Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells

CARD 11 acts as a gatekeeper for adaptive immune responses after T cell or B cell antigen receptor (TCR/BCR) ligation on lymphocytes. PKC theta/beta-catalyzed phosphorylation of CARD11 promotes the assembly of the CARD11-BCL10-MALT1 (CBM) complex and lymphocyte activation. Here, we demonstrated that PKC theta/beta-dependent CARD11 phosphorylation also suppressed CARD11 functions in T or B cells. Through mass spectrometry-based proteomics analysis, we identified multiple constitutive and inducible CARD11 phosphorylation sites in T cells. We demonstrated that a single TCR- or BCR-inducible phosphorylation on Ser 893 in the carboxyl terminus of CARD1 1 prevented the activation of the transcription factor NF-kappa B, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser(893) phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton's tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser 893 in CARD11 by PKCO controlled the strength of CARD11 scaffolding by impairing the formation of the CBM complex. Thus, PKCO simultaneously catalyzes both stimulatory and inhibitory CARD11 phosphorylation events, which shape the strength of CARD11 signaling in lymphocytes

MALT1 Phosphorylation Controls Activation of T Lymphocytes and Survival of ABC-DLBCL Tumor Cells

The CARMA1/CARD11-BCL10-MALT1 (CBM) complex bridges T and B cell antigen receptor (TCR/BCR) ligation to MALT1 protease activation and canonical nuclear factor kappa B (NF-kappa B) signaling. Using unbiased mass spectrometry, we discover multiple serine phosphorylation sites in the MALT1 C terminus after T cell activation. Phospho-specific antibodies reveal that CBM-associated MALT1 is transiently hyper-phosphorylated upon TCR/CD28 co-stimulation. We identify a dual role for CK1 alpha as a kinase that is essential for CBM signalosome assembly as well as MALT1 phosphorylation. Although MALT1 phosphorylation is largely dispensable for protease activity, it fosters canonical NF-kappa B signaling in Jurkat and murine CD4 T cells. Moreover, constitutive MALT1 phosphorylation promotes survival of activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) cells addicted to chronic BCR signaling. Thus, MALT1 phosphorylation triggers optimal NF-kappa B activation in lymphocytes and survival of lymphoma cells

Dipolar versus multipolar dynamos: the influence of the background density stratification

Context: dynamo action in giant planets and rapidly rotating stars leads to a broad variety of magnetic field geometries including small scale multipolar and large scale dipole-dominated topologies. Previous dynamo models suggest that solutions become multipolar once inertia becomes influential. Being tailored for terrestrial planets, most of these models neglected the background density stratification. Aims: we investigate the influence of the density stratification on convection-driven dynamo models. Methods: three-dimensional nonlinear simulations of rapidly rotating spherical shells are employed using the anelastic approximation to incorporate density stratification. A systematic parametric study for various density stratifications and Rayleigh numbers allows to explore the dependence of the magnetic field topology on these parameters. Results: anelastic dynamo models tend to produce a broad range of magnetic field geometries that fall on two distinct branches with either strong dipole-dominated or weak multipolar fields. As long as inertia is weak, both branches can coexist but the dipolar branch vanishes once inertia becomes influential. The dipolar branch also vanishes for stronger density stratifications. The reason is the concentration of the convective columns in a narrow region close to the outer boundary equator, a configuration that favors non-axisymmetric solutions. In multipolar solutions, zonal flows can become significant and participate in the toroidal field generation. Parker dynamo waves may then play an important role close to onset of dynamo action leading to a cyclic magnetic field behavior. Conclusion: Our simulations also suggest that the fact that late M dwarfs have dipolar or multipolar magnetic fields can be explained in two ways. They may differ either by the relative influence of inertia or fall into the regime where both types of solutions coexist.Comment: 13 pages, 13 figures, 2 tables, accepted for publication in A&

Metabolic Responses of Subtropical Microplankton After a Simulated Deep-Water Upwelling Event Suggest a Possible Dominance of Mixotrophy Under Increasing CO2 Levels

