Identification of transcriptional regulatory networks specific to pilocytic astrocytoma.

BackgroundPilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours.MethodsRNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization.ResultsIn this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, and identified 792 genes that demonstrated consistent differential expression between independent sets of PA and non-malignant specimens. From this entire 792 gene set, we used the previously described PAP tool to assemble a core transcriptional regulatory network composed of 6 transcription factor genes (TFs) and 24 target genes, for a total of 55 interactions. A similar analysis of oligodendroglioma and glioblastoma multiforme (GBM) gene expression data sets identified distinct, but overlapping, networks. Most importantly, comparison of each of the brain tumor type-specific networks revealed a network unique to PA that included repressed expression of ONECUT2, a gene frequently methylated in other tumor types, and 13 other uniquely predicted TF-gene interactions.ConclusionsThese results suggest specific transcriptional pathways that may operate to create the unique molecular phenotype of PA and thus opportunities for corresponding targeted therapeutic intervention. Moreover, this study also demonstrates how integration of gene expression data with TF-gene and TF-TF interaction data is a powerful approach to generating testable hypotheses to better understand cell-type specific genetic programs relevant to cancer

Childhood Development after Cochlear Implantation (CDaCI) study: Design and baseline characteristics

Children with severe to profound sensorineural hearing loss face communication challenges that influence language, psychosocial and scholastic performance. Clinical studies over the past 20 years have supported wider application of cochlear implants in children. The Childhood Development after Cochlear Implantation (CDaCI) study is the first longitudinal multicentre, national cohort study to evaluate systematically early cochlear implant (CI) outcomes in children. The objective of the study was to compare children who have undergone cochlear implantation, with similarly aged hearing peers across multiple domains, including oral language development, auditory performance, psychosocial and behavioural functioning, and quality of life. The CDaCI study is a multicentre national cohort study of CI children and normal hearing (NH) peers. Eligibility criteria include informed consent, age less than 5 years, pre- or post-lingually deaf, developmental criteria met, commitment to educate the child in English and bilateral cochlear implants. All children had a standardised baseline assessment that included demographics, hearing and medical history, communication history, language measures, cognitive tests, speech recognition, an audiological exam, psychosocial assessment including parent-child videotapes and parent reported quality of life. Follow-up visits are scheduled at six-month intervals and include a standardised assessment of the full battery of measures. Quality assurance activities were incorporated into the design of the study. A total of 188 CI children and 97 NH peers were enrolled between November 2002 and December 2004. The mean age, gender and race of the CI and NH children are comparable. With regard to parental demographics, the CI and NH children's families are statistically different. The parents of CI children are younger, and not as well educated, with 49% of CI parents reporting college graduation vs. 84% of the NH parents. The income of the CI parents is also lower than the NH parents. Assessments of cognition suggest that there may be baseline differences between the CI and NH children; however the scores were high enough to suggest language learning potential. The observed group differences identified these baseline characteristics as potential confounders which may require adjustment in analyses of outcomes. This longitudinal cohort study addresses questions related to high variability in language outcomes. Identifying sources of that variance requires research designs that: characterise potential predictors with accuracy, use samples that adequately power a study, and employ controls and approaches to analysis that limit bias and error. The CDaCI study was designed to generate a more complete picture of the interactive processes of language learning after implantation. Copyright © 2007 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56091/1/333_ftp.pd

XUV digital in-line holography using high-order harmonics

A step towards a successful implementation of timeresolved digital in-line holography with extreme ultraviolet radiation is presented. Ultrashort XUV pulses are produced as high-order harmonics of a femtosecond laser and a Schwarzschild objective is used to focus harmonic radiation at 38 nm and to produce a strongly divergent reference beam for holographic recording. Experimental holograms of thin wires are recorded and the objects reconstructed. Descriptions of the simulation and reconstruction theory and algorithms are also given. Spatial resolution of few hundreds of nm is potentially achievable, and micrometer resolution range is demonstrated.Comment: 8 pages, 8 figure

Crosswalk study on blood collection-tube types for Alzheimer's disease biomarkers

Introduction: Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [ A β ] 42 , A β 40 , phosphorylated tau [ p - ta u 181 , total tau [t-tau], neurofilament light chain [NfL], A β 42 40 , and p - ta u 181 A β 42 ) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). Methods: Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. Results: Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL ( R 2 = 0.94), adequate for amyloid ( R 2 = 0.40-0.69), and weaker for t-tau ( R 2 = 0.04-0.42) and p - ta u 181 ( R 2 = 0.22-0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTa u 181 A β 42 ( d = 1.29). Discussion: AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood

A Vulnerability Assessment of Fish and Invertebrates to Climate Change on the Northeast U.S. Continental Shelf

Climate change and decadal variability are impacting marine fish and invertebrate species worldwide and these impacts will continue for the foreseeable future. Quantitative approaches have been developed to examine climate impacts on productivity, abundance, and distribution of various marine fish and invertebrate species. However, it is difficult to apply these approaches to large numbers of species owing to the lack of mechanistic understanding sufficient for quantitative analyses, as well as the lack of scientific infrastructure to support these more detailed studies. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species with existing information. These methods combine the exposure of a species to a stressor (climate change and decadal variability) and the sensitivity of species to the stressor. These two components are then combined to estimate an overall vulnerability. Quantitative data are used when available, but qualitative information and expert opinion are used when quantitative data is lacking. Here we conduct a climate vulnerability assessment on 82 fish and invertebrate species in the Northeast U.S. Shelf including exploited, forage, and protected species. We define climate vulnerability as the extent to which abundance or productivity of a species in the region could be impacted by climate change and decadal variability. We find that the overall climate vulnerability is high to very high for approximately half the species assessed; diadromous and benthic invertebrate species exhibit the greatest vulnerability. In addition, the majority of species included in the assessment have a high potential for a change in distribution in response to projected changes in climate. Negative effects of climate change are expected for approximately half of the species assessed, but some species are expected to be positively affected (e.g., increase in productivity or move into the region). These results will inform research and management activities related to understanding and adapting marine fisheries management and conservation to climate change and decadal variability

Late phonological development in Spanish children with bilateral hearing loss / Desarrollo fonologico tardio en ninos espanoles con perdidas auditivas bilaterales

This study has a twofold objective: to analyse and compare the phonological processes in a sample of Spanish children with hearing loss, both with a cochlear implant and with a hearing aid, with a group with normal hearing; and to determine whether there are differences between the participants with a cochlear implant and with a hearing aid in the frequency and nature of the phonological processes. The sample is made up of 168 participants, eight with hearing loss (four with an implant and four with a hearing aid) and 160 with normal hearing. Samples of spontaneous speech were collected and transcribed using the tools from the CHILDES project. For the analysis, the phonological processes paradigm was adopted, evaluating phonological development based on normative error rates. The participants with a hearing loss show slower phonological development in terms of phonological processes, along with atypical processes. Furthermore, the participants with cochlear implants committed more phonological errors than those that wear a hearing aid. The implications of the results are discussed, and it is recommended that auditory stimulation should be done early in children with hearing loss regardless of their technical aid

Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease

IMPORTANCE: Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile. OBJECTIVE: To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. EXPOSURES: Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240). MAIN OUTCOMES AND MEASURES: Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET. RESULTS: A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile. CONCLUSION AND RELEVANCE: Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals