Protocol for a Multicenter Study

Background: In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design: A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion: We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha- synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD. Clinical trail registration: TRN NCT03043768

An integrated digital research environment: DFG perspectives

Purpose: The article focuses on the vision that the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) pursues with its funding programmes in the field of digital information provision. Design/methodology/approach: The first section of the article sketches out the strategic decisions which determine the funding policy of the DFG in the field of digital information, while the second section describes in more detail the central funding schemes of the DFG in the field of digital information. Findings: The funding policy of the DFG seeks to build an integrated digital research environment that includes scholarly publications and primary research data as well as new forms of communication in virtual research and work environments. But it will be only by the common effort of scholars, libraries and providers of scholarly information, funders, publishers and fee collecting agencies that the vision of an integrated digital research environment will come true. Originality / value: The outline of the funding programmes of the DFG in the area of digital information provision will be of interest to librarians and information professionals seeking information about library funding policies and strategies in Germany

An integrated digital research environment: DFG perspectives

Purpose: The article focuses on the vision that the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) pursues with its funding programmes in the field of digital information provision. Design/methodology/approach: The first section of the article sketches out the strategic decisions which determine the funding policy of the DFG in the field of digital information, while the second section describes in more detail the central funding schemes of the DFG in the field of digital information. Findings: The funding policy of the DFG seeks to build an integrated digital research environment that includes scholarly publications and primary research data as well as new forms of communication in virtual research and work environments. But it will be only by the common effort of scholars, libraries and providers of scholarly information, funders, publishers and fee collecting agencies that the vision of an integrated digital research environment will come true. Originality / value: The outline of the funding programmes of the DFG in the area of digital information provision will be of interest to librarians and information professionals seeking information about library funding policies and strategies in Germany

A critical review of white matter changes in Huntington’s disease

Huntington’s disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington’s disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are due to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the ‘De-myelination hypothesis’ of Huntington’s disease, and demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington’s brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington’s associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in MRI techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This, in turn, will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials

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

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

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

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

Differential requirements for the chemokine receptor CCR7 in T cell activation during Listeria monocytogenes infection

Effective priming of T cell responses depends on cognate interactions between naive T cells and professional antigen-presenting cells (APCs). This contact is the result of highly coordinated migration processes, in which the chemokine receptor CCR7 and its ligands, CCL19 and CCL21, play a central role. We used the murine Listeria monocytogenes infection model to characterize the role of the CCR7/CCR7 ligand system in the generation of T cell responses during bacterial infection. We demonstrate that efficient priming of naive major histocompatibility complex (MHC) class Ia–restricted CD8+ T cells requires CCR7. In contrast, MHC class Ib–restricted CD8+ T cells and MHC class II–restricted CD4+ T cells seem to be less dependent on CCR7; memory T cell responses are independent of CCR7. Infection experiments with bone marrow chimeras or mice reconstituted with purified T cell populations indicate that CCR7 has to be expressed on CD8+ T cells and professional APCs to promote efficient MHC class Ia–restricted T cell priming. Thus, different T cell subtypes and maturation stages have discrete requirements for CCR7

Physiotherapists implicitly evaluate bending and lifting with a round back as dangerous

© 2018 Elsevier Ltd. Background: Beliefs can be assessed using explicit measures (e.g. questionnaires) that rely on information of which the person is ‘aware’ and willing to disclose. Conversely, implicit measures evaluate beliefs using computer-based tasks that allow reduced time for introspection thus reflecting ‘automatic’ associations. Thus far, physiotherapists’ beliefs about back posture and safety have not been evaluated with implicit measures. Objectives: (1) Evaluate implicit associations between bending lifting back posture (straight-back vs round-back) and safety (safe vs danger); (2) Explore correlations between implicit and explicit measures of beliefs towards vulnerability of the back. Design: Exploratory cross-sectional quantitative study. Methods: 47 musculoskeletal physiotherapists completed explicit measures of fear of movement (TSK-HC), back beliefs (BackPAQDanger) and beliefs related to bending and lifting back posture and safety (BSB). An Implicit Association Test (IAT) was used to assess implicit associations between (i) images of people bending/lifting with a ‘round-back’ or with a ‘straight-back’ posture, and (ii) words representing ‘safety’ and ‘danger’. A one-sample t-test assessed the degree and direction of the sample's IAT score. Cohen's d provided an effect size of the estimated bias. Correlation between IAT and each explicit measure was assessed using Pearson's coefficient. Results: The sample displayed an implicit association between ‘round-back’ and ‘danger’ (µ = 0.213, 95% CI [0.075-0.350], p =.003), with an effect size magnitude of 0.45. There were fair to moderate correlations between IAT and BSB (r = 0.320, 95% CI [0.036-0.556], p =.029) and, IAT and BackPAQDanger (r = 0.413, 95%CI [0.143-0.626], p =.004). Conclusions: Physiotherapists displayed an implicit bias towards bending and lifting with a round-back as dangerous