, providing detrital U–Pb ages between 3130 and 620 Ma. These data suggest Laurentian provenance, implying the existence of an early Caledonian (Taconian) HP fragment of Laurentian crust in the southern Scandinavian Caledonides. Several rims and recrystallized zircon patches yielded U–Pb ages averaging at 469 ± 6 Ma (2σ). These are identical to the Lu–Hf ages of the eclogites and underscore the importance of Taconian metamorphism in this part of the Caledonides. The main phengite Rb–Sr age cluster at 424.4 ± 4.6 Ma provides time constraints on the amphibolite-facies recrystallization of former high-Si phengite. Five out of seven biotite Rb–Sr ages were identical, yielding a weighted mean age of 413.6 ± 2.6 Ma. Low-Si phengite and biotite in three samples gave <em>c</em>. 400 Ma ages. The Rb–Sr data record the mid-crustal emplacement of the exotic Jæren nappe and its subsequent unroofing along the western edge of Baltica during the backsliding and collapse of the Scandian orogenic front. </p

Spontaneous curvature of phosphatidic acid and lysophosphatidic acid.

The formation of phosphatidic acid (PA) from lysophosphatidic acid (LPA), diacylglycerol, or phosphatidylcholine plays a key role in the regulation of intracellular membrane fission events, but the underlying molecular mechanism has not been resolved. A likely possibility is that PA affects local membrane curvature facilitating membrane bending and fission. To examine this possibility, we determined the spontaneous radius of curvature (R0p) of PA and LPA, carrying oleoyl fatty acids, using well-established X-ray diffraction methods. We found that, under physiological conditions of pH and salt concentration (pH 7.0, 150 mM NaCl), the R0p values of PA and LPA were -46 Å and +20 Å, respectively. Thus PA has considerable negative spontaneous curvature while LPA has the most positive spontaneous curvature of any membrane lipid measured to date. The further addition of Ca2+ did not significantly affect lipid spontaneous curvature; however, omitting NaCl from the hydration buffer greatly reduced the spontaneous curvature of PA, turning it into a cylindrically shaped lipid molecule (R0p of -1.3 _ 102 Å). Our quantitative data on the spontaneous radius of curvature of PA and LPA at a physiological pH and salt concentration will be instrumental in developing future models of biomembrane fission

An electrostatic/hydrogen bond switch as the basis for the specific interaction of phosphatidic acid with proteins

Phosphatidic acid (PA) is a minor but important phospholipid that, through specific interactions with proteins, plays a central role in several key cellular processes. The simple yet unique structure of PA, carrying just a phosphomonoester head group, suggests an important role for interactions with the positively charged essential residues in these proteins. We analyzed by solid-state magic angle spinning 31P NMR and molecular dynamics simulations the interaction of low concentrations of PA in model membranes with positively charged side chains of membrane-interacting peptides. Surprisingly, lysine and arginine residues increase the charge of PA, predominantly by forming hydrogen bonds with the phosphate of PA, thereby stabilizing the protein-lipid interaction. Our results demonstrate that this electrostatic/hydrogen bond switch turns the phosphate of PA into an effective and preferred docking site for lysine and arginine residues. In combination with the special packing properties of PA, PA may well be nature’s preferred membrane lipid for interfacial insertion of positively charged membrane protein domains

Filtering fens: Mechanisms explaining phosphorus-limited hotspots of biodiversity in wetlands adjacent to heavily fertilized areas

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