Analysis of parasite-specific T cells and cellular interactions in the spleen during <em>Plasmodium berghei</em> induced experimental cerebral malaria

Vector-transmitted parasitic infections are a global health problem. Diseases such as malaria are a major health threat and economic burden for developing countries. In Sub-Saharan Africa malaria causing Plasmodium parasites may evoke life threatening complications, which mainly affect children under the age of five years. Pathogenesis of cerebral malaria is a multifactorial complex process that involves inflammatory mediators such as effector T cells and IFN-γ. Time, origin and cellular and molecular factors involved in early immune responses priming effector T cells responsible for the pathogenesis of cerebral malaria have been less investigated. In our study we were able to determine the presence of parasite specific cytotoxic T cells in spleen and brain during Plasmodium berghei infection. This enabled us to analyse cellular interactions involved in the priming of T cells directed against the parasite. The place of essential T cell priming during Plasmodium infections was determined in splenectomised mice, in which effector responses were reduced and experimental cerebral malaria (ECM) pathology was absent. Depletion of antigen- presenting cells, involved in maintaining the organized splenic structure, abrogated T cell priming and resulted in the loss of effector responses. Without either macrophages, DCs or B cells lytic activity and IFN-γ production by parasite-specific T cells was diminished and in the absence of effector responses ECM progression was suppressed. In detail, we provide evidence that macrophages, B cells and dendritic cells, as well as CD4+ T cells together with TLR-9 and IL-12 signalling comprise complex interactions affecting T cell generation during blood stage malaria leading to neuropathology. Taken together our study suggests, that early immune responses during P. berghei infection are generated in the spleen and that distinct cells and cytokines drive gen-eration of parasite-specific T cells leading to subsequent pathology.Durch Vektoren übertragene Parasiteninfektionen stellen weltweit eine große Herausforderung dar. Krankheiten, wie z.B. Malaria bergen große gesundheitliche, aber auch ökonomische Risiken. Malaria, ausgelöst durch eine Plasmodium- Infektion, ist eine schwerwiegende Krankheit mit zum Teil lebensgefährlichen Komplikationen, die insbesondere Kinder unter fünf Jahren betreffen. Die Pathogenese von zerebraler Malaria ist ein multifaktorieller und komplexer Entzündungsprozess, bei dem Effektor T-Zellen und IFN-γ eine wichtige Rolle spielen. Obwohl T-Zellen stark in die Entwicklung zerebraler Malaria involviert sind, ist über Ursprung, zeitliche Abfolge und zelluläre und molekulare Prozesse der frühen Immunantwort, die für die Aktivierung von Effektor T-Zellen verantwortlich sind, bisher wenig bekannt. Wir konnten die Existenz von Parasiten-spezifischen zytotoxischen T-zellen in der Milz und im Gehirn während einer Plasmodium berghei ANKA Infektion in einem Mausmodell nachweisen. Das Entfernen der Milz ging mit einem reduziertem Risiko der zerebrale Malaria und einer verminderten Entzündungsreaktion einher. Dies zeigte, dass Effektor T-Zellen in der Milz generiert werden. Durch die Depletion Antigen-präsentierender Zellen, welche strukturgebend für die Milzarchitektur sind, wurde die Generierung und Aktivierung von Effektor T- Zellen verhindert und inflammatorische Reaktionen unterbunden. In Abwesenheit von Makrophagen, dendritischen Zellen, oder B-Zellen war die zytotoxische Aktivität und die INF-γ Antwort reduziert und neuropathologische Symptome blieben aus. Dies deutet darauf hin, dass komplexe Interaktionen von Makrophagen, B- Zellen, und dendritische Zellen, sowie CD4+ T Helfer Zellen zusammen mit TLR-9 und IL-12 Signalwegen, die T-Zell-Generierung in einer Plasmodium-Infektion und somit die Pathogenese von zerebraler Malaria stark beeinflussen. Zusammengefasst liefert dieses Projekt Hinweise dafür, dass die frühe Immunantwort gegen den Parasiten in der Milz hervorgerufen wird, wobei spezifisch Immunzellen und Zytokine an der Bildung von Effektor T-Zellen beteiligt sind, welche wiederum zu der Entstehung von neurologischen Schäden führen

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Fluorofluorophores: Fluorescent Fluorous Chemical Tools Spanning the Visible Spectrum

“Fluoro” refers to both fluorescent and fluorinated compounds. Despite the shared prefix, there are very few fluorescent molecules that are soluble in perfluorinated solvents. This paucity is surprising, given that optical microscopy is a ubiquitous technique throughout the physical sciences and the orthogonality of fluorous materials is a commonly exploited strategy in synthetic chemistry, materials science, and chemical biology. We have addressed this shortage by synthesizing a panel of “fluorofluorophores,” fluorescent molecules containing high weight percent fluorine with optical properties spanning the visible spectrum. We demonstrate the utility of these fluorofluorophores by preparing fluorescent perfluorocarbon nanoemulsions.National Science Foundation (U.S.) (ECCS-0939514

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term ‘prebiotic’ by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia