Cytokine and Protein Markers of Leprosy Reactions in Skin and Nerves: Baseline Results for the North Indian INFIR Cohort

Leprosy affects skin and peripheral nerves. Although we have effective antibiotics to treat the mycobacterial infection, a key part of the disease process is the accompanying inflammation. This can worsen after starting antibacterial treatment with episodes of immune mediated inflammation, so called ‘reactions’. These reactions are associated with worsening of the nerve damage. We recruited a cohort of 303 newly diagnosed leprosy patients in North India with the aim of understanding and defining the pathological processes better. We took skin and nerve biopsies from patients and examined them to define which molecules and mediators of inflammation were present. We found high levels of the cytokines Tumour Necrosis Factor alpha, Transforming Growth Factor beta and inducible Nitric Oxide Synthase in biopsies from patients with reactions. We also found high levels of bacteria and inflammation in the nerves. These experiments tell us that we need to determine which other molecules are present and to explore ways of switching off the production of these pro-inflammatory molecules

Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy

COMRADES determines in vivo RNA structures and interactions.

The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs.This work was supported by Cancer Research UK (C13474/A18583, C6946/A14492) and the Wellcome Trust (104640/Z/14/Z, 092096/Z/10/Z) to E.A.M. O.Z. was supported by the Human Frontier Science Program (HFSP, LT000558/2015), the European Molecular Biology Organization (EMBO, ALTF1622-2014), and the Blavatnik Family Foundation postdoctoral fellowship. G.K. and M.G. were supported by Wellcome Trust grant 207507 and UK Medical Research Council. A.T.L.L. and J.C.M. were supported by core funding from Cancer Research UK (award no. 17197 to JCM). J.C.M was also supported by core funding from EMBL. I.G. and L.W.M. were supported by the Wellcome Trust Senior Fellowship in Basic Biomedical Science to I.G. (207498/Z/17/Z). I.J.M., L.F.G. and J.S.-G. were supported by grants R01GM104475 and R01GM115649 from NIGMS. C.K.K was supported by City University of Hong Kong Projects 9610363 and 7200520, Croucher Foundation Project 9500030 and Hong Kong RGC Projects 9048103 and 9054020. C.-F.Q. was supported by the NSFC Excellent Young Scientist Fund 81522025 and the Newton Advanced Fellowship from the Academy of Medical Sciences, UK

Expression and Processing of a Small Nucleolar RNA from the Epstein-Barr Virus Genome

Small nucleolar RNAs (snoRNAs) are localized within the nucleolus, a sub-nuclear compartment, in which they guide ribosomal or spliceosomal RNA modifications, respectively. Up until now, snoRNAs have only been identified in eukaryal and archaeal genomes, but are notably absent in bacteria. By screening B lymphocytes for expression of non-coding RNAs (ncRNAs) induced by the Epstein-Barr virus (EBV), we here report, for the first time, the identification of a snoRNA gene within a viral genome, designated as v-snoRNA1. This genetic element displays all hallmark sequence motifs of a canonical C/D box snoRNA, namely C/C′- as well as D/D′-boxes. The nucleolar localization of v-snoRNA1 was verified by in situ hybridisation of EBV-infected cells. We also confirmed binding of the three canonical snoRNA proteins, fibrillarin, Nop56 and Nop58, to v-snoRNA1. The C-box motif of v-snoRNA1 was shown to be crucial for the stability of the viral snoRNA; its selective deletion in the viral genome led to a complete down-regulation of v-snoRNA1 expression levels within EBV-infected B cells. We further provide evidence that v-snoRNA1 might serve as a miRNA-like precursor, which is processed into 24 nt sized RNA species, designated as v-snoRNA124pp. A potential target site of v-snoRNA124pp was identified within the 3′-UTR of BALF5 mRNA which encodes the viral DNA polymerase. V-snoRNA1 was found to be expressed in all investigated EBV-positive cell lines, including lymphoblastoid cell lines (LCL). Interestingly, induction of the lytic cycle markedly up-regulated expression levels of v-snoRNA1 up to 30-fold. By a computational approach, we identified a v-snoRNA1 homolog in the rhesus lymphocryptovirus genome. This evolutionary conservation suggests an important role of v-snoRNA1 during γ-herpesvirus infection

Use of beneficial bacteria and their secondary metabolites to control grapevine pathogen diseases

Grapevine is one of the most important economic crops yielding berries, wine products as well as derivates. However, due to the large array of pathogens inducing diseases on this plant, considerable amounts of pesticides—with possible negative impact on the environment and health—have been used and are currently used in viticulture. To avoid negative impacts of such products and to ensure product quality, a substantial fraction of pesticides needs to be replaced in the near future. One solution can be related to the use of beneficial bacteria inhabiting the rhizo- and/or the endosphere of plants. These biocontrol bacteria and their secondary metabolites can reduce directly or indirectly pathogen diseases by affecting pathogen performance by antibiosis, competition for niches and nutrients, interference with pathogen signaling or by stimulation of host plant defenses. Due to the large demand for biocontrol of grapevine diseases, such biopesticides, their modes of actions and putative consequences of their uses need to be described. Moreover, the current knowledge on new strains from the rhizo- and endosphere and their metabolites that can be used on grapevine plants to counteract pathogen attack needs to be discussed. This is in particular with regard to the control of root rot, grey mould, trunk diseases, powdery and downy mildews, pierce’s disease, grapevine yellows as well as crown gall. Future prospects on specific beneficial microbes and their secondary metabolites that can be used as elicitors of plant defenses and/or as biocontrol agents with potential use in a more sustainable viticulture will be further discussed

The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways