An improved ontological representation of dendritic cells as a paradigm for all cell types

The Cell Ontology (CL) is designed to provide a standardized representation of cell types for data annotation. Currently, the CL employs multiple is_a relations, defining cell types in terms of histological, functional, and lineage properties, and the majority of definitions are written with sufficient generality to hold across multiple species. This approach limits the CL’s utility for cross-species data integration. To address this problem, we developed a method for the ontological representation of cells and applied this method to develop a dendritic cell ontology (DC-CL). DC-CL subtypes are delineated on the basis of surface protein expression, systematically including both species-general and species-specific types and optimizing DC-CL for the analysis of flow cytometry data. This approach brings benefits in the form of increased accuracy, support for reasoning, and interoperability with other ontology resources. 104. Barry Smith, “Toward a Realistic Science of Environments”, Ecological Psychology, 2009, 21 (2), April-June, 121-130. Abstract: The perceptual psychologist J. J. Gibson embraces a radically externalistic view of mind and action. We have, for Gibson, not a Cartesian mind or soul, with its interior theater of contents and the consequent problem of explaining how this mind or soul and its psychological environment can succeed in grasping physical objects external to itself. Rather, we have a perceiving, acting organism, whose perceptions and actions are always already tuned to the parts and moments, the things and surfaces, of its external environment. We describe how on this basis Gibson sought to develop a realist science of environments which will be ‘consistent with physics, mechanics, optics, acoustics, and chemistry’

Overview of the COVID-19 text mining tool interactive demonstration track in BioCreative VII

The coronavirus disease 2019 (COVID-19) pandemic has compelled biomedical researchers to communicate data in real time to establish more effective medical treatments and public health policies. Nontraditional sources such as preprint publications, i.e. articles not yet validated by peer review, have become crucial hubs for the dissemination of scientific results. Natural language processing (NLP) systems have been recently developed to extract and organize COVID-19 data in reasoning systems. Given this scenario, the BioCreative COVID-19 text mining tool interactive demonstration track was created to assess the landscape of the available tools and to gauge user interest, thereby providing a two-way communication channel between NLP system developers and potential end users. The goal was to inform system designers about the performance and usability of their products and to suggest new additional features. Considering the exploratory nature of this track, the call for participation solicited teams to apply for the track, based on their system’s ability to perform COVID-19-related tasks and interest in receiving user feedback. We also recruited volunteer users to test systems. Seven teams registered systems for the track, and >30 individuals volunteered as test users; these volunteer users covered a broad range of specialties, including bench scientists, bioinformaticians and biocurators. The users, who had the option to participate anonymously, were provided with written and video documentation to familiarize themselves with the NLP tools and completed a survey to record their evaluation. Additional feedback was also provided by NLP system developers. The track was well received as shown by the overall positive feedback from the participating teams and the users.National Institutes of Health Office of Research Infrastructure Programs (R01OD010929 to M.T. and K.D.); Canadian Institutes of Health Research (FDN-167277 to M.T.); Canada Research Chair in Systems and Synthetic Biology (to M.T.); National Institutes of Health (2U24HG007822-08, 1R35 GM141873-01 to K.E.R. and C.N.A); Spanish Plan for the Advancement of Language Technology and Proyectos I+D+i2020-AI4PROFHEALTH (PID2020-119266RA-I00 to M.K.); MITRE (W56KGU-18-D-0004 to L.H. and T.K.). The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official government position, policy or decision.Peer ReviewedPostprint (published version

An improved ontological representation of dendritic cells as a paradigm for all cell types

<p>Abstract</p> <p>Background</p> <p>Recent increases in the volume and diversity of life science data and information and an increasing emphasis on data sharing and interoperability have resulted in the creation of a large number of biological ontologies, including the Cell Ontology (CL), designed to provide a standardized representation of cell types for data annotation. Ontologies have been shown to have significant benefits for computational analyses of large data sets and for automated reasoning applications, leading to organized attempts to improve the structure and formal rigor of ontologies to better support computation. Currently, the CL employs multiple <it>is_a </it>relations, defining cell types in terms of histological, functional, and lineage properties, and the majority of definitions are written with sufficient generality to hold across multiple species. This approach limits the CL's utility for computation and for cross-species data integration.</p> <p>Results</p> <p>To enhance the CL's utility for computational analyses, we developed a method for the ontological representation of cells and applied this method to develop a dendritic cell ontology (DC-CL). DC-CL subtypes are delineated on the basis of surface protein expression, systematically including both species-general and species-specific types and optimizing DC-CL for the analysis of flow cytometry data. We avoid multiple uses of <it>is_a </it>by linking DC-CL terms to terms in other ontologies via additional, formally defined relations such as <it>has_function</it>.</p> <p>Conclusion</p> <p>This approach brings benefits in the form of increased accuracy, support for reasoning, and interoperability with other ontology resources. Accordingly, we propose our method as a general strategy for the ontological representation of cells. DC-CL is available from <url>http://www.obofoundry.org</url>.</p

Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: From biological biomarkers to clinical syndromes

Background According to the 2018 NIA-AA research framework, Alzheimer's disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-beta (A beta) and phosphorylated tau protein (p-tau) deposition-assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis-is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers. Methods We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using A beta-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated. Results Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers' profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF A beta levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two A beta biomarkers was 89%. Conclusions The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET A beta biomarkers were found to be not perfectly interchangeable to quantify the A beta burden, possibly because they measure different aspects of AD pathology

Profiling of ubiquitination pathway genes in peripheral cells from patients with frontotemporal dementia due to C9ORF72 and GRN mutations

We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion

Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the \u27hydrophobic motif\u27 of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes. Sci Rep 2018 Apr 25; 8(1):6518

Usefulness of multi-parametric MRI for the investigation of posterior cortical atrophy

Background Posterior Cortical Atrophy (PCA) is a neurodegenerative disease characterized by a progressive decline in selective cognitive functions anatomically referred to occipital, parietal and temporal brain regions, whose diagnosis is rather challenging for clinicians. The aim of this study was to assess, using quantitative Magnetic Resonance Imaging techniques, the pattern of regional grey matter loss and metabolism in individuals with PCA to improve pathophysiological comprehension and diagnostic confidence. Methods We enrolled 5 patients with PCA and 5 matched controls who all underwent magnetic resonance imaging (MRI) and spectroscopy (MRS). Patients also underwent neuropsychological and cerebrospinal fluid (CSF) assessments. MRI data were used for unbiased assessment of regional grey matter loss in PCA patients compared to controls. MRS data were obtained from a set of brain regions, including the occipital lobe and the centrum semiovale bilaterally, and the posterior and anterior cingulate. Results VBM analysis documented the presence of focal brain atrophy in the occipital lobes and in the posterior parietal and temporal lobes bilaterally but more pronounced on the right hemisphere. MRS revealed, in the occipital lobes and in the posterior cingulate cortex of PCA patients, reduced levels of N-Acetyl Aspartate (NAA, a marker of neurodegeneration) and increased levels of Myo-Inositol (Ins, a glial marker), with no hemispheric lateralization. Conclusion The bilateral but asymmetric pattern of regional grey matter loss is consistent with patients' clinical and neuropsychological features and with previous literature. The MRS findings reveal different stages of neurodegeneration (neuronal loss; gliosis), which coexist and likely precede the occurrence of brain tissue loss, and might represent early biomarkers. In conclusion, this study indicates the potential usefulness of a multi-parametric MRI approach for an early diagnosis and staging of patients with PCA

Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy

OBJECTIVE: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy (1H MRS), in intrauterine growth-restricted (IUGR) fetuses. STUDY DESIGN: In vivo human fetal brain lactate detection was determined by 1H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth. RESULTS: 1H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery. CONCLUSION: 1H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by 1H MRS may represent a possible marker of in utero cerebral injury or underperfusion

The novel GRN g.1159-1160delTG mutation is associated with behavioral variant frontotemporal dementia

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration and are associated with a wide phenotypic heterogeneity. Here, we describe two probands with behavioral variant frontotemporal dementia with a novel mutation in this gene (1159-1160delTG). Both had a positive family history for dementia and showed atypical features at imaging. Their progranulin plasma levels were undetectable, and the mutation was not present in cDNA, suggesting haploinsufficiency. Progranulin levels were low even in asymptomatic carriers of the variant. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers