Mixing and matching mitochondrial aminoacyl synthetases and their tRNAs: a new way to treat respiratory chain disorders?

Peer reviewe

Large-N spacetime reduction and the sign and silver-blaze problems of dense QCD

We study the spacetime-reduced (Eguchi-Kawai) version of large-N QCD with nonzero chemical potential. We explore a method to suppress the sign fluctuations of the Dirac determinant in the hadronic phase; the method employs a re-summation of gauge configurations that are related to each other by center transformations. We numerically test this method in two dimensions, and find that it successfully solves the silver-blaze problem. We analyze the system further, and measure its free energy F, the average phase theta of its Dirac determinant, and its chiral condensate . We show that F and are independent of mu in the hadronic phase but that, as chiral perturbation theory predicts, the quenched chiral condensate drops from its mu=0 value when mu~(pion mass)/2. Finally, we find that the distribution of theta qualitatively agrees with further, more recent, predictions from chiral perturbation theory.Comment: 43 pages, 17 figure

Gut γδ T cells as guardians, disruptors and instigators of cancer

Colorectal cancer is the third most common cancer worldwide with nearly 2 million cases per year. Immune cells and inflammation are a critical component of colorectal cancer progression, and they are used as reliable prognostic indicators of patient outcome. With the growing appreciation for immunology in colorectal cancer, interest is growing on the role γδ T cells have to play, as they represent one of the most prominent immune cell populations in gut tissue. This group of cells consists of both resident populations—γδ intraepithelial lymphocytes (γδ IELs)—and transient populations that each has unique functions. The homeostatic role of these γδ T cell subsets is to maintain barrier integrity and prevent microorganisms from breaching the mucosal layer, which is accomplished through crosstalk with enterocytes and other immune cells. Recent years have seen a surge in discoveries regarding the regulation of γδ IELs in the intestine and the colon with particular new insights into the butyrophilin family. In this review, we discuss the development, specialities, and functions of γδ T cell subsets during cancer progression. We discuss how these cells may be used to predict patient outcome, as well as how to exploit their behavior for cancer immunotherapy

Assessing the Role of CD103 in Immunity to an Intestinal Helminth Parasite

In the intestine, the integrin CD103 is expressed on a subset of T regulatory (T(reg)) cells and a population of dendritic cells (DCs) that produce retinoic acid and promote immune homeostasis. However, the role of CD103 during intestinal helminth infection has not been tested.We demonstrate that CD103 is dispensable for the development of protective immunity to the helminth parasite Trichuris muris. While we observed an increase in the frequency of CD103(+) DCs in the lamina propria (LP) following acute high-dose infection with Trichuris, lack of CD103 had no effect on the frequency of CD11c(+) DCs in the LP or mesenteric lymph nodes (mLN). CD103-deficient (CD103(-/-)) mice develop a slightly increased and earlier T cell response but resolve infection with similar kinetics to control mice. Similarly, low-dose chronic infection of CD103(-/-) mice with Trichuris resulted in no significant difference in immunity or parasite burden. Absence of CD103 also had no effect on the frequency of CD4(+)CD25(+)Foxp3(+) T(reg) cells in the mLN or LP.These results suggest that CD103 is dispensable for intestinal immunity during helminth infection. Furthermore, lack of CD103 had no effect on DC or T(reg) recruitment or retention within the large intestine

Flux moduli stabilisation, Supergravity algebras and no-go theorems

We perform a complete classification of the flux-induced 12d algebras compatible with the set of N=1 type II orientifold models that are T-duality invariant, and allowed by the symmetries of the T^6/(Z_2 x Z_2) isotropic orbifold. The classification is performed in a type IIB frame, where only H_3 and Q fluxes are present. We then study no-go theorems, formulated in a type IIA frame, on the existence of Minkowski/de Sitter (Mkw/dS) vacua. By deriving a dictionary between the sources of potential energy for the three moduli (S, T and U) in types IIA and IIB, we are able to combine algebra results and no-go theorems. The outcome is a systematic procedure for identifying phenomenologically viable models where Mkw/dS vacua may exist. We present a complete table of the allowed algebras and the viability of their resulting scalar potential, and we point at the models which stand any chance of producing a fully stable vacuum.Comment: Version published in JHE

Charting the landscape of N=4 flux compactifications

We analyse the vacuum structure of isotropic Z_2 x Z_2 flux compactifications, allowing for a single set of sources. Combining algebraic geometry with supergravity techniques, we are able to classify all vacua for both type IIA and IIB backgrounds with arbitrary gauge and geometric fluxes. Surprisingly, geometric IIA compactifications lead to a unique theory with four different vacua. In this case we also perform the general analysis allowing for sources compatible with minimal supersymmetry. Moreover, some relevant examples of type IIB non-geometric compactifications are studied. The computation of the full N=4 mass spectrum reveals the presence of a number of non-supersymmetric and nevertheless stable AdS_4 vacua. In addition we find a novel dS_4 solution based on a non-semisimple gauging.Comment: Minor corrections and references added. Version published in JHE

Exceptional Flux Compactifications

We consider type II (non-)geometric flux backgrounds in the absence of brane sources, and construct their explicit embedding into maximal gauged D=4 supergravity. This enables one to investigate the critical points, mass spectra and gauge groups of such backgrounds. We focus on a class of type IIA geometric vacua and find a novel, non-supersymmetric and stable AdS vacuum in maximal supergravity with a non-semisimple gauge group. Our construction relies on a non-trivial mapping between SL(2) x SO(6,6) fluxes, SU(8) mass spectra and gaugings of E7(7) subgroups.Comment: 51 pages, 2 figures and 4 tables. v3: change of SO(6,6) spinorial conventions, published versio

Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis

NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells

Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis