Vaccine-induced skewing of T cell responses protects against Chikungunya virus disease

Chikungunya virus (CHIKV) infections can cause severe and debilitating joint and muscular pain that can be long lasting. Current CHIKV vaccines under development rely on the generation of neutralizing antibodies for protection; however, the role of T cells in controlling CHIKV infection and disease is still unclear. Using an overlapping peptide library, we identified the CHIKV-specific T cell receptor epitopes recognized in C57BL/6 infected mice at 7 and 14 days post-infection. A fusion protein containing peptides 451, 416, a small region of nsP4, peptide 47, and an HA tag (CHKVf5) was expressed using adenovirus and cytomegalovirus-vectored vaccines. Mice vaccinated with CHKVf5 elicited robust T cell responses to higher levels than normally observed following CHIKV infection, but the vaccine vectors did not elicit neutralizing antibodies. CHKVf5-vaccinated mice had significantly reduced infectious viral load when challenged by intramuscular CHIKV injection. Depletion of both CD

Geometrical Models for Substitutions

International audienceWe consider a substitution associated with the Arnoux-Yoccoz interval exchange transformation (IET) related to the tribonacci substitution. We construct the so-called stepped lines associated with the fixed points of the substitution in the abelianization (symbolic) space. We analyze various projections of the stepped line, recovering the Rauzy fractal, a Peano curve related to work in [Arnoux 88], another Peano curve related to the work of [McMullen 09] and [Lowenstein et al. 07], and also the interval exchange transformation itself

Structural Basis for the Restoration of TCR Recognition of an MHC Allelic Variant by Peptide Secondary Anchor Substitution

Major histocompatibility complex (MHC) class I variants H-2Kb and H-2Kbm8 differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against Kb–HSV8 cannot recognize H-2Kbm8–HSV8. However, substitution of SerP2 to GluP2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2Kbm8–H2E was recognized whereas H-2Kb–H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface

Formation of Pyrazol-1,3,4-Thiadiazoles through 1,3-Dipolar Cycloadditions of 3-Thioxo-[1,2,4]-Triazepin-5-one with Nitrilimines: An Experimental and Computational study

In this work the results of experimental and computational study of the title compounds and some ancillary compounds are reported. Two bicyclic pyrazol-1,3,4-thiadiazole derivatives were synthesized by reaction between 6-dimethylaminomethylene-3-thioxo-[1,2,4]- triazepin-5-one 1 and several nitrilimines 2a-f to give corresponding spirocycloadducts 3a-f, which undergo a rapid rearrangement leading to the new bicyclic compounds, 4a-f and 5a-f. These obtained bicyclic products were characterized by 1H and 13C NMR spectroscopy and finally by X-ray crystallography. Theoretical calculations have been carried out using DFT methods to rationalize the formation of the two new bicyclic compounds. Two reaction types are involved in the formation of the compounds 4a-f and 5a-f. The first one is a 1,3-dipolar cycloaddition reaction between 1 acting as dipolarophile and 2a-f as dipoles. The results indicate that the cycloaddition between 1 and 2g, as model of 2a-c, takes place via a high asynchronous bond-formation process. The regioselectivity obtained from the calculations is in complete agreement with the formation of the unique spirocycloadducts 3a-f. The second reaction leading to the formation of the final products is a domino process that is initiated by the quick and irreversible cleavage in a catalytic acid environment of triazepenic ring

Generalized quasiperiodic Rauzy tilings

We present a geometrical description of new canonical $d$-dimensional codimension one quasiperiodic tilings based on generalized Fibonacci sequences. These tilings are made up of rhombi in 2d and rhombohedra in 3d as the usual Penrose and icosahedral tilings. Thanks to a natural indexing of the sites according to their local environment, we easily write down, for any approximant, the sites coordinates, the connectivity matrix and we compute the structure factor.Comment: 11 pages, 3 EPS figures, final version with minor change

Inhibitors of the heat shock protein 90: from cancer clinical trials to neurodegenerative diseases

Deep insight on Inhibitors of the heat shock protein 90: from cancer clinical trials to neurodegenerative diseases