In the autumn of 2014, nine large mesocosms were deployed in the oligotrophic subtropical North-Atlantic coastal waters off Gran Canaria (Spain). Their deployment was designed to address the acidification effects of CO2 levels from 400 to 1,400 mu atm, on a plankton community experiencing upwelling of nutrient-rich deep water. Among other parameters, chlorophyll a (chl-a), potential respiration (Phi), and biomass in terms of particulate protein (B) were measured in the microplankton community (0.7-50.0 mu m) during an oligotrophic phase (Phase I), a phytoplankton-bloom phase (Phase II), and a post-bloom phase (Phase III). Here, we explore the use of the Phi/chl-a ratio in monitoring shifts in the microplankton community composition and its metabolism. Phi/chl-a values below 2.5 mu L O-2 h(-1) (mu g chl-a)(-1) indicated a community dominated by photoautotrophs. When Phi/chl-a ranged higher, between 2.5 and 7.0 mu L O-2 h(-1) (pg chl-a)(-1) , it indicated a mixed community of phytoplankton, microzooplankton and heterotrophic prokaryotes. When Phi/chl-a rose above 7.0 mu L O-2 h(-1) (mu g chl-a)(-1), it indicated a community where microzooplankton proliferated (>10.0 mu L O-2 h(-1) (mu g chl-a)(-1)), because heterotrophic dinoflagellates bloomed. The first derivative of B, as a function of time (dB/dt), indicates the rate of protein build-up when positive and the rate of protein loss, when negative. It revealed that the maximum increase in particulate protein (biomass) occurred between 1 and 2 days before the chl-a peak. A day after this peak, the trough revealed the maximum net biomass loss. This analysis did not detect significant changes in particulate protein, neither in Phase I nor in Phase III. Integral analysis of Phi/chl-a and B, over the duration of each phase, for each mesocosm, reflected a positive relationship between 4) and pCO(2) during Phase II [alpha = 230.10-5 mu L O-2 h(-1) L-1 (patm CO2)(-1) (phase-day)(-1), R-2 = 0.30] and between chl-a and pCO(2) during Phase III [alpha = 100.10(-5) Ag chl-a L-1 (mu atmCO(2))(-1) (phase-day)(-1), R-2 = 0.84]. At the end of Phase II, a harmful algal species (HAS), Vicicitus globosus, bloomed in the high pCO(2) mesocosms. In these mesocosms, microzooplankton did not proliferate, and chl-a retention time in the water column increased. In these V globosus-disrupted communities, the (Phi/chl-a ratio [4.1 +/- 1.5 /mu L O-2 h(-1) (mu g chl-a)(-1)] was more similar to the Phi/chl-a ratio in a mixed plankton community than to a photoautotroph-dominated one

Turbulent magnetic Prandtl number and magnetic diffusivity quenching from simulations

Forced turbulence simulations are used to determine the turbulent kinematic viscosity, nu_t, from the decay rate of a large scale velocity field. Likewise, the turbulent magnetic diffusivity, eta_t, is determined from the decay of a large scale magnetic field. In the kinematic regime, when the field is weak, the turbulent magnetic Prandtl number, nu_t/eta_t, is about unity. When the field is nonhelical, eta_t is quenched when magnetic and kinetic energies become comparable. For helical fields the quenching is stronger and can be described by a dynamical quenching formula.Comment: 7 pages, 6 figure

Constructing TI-Friendly Substitution Boxes Using Shift-Invariant Permutations

The threat posed by side channels requires ciphers that can be efficiently protected in both software and hardware against such attacks. In this paper, we proposed a novel Sbox construction based on iterations of shift-invariant quadratic permutations and linear diffusions. Owing to the selected quadratic permutations, all of our Sboxes enable uniform 3-share threshold implementations, which provide first order SCA protections without any fresh randomness. More importantly, because of the shift-invariant property, there are ample implementation trade-offs available, in software as well as hardware. We provide implementation results (software and hardware) for a four-bit and an eight-bit Sbox, which confirm that our constructions are competitive and can be easily adapted to various platforms as claimed. We have successfully verified their resistance to first order attacks based on real acquisitions. Because there are very few studies focusing on software-based threshold implementations, our software implementations might be of independent interest in this regard

Evaluation and reduction of magnetic resonance imaging artefacts induced by distinct plates for osseous fixation: an in vitro study @ 3 T

Objectives: To analyze MRI artefacts induced at 3 T by bioresorbable, titanium (TI) and glass fibre reinforced composite (GFRC) plates for osseous reconstruction.Methods: Fixation plates including bioresorbable polymers (Inion CPS, Inion Oy, Tampere, Finland; Rapidsorb, DePuy Synthes, Umkirch, Germany; Resorb X, Gebrueder KLS Martin GmbH, Tuttlingen, Germany), GFRC (Skulle Implants Oy, Turku, Finland) and TI plates of varying thickness and design (DePuy Synthes, Umkirch, Germany) were embedded in agarose gel and a 3 T MRI was performed using a standard protocol for head and neck imaging including T1W and T2W sequences. Additionally, different artefact reduction techniques (slice encoding for metal artefact reduction & ultrashort echo time) were used and their impact on the extent of artefacts evaluated for each material.Results: All TI plates induced significantly more artefacts than resorbable plates in T1W and T2W sequences. GFRCs induced the least artefacts in both sequences. The total extent of artefacts increased with plate thickness and height. Plate thickness had no influence on the percentage of overestimation in all three dimensions. TI-induced artefacts were significantly reduced by both artefact reduction techniques.Conclusions: Polylactide, GFRC and magnesium plates produce less susceptibility artefacts in MRI compared to TI, while the dimensions of TI plates directly influence artefact extension. Slice encoding for metal artefact reduction and ultrashort echo time significantly reduce metal artefacts at the expense of scan time or image resolution

Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML