Application of satellite precipitation data to analyse and model arbovirus activity in the tropics

Background: Murray Valley encephalitis virus (MVEV) is a mosquito-borne Flavivirus (Flaviviridae: Flavivirus) which isclosely related to Japanese encephalitis virus, West Nile virus and St. Louis encephalitis virus. MVEV is enzootic innorthern Australia and Papua New Guinea and epizootic in other parts of Australia. Activity of MVEV in WesternAustralia (WA) is monitored by detection of seroconversions in flocks of sentinel chickens at selected sample sitesthroughout WA.Rainfall is a major environmental factor influencing MVEV activity. Utilising data on rainfall and seroconversions,statistical relationships between MVEV occurrence and rainfall can be determined. These relationships can be usedto predict MVEV activity which, in turn, provides the general public with important information about diseasetransmission risk. Since ground measurements of rainfall are sparse and irregularly distributed, especially in northWA where rainfall is spatially and temporally highly variable, alternative data sources such as remote sensing (RS)data represent an attractive alternative to ground measurements. However, a number of competing alternatives areavailable and careful evaluation is essential to determine the most appropriate product for a given problem.Results: The Tropical Rainfall Measurement Mission (TRMM) Multi-satellite Precipitation Analysis (TMPA) 3B42product was chosen from a range of RS rainfall products to develop rainfall-based predictor variables and buildlogistic regression models for the prediction of MVEV activity in the Kimberley and Pilbara regions of WA. Twomodels employing monthly time-lagged rainfall variables showed the strongest discriminatory ability of 0.74 and0.80 as measured by the Receiver Operating Characteristics area under the curve (ROC AUC).Conclusions: TMPA data provide a state-of-the-art data source for the development of rainfall-based predictivemodels for Flavivirus activity in tropical WA. Compared to ground measurements these data have the advantage ofbeing collected spatially regularly, irrespective of remoteness. We found that increases in monthly rainfall andmonthly number of days above average rainfall increased the risk of MVEV activity in the Pilbara at a time-lag oftwo months. Increases in monthly rainfall and monthly number of days above average rainfall increased the risk ofMVEV activity in the Kimberley at a lag of three months.I

a versatile tool for the analysis and integrative visualization of DNA copy number variants

Background The analysis of DNA copy number variants (CNV) has increasing impact in the field of genetic diagnostics and research. However, the interpretation of CNV data derived from high resolution array CGH or NGS platforms is complicated by the considerable variability of the human genome. Therefore, tools for multidimensional data analysis and comparison of patient cohorts are needed to assist in the discrimination of clinically relevant CNVs from others. Results We developed GenomeCAT, a standalone Java application for the analysis and integrative visualization of CNVs. GenomeCAT is composed of three modules dedicated to the inspection of single cases, comparative analysis of multidimensional data and group comparisons aiming at the identification of recurrent aberrations in patients sharing the same phenotype, respectively. Its flexible import options ease the comparative analysis of own results derived from microarray or NGS platforms with data from literature or public depositories. Multidimensional data obtained from different experiment types can be merged into a common data matrix to enable common visualization and analysis. All results are stored in the integrated MySQL database, but can also be exported as tab delimited files for further statistical calculations in external programs. Conclusions GenomeCAT offers a broad spectrum of visualization and analysis tools that assist in the evaluation of CNVs in the context of other experiment data and annotations. The use of GenomeCAT does not require any specialized computer skills. The various R packages implemented for data analysis are fully integrated into GenomeCATs graphical user interface and the installation process is supported by a wizard. The flexibility in terms of data import and export in combination with the ability to create a common data matrix makes the program also well suited as an interface between genomic data from heterogeneous sources and external software tools. Due to the modular architecture the functionality of GenomeCAT can be easily extended by further R packages or customized plug-ins to meet future requirements

Genome-Wide Analysis of Interchromosomal Interaction Probabilities Reveals Chained Translocations and Overrepresentation of Translocation Breakpoints in Genes in a Cutaneous T-Cell Lymphoma Cell Line

In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes. Simultaneously arising and misrepaired DNA double-strand breaks are also the cause of another phenomenon called chromoplexy, which is characterized by the presence of chained translocations and interlinking deletion bridges involving several chromosomes. In this study, we demonstrate the genome-wide identification of chromosomal translocations based on the analysis of translocation-associated changes in spatial proximities of chromosome territories on the example of the cutaneous T-cell lymphoma cell line Se-Ax. We have used alterations of intra- and interchromosomal interaction probabilities as detected by genome-wide chromosome conformation capture (Hi-C) to infer the presence of translocations and to fine-map their breakpoints. The outcome of this analysis was subsequently compared to datasets on DNA copy number alterations and gene expression. The presence of chained translocations within the Se-Ax genome, partly connected by intervening deletion bridges, indicates a role of chromoplexy in the etiology of this cutaneous T-cell lymphoma. Notably, translocation breakpoints were significantly overrepresented in genes, which highlight gene-associated biological processes like transcription or other gene characteristics as a possible cause of the observed complex rearrangements. Given the relevance of chromosomal aberrations for basic and translational research, genome-wide high-resolution analysis of structural chromosomal aberrations will gain increasing importance

Interstitial deletion 2p11.2-p12: Report of a patient with mental retardation and review of the literature

Deletions of chromosome bands 2p11.2 and 2p12 are rare, and only six patients have been reported to date. Here, we report on a 5-year-old girl with an 11.4 Mb interstitial deletion of chromosome bands 2p11.2-p12 and the characterization of this deletion by high-resolution array CGH. The patient presented with mental retardation, microcephaly and short stature. Facial features included broad nasal bridge, frontal bossing and mild dolichocephaly. Phenotypic comparison with previously published patients failed to reveal a consistent clinical pattern apart from developmental delay/mental retardation, which is probably due to different sizes and/or positions of the individual deletions. Among the 40 known genes deleted in our patient is REEP1, haploinsufficiency of which causes autosomal dominant spastic paraplegia type 31 (SPG31, OMIM 610250). Additional patients with well-characterized deletions within 2p11.2 and 2p12 will be needed to determine the role of individual genes for the clinical manifestations

PD-L1 is expressed on isolated LCs and in LCs <i>in situ</i> of ACD patients.

<p>A. Left side: Immunofluorescence microscopy analysis of the expression of langerin and PD-L1 on the surface of human MoLCs and LCs derived from blood monocytes and epidermal tissue of healthy donors, respectively. Right side: Expression of langerin and CD1a in MoLCs (upper chart) and LCs (lower chart) detected by flow cytometry. Bar = 10 µm. B. Expression of HLA-DR and PD-L1 in skin sections of ACD donors before and 72 hours after challenge with 5% NiSO₄, as detected by confocal laser scanning microscopy. Representative images of two stack series in the epidermal layer are shown. Bar = 10 µm.</p

Human Langerhans Cells Control Th Cells via Programmed Death-Ligand 1 in Response to Bacterial Stimuli and Nickel-Induced Contact Allergy

<div><p>Langerhans cells (LCs) are suspected to initiate inflammatory immune responses to contact allergens and pathogenic bacteria. In chronic infectious diseases, programmed death ligand (PD-L) 1 exhibits both inhibitory and costimulatory functions on T cell-mediated activation and tolerance. Here, we investigated the effects of contact allergens and bacterial stimuli on PD-L1 expression in LCs and the effects of altered PD-L1 expression on cytokine release of subsequently cocultured T cells. Monocyte-derived LCs (MoLCs), LCs, and skin sections of patients suffering from allergic contact dermatitis were challenged with nickel and then analyzed for PD-L1 expression by confocal laser scanning microscopy and flow cytometry. In blocking experiments, we found that the release of Th cell specific cytokines was dependent on both stimulation of LCs and inhibition of PD-L1-PD-1 interactions. Stimulation with peptidoglycan (PGN) or lipopolysaccharide (LPS) and blockage of PD-L1 with a specific antibody triggered the release of high levels of IL-17, IL-22, TNF-α, and IFN-γ in CD4⁺T cells. If nickel was used as a stimulus, blockage of PD-L1 led to high amounts of TNF-α and IL-22. A closer look revealed PD-L1-dependent upregulation of IL-17 secretion in FACS-sorted CCR6⁺/CCR4⁺ T memory cells. In the presence of anti-PD-L1, PGN induced secretion of IFN-γ and IL-17 in total CCR6⁺ cells, while nickel triggered secretion of IFN-γ and IL-17 exclusively in CCR6⁺/CCR4⁺ cells. Our findings suggest that PD-L1 on LCs plays a crucial role in type IV allergic reactions and in response to bacterial stimuli by controlling the nature of inflammatory Th cell responses.</p> </div

Blockage of PD-L1 enhances cytokine release from stimulated Th cells.

<p>A. FACS analyses of CD86 or PD-L1 on MoLCs, dark gray, or isotype-controls, light gray. Numbers depicted in the histograms show mean fluorescence intensities. MoLCs were stimulated by LPS or PGN for 24 hours. Histograms shown are from the same donor representative for results obtained with three different donors. B <b>–</b> E. Secretion of cytokines by CD4⁺T cells in coculture with MoLCs. MoLCs were stimulated by LPS or PGN (as in A.), and incubated with IgG1, anti-PD-L1, or anti-CD86. Secretion of IL-17, IL-22, TNF-α, and IFN-γ in pg/ml was detected via ELISA 7 days after starting the coculture. Data shown are from 4 different donors, indicated by the following symbols: ▴, ▪, •, ♦. Wo, without stimulus.</p