Cystatin cures visceral leishmaniasis by NF-κB mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-Tpl2-ERK pathway

Cystatin could completely cure experimental visceral leishmaniasis by switching the differentiation of Th2 cells to Th1 type, as well as upregulating NO, and activation of NF-κB played a major role in these processes. Analysis of upstream signaling events revealed that TLR 2/4-mediated MyD88-dependent participation of IL-1R-activated kinase (IRAK)1, TNF receptor-associated factor (TRAF)6 and TGFβ-activated kinase (TAK)1 is essential to induce cystatin-mediated IκB kinase (IKK)/NF-κB activation in macrophages. Cystatin plus IFN-γ activated the IKK complex to induce phosphorylation-mediated degradation of p105, the physiological partner and inhibitor of the MEK kinase, tumor progression locus 2 (Tpl-2). Consequently, Tpl-2 was liberated from p105, thereby stimulating activation of the MEK/ERK MAPK cascade. Cystatin plus IFN-γ-induced IKK-β post-transcriptionally modified p65/RelA subunit of NF-κB by dual phosphorylation in infected phagocytic cells. IKK induced the phosphorylation of p65 directly on Ser-536 residue whereas phosphorylation on Ser 276 residue was by sequential activation of Tpl-2/MEK/ERK/MSK1. Collectively, the present study indicates that cystatin plus IFN-γ-induced MyD88 signaling may bifurcate at the level of IKK, leading to a divergent pathway regulating NF-κB activation by IκBα phosphorylation and by p65 transactivation through Tpl-2/MEK/ERK/MSK1

Comparative study of Kondo effect in Vanadium dichalcogenides VX2_2 (X=Se & Te)

We report on the electrical transport, magnetotransport, and magnetic properties studies on the transition metal dichalcogenides VSe$_2$ and VTe$_2$ and draw a comprehensive comparison between them. We observe Kondo effect in both systems induced by the exchange interaction between localized moments and conduction electrons at low temperature, resulting into resistance upturn at 6 K for VSe$_2$ and 17 K for VTe$_2$. From the field dependent resistance measurements we find that the data is fitted best with modified Hamann equation corrected by the quantum Brillouin function for VSe$_2$, while the data is fitted best with modified Hamann equation corrected by the classical Langevin function for VTe$_2$. Interestingly, we observe a contrasting magnetoresistance (MR) property between these systems across the Kondo temperature. That means, negative MR is found in both systems in the Kondo state. In the normal state MR is positive for VSe$_2$, while it is negligible for VTe$_2$. In addition, both systems show weak ferromagnetism at low temperature due to intercalated V atoms

Effect on the Electronic and Magnetic Properties of Antiferromagnetic Topological Insulator MnBi2_2Te4_4 with Sn Doping

We thoroughly investigate the effect of nonmagnetic Sn doping on the electronic and magnetic properties of antiferromagnetic topological insulator MnBi$_2$Te$_4$. We observe that Sn doping reduces the out-of-plane antiferromagnetic (AFM) interactions in MnBi$_2$Te$_4$ up to 68\% of Sn concentration and above the system is found to be paramagnetic. In this way, the anomalous Hall effect observed at a very high field of 7.8 T in MnBi$_2$Te$_4$ is reduced to 2 T with 68\% of Sn doping. Electrical transport measurements suggest that all compositions are metallic in nature, while the low-temperature resistivity is sensitive to the AFM ordering and to the doping-induced disorder. Hall effect study demonstrates that Sn actually dopes electrons into the system, thus, enhancing the electron carrier density almost by two orders at 68\% of Sn. In contrast, SnBi$_2$Te$_4$ is found to be a p-type system. Angle-resolved photoemission spectroscopy (ARPES) studies show that the topological properties are intact at least up to 55\% of Sn as the Dirac surface states are present in the valance band, but in SnBi$_2$Te$_4$ we are unable to detect the topological states due to heavy hole doping. Overall, Sn doping significantly affects the electronic and magnetic properties of MnBi$_2$Te$_4$.Comment: 8 pages and 6 figure

Weak Electronic Correlations Observed in Magnetic Weyl Semimetal Mn3_3Ge

Using angle-resolved photoemission spectroscopy (ARPES) and density functional theory (DFT) calculations, we systematically studied the electronic band structure of Mn$_3$Ge in the vicinity of the Fermi level. We observe several bands crossing the Fermi level, confirming the metallic nature of the studied system. We further observe several flat bands along various high symmetry directions, consistent with the DFT calculations. The calculated partial density of states (PDOS) suggests a dominant Mn $3d$ orbital contribution to the total valence band DOS. With the help of orbital-resolved band structure calculations, we qualitatively identify the orbital information of the experimentally obtained band dispersions. Out-of-plane electronic band dispersions are explored by measuring the ARPES data at various photon energies. Importantly, our study suggests relatively weaker electronic correlations in Mn$_3$Ge compared to Mn$_3$Sn.Comment: 11 pages, 3 figures. To appear in the Journal of Physics: Condensed Matte

Jagged/Notch-mediated divergence of immune cell crosstalk maintains anti-inflammatory response in visceral leishmaniasis

Notch signaling governs crucial aspects of intercellular communication spanning antigen-presenting cells and T-cells. In this study, we investigate how L. donovani takes advantage of this pathway to quell host immune responses. We report induction of Notch ligand, Jagged1 in L. donovani-infected bone marrow macrophages (BMMфs) and subsequent activation of RBPJκ in T cells, which in turn, upregulates transcription factor GATA3. Activated RBPJκ also associates with histone acetyltransferase, p300, which binds with Bcl2L12 promoter and enhances its expression. Interaction of Bcl2L12 with GATA3 in CD4(+) T cells facilitates its binding to IL-10 and IL-4 promoters, thereby increasing the secretion of these cytokines. Silencing Jagged1 hindered these events in a BMMф-T cell co-culture system. Upon further scrutiny, we found that parasite LPG induces the host PI3K/Akt pathway, which activates β-catenin and Egr1, the two transcription factors responsible for driving Jagged1 expression. Vivo morpholino-silencing of Jagged1 suppresses anti-inflammatory cytokine responses and reduces organ parasite burden in L. donovani-infected Balb/c mice, suggesting that L. donovani induced host Jagged1/Notch signaling skews macrophage-T cell crosstalk into disease-promoting Th2 mode in experimental VL

Curative Effect of 18β-Glycyrrhetinic Acid in Experimental Visceral Leishmaniasis Depends on Phosphatase-Dependent Modulation of Cellular MAP Kinases

We earlier showed that 18β-glycyrrhetinic acid (GRA), a pentacyclic triterpenoid from licorice root, could completely cure visceral leishmaniasis in BALB/c mouse model. This was associated with induction of nitric oxide and proinflammatory cytokine production through the up regulation of NF-κB. In the present study we tried to decipher the underlying cellular mechanisms of the curative effect of GRA. Analysis of MAP kinase pathways revealed that GRA caused strong activation of p38 and to a lesser extent, ERK in bone marrow-derived macrophages (BMDM). Almost complete abrogation of GRA-induced cytokine production in presence of specific inhibitors of p38 and ERK1/2 confirmed the involvement of these MAP kinases in GRA-mediated responses. GRA induced mitogen- and stress-activated protein kinase (MSK1) activity in a time-dependent manner suggested that GRA-mediated NF-κB transactivation is mediated by p38, ERK and MSK1 pathway. As kinase/phosphatase balance plays an important role in modulating infection, the effect of GRA on MAPK directed phosphatases (MKP) was studied. GRA markedly reduced the expression and activities of three phosphatases, MKP1, MKP3 and protein phosphatase 2A (PP2A) along with a substantial reduction of p38 and ERK dephosphorylation in infected BMDM. Similarly in the in vivo situation, GRA treatment of L. donovani-infected BALB/c mice caused marked reduction of spleen parasite burden associated with concomitant decrease of individual phosphatase levels. However, activation of kinases also played an important role as the protective effect of GRA was significantly abrogated by pharmacological inhibition of p38 and ERK pathway. Curative effect of GRA may, therefore, be associated with restoration of proper cellular kinase/phosphatase balance, rather than modulation of either kinases or phosphatases

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe