1,720,994 research outputs found
Author Correction: Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer’s disease
No full textWhole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer’s disease
No full textAbstract
In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.National Institute on Aging http://dx.doi.org/10.13039/100000049National Institute of General Medical Sciences http://dx.doi.org/10.13039/100000057Foundation for the National Institutes of Health http://dx.doi.org/10.13039/100000009European Research Council http://dx.doi.org/10.13039/501100000781Science Foundation Ireland http://dx.doi.org/10.13039/50110000160
Involvement of neutrophils in immediate hypersensitivity reactions to betalactames
No full textCette thèse vise à découvrir de nouveaux biomarqueurs et à enquêter sur le rôle des neutrophiles, en particulier leur production de pièges extracellulaires de neutrophiles (NET), dans les réactions anaphylactiques. L'objectif est d'améliorer notre compréhension de l'anaphylaxie, en particulier dans les cas où l'implication des IgE n'est pas claire, en utilisant deux approches principales. Dans le contexte des réactions d'hypersensibilité immédiate aux béta-lactamines (BL), généralement associées à des mécanismes médiés par les IgE, certains cas présentent des taux d'IgE spécifiques du sérum (sIgE) faibles ou indétectables et une élévation minimale de la tryptase. Cette étude vise à déterminer si l'activation des neutrophiles et la libération de NET sont impliquées dans les réactions d'hypersensibilité aux BL.L'étude a analysé les composants des NET chez 34 patients présentant des réactions d'hypersensibilité aux BL confirmées, malgré des preuves limitées de sIgE et de tryptase. Les résultats ont montré une augmentation des niveaux de neutrophil elastase (NE), myeloperoxidase (MPO)-DNA, ADN libre et de l'activité de la DNase, ainsi qu'une augmentation de l'IL8 et une diminution de l'IL4 et de l'IL13. Ces résultats ont été obtenus comparativement à un groupe témoin. L'étude a révélé que NE, MPO-DNA et l'activité de DNase sont restés élevés jusqu'à deux heures plus tard. En revanche, l'ADN libre et CXCR2 ont diminué significativement. NE était corrélé avec l'IL8 et CXCR2, et l'activation des neutrophiles par l'intermédiaire de l'axe IL8-CXCR2 était évidente. En outre, l'activité de la DNase diminuait avec la gravité croissante des réactions d'hypersensibilité.En conclusion, les réactions d'hypersensibilité aux BL avec des taux faibles d'IgE spécifiques et une élévation limitée de la tryptase impliquent l'activation des neutrophiles et la libération de NE et de NET par l'intermédiaire de l'axe IL8-CXCR2. Cela éclaire la physiopathologie indépendante des IgE de ces réactions et peut potentiellement améliorer leur diagnostic.L'anaphylaxie, une réaction d'hypersensibilité immédiate de type sévère, est généralement associée à l'activation immunologique des lymphocytes B par des allergènes. Cependant, ce mécanisme bien connu n'explique pas complètement la diversité des présentations cliniques et immunologiques de l'anaphylaxie. Cette revue systématique des études protéomiques et métabolomiques visait à améliorer notre compréhension de l'anaphylaxie et à identifier de potentiels biomarqueurs.La revue a inclus 12 publications parmi les 137 examinées, comprenant sept études de protéomique et cinq études de métabolomique. Une méta-analyse des études humaines a identifié 118 protéines avec des niveaux d'expression variables dans au moins deux études. En plus des voies bien établies impliquant l'activation des mastocytes et des basophiles, l'analyse fonctionnelle a révélé un important enrichissement de processus liés à l'activation des neutrophiles, à la dégranulation des plaquettes et à des voies métaboliques impliquant l'acide arachidonique et l'acide icosatétraénoïque. L'analyse du métabolome dans différents modèles a identifié 13 métabolites communs, dont l'acide arachidonique, le tryptophane et les lysophosphatidylcholines lysoPC(18:0).En conclusion, cette revue met en lumière le rôle sous-estimé des neutrophiles et des plaquettes dans les mécanismes pathologiques des réactions anaphylactiques. Bien que basées sur un nombre limité de publications, ces découvertes devraient être confirmées dans le cadre d'études humaines de plus grande envergure et ont le potentiel de guider le développement de nouveaux biomarqueurs pour l'anaphylaxie.This thesis had the aims to discover new biomarkers and investigate the role of neutrophils, specifically their production of NETs, in anaphylactic reactions. The goal is to advance our understanding of anaphylaxis, particularly in cases where the involvement of IgE is unclear, using two main approaches:1. A review of omics studies in both clinical and experimental settings, followed by a meta-analysis of the collected data (Part A).2. A clinical study designed to validate the findings, with a specific focus on the role of neutrophils. Neutrophils and their extracellular traps (NETs) have been of interest in other inflammatory contexts and may significantly contribute to immune responses and the severity of anaphylactic reactions (Part B).In the context of immediate hypersensitivity reactions (IHR) to betalactams (BLs), typically associated with IgE-mediated mechanisms, some cases exhibit low or undetectable serum-specific IgE (sIgE) levels and minimal tryptase elevation. This study investigates whether neutrophil activation and the release of NETs are involved in BL IHRs.The study analyzed components of NETs in 34 patients with confirmed BL IHRs who had positive skin tests and challenge tests, despite limited evidence of sIgE and tryptase. The analysis was conducted during the first 15 minutes (T0) and up to two hours later (T0+2) during IHRs.Patients with BL IHRs exhibited elevated levels of neutrophil elastase (NE), myeloperoxidase (MPO)-DNA, cell-free DNA, and DNase activity, as well as increased IL8 and decreased IL4 and IL13 at T0 compared to controls. NE, MPO-DNA, and DNase activity remained elevated at T0+2, while cell-free DNA and CXCR2 decreased significantly. NE correlated with IL8 and CXCR2 at T0 and remained positively associated with CXCR2 at T0+2. The activation of neutrophils through the IL8-CXCR2 axis was evident, with a strong correlation between the two markers at T0. Furthermore, there was a significant trend of decreased DNase activity with increasing severity of IHRs.In conclusion, BL IHRs with low sIgE and limited tryptase elevation involve neutrophil activation and the release of NE and NETs via the IL8-CXCR2 axis, shedding light on the IgE-independent pathophysiology of these reactions and potentially improving their diagnosis.Anaphylaxis, a severe immediate-type hypersensitivity reaction, is conventionally linked to the immunological activation of B-cells by allergens. However, this well-known mechanism does not fully explain the diverse clinical and immunological presentations of anaphylaxis. This systematic review of proteomic and metabolomic studies aimed to enhance our understanding of anaphylaxis and identify potential biomarkers.The review involved a comprehensive search in PubMed, Scopus, and Web of Science until May 2023 to identify relevant proteomic and metabolomic studies in both human and experimental models.Out of 137 publications, 12 were selected for analysis, comprising seven proteome studies and five metabolome studies. A meta-analysis of human studies identified 118 proteins with varying expression levels in at least two studies. In addition to the well-established pathways involving mast cell and basophil activation, the functional analysis revealed a significant enrichment of processes related to neutrophil activation, platelet degranulation, and metabolic pathways associated with arachidonic acid and icosatetraenoic acid. The metabolome analysis across various models identified 13 common metabolites, including arachidonic acid, tryptophan, and lysoPC(18:0) lysophosphatidylcholines.In conclusion, this review underscores the underestimated role of neutrophils and platelets in the pathological mechanisms of anaphylactic reactions. While based on a limited number of publications, these findings should be confirmed in larger human studies and have the potential to guide the development of new biomarkers for anaphylaxis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Constraint-based modeling of host-microbe and microbe-microbe metabolic interactions in the human gut
No full textHumans harbor a complex microbial ecosystem in their intestines. This human gut microbiota performs essential functions for host health and wellbeing. Disruption, or dysbiosis, in gut microbiota composition has been directly linked to the pathogenesis of complex diseases. Understanding the mechanisms behind these links between microbiota and host health and disease states requires predictive, mechanistic computational models. Constraint-based metabolic modeling uses manually curated and validated metabolic reconstructions that constitute a genomically, genetically and biochemically structured knowledge base of a target organism. These reconstructions can be converted into mathematical models that allow the in silico prediction of an organism’s phenotype under given environmental constraints Constraint-based modeling has been successfully applied to predict multispecies interactions but rarely in the context of host-microbe interactions. In this thesis, a framework for predicting metabolic interactions between a host and its gut symbionts was developed. As reconstructions of representative gut symbionts were lacking prior to this thesis, metabolic reconstructions targeting representatives of the two main phyla in the gut microbiota were manually constructed and validated. These reconstructions were first applied to predict the metabolic interactions between a model gut symbiont and its murine host, and, using a combined in silico/ in vitro approach, the metabolic potential of an abundant but poorly studied beneficial microbe. Subsequently, using nine additional published manually curated reconstructions, a model gut community was constructed in silico. Linking the model community with a global reconstruction of a human cell enabled the systematic prediction of the microbes’ potential to affect human metabolism. The in silico approach demonstrated the gut microbiota’s potential to act as an additional organ from the host perspective. Moreover, the 11 microbes were joint pairwise in all combinations and mutualistic, commensal, parasitic, and competitive interactions were investigated on varying nutrient environments. The potential to engage in mutualistic cross-feeding was species-specific and predicted to be highly dependent on anoxic conditions.
In summary, using constraint-based modeling, host-microbe and microbe-microbe metabolic interactions were predicted in a bottom-up, mechanistic manner. The multispecies modeling framework developed in the course of this thesis can readily incorporate any host and number of microbes and will have valuable applications for elucidating the gut ecosystem and its effects on the human host.Marie Skłodowska-Curie actions (International Reintegration grant 19 No. 249261)
Luxembourg National Research Fund (ATTRACT programme grant FNR/A12/01
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Microbiome Modelling Toolbox 2.0: efficient, tractable modelling of microbiome communities
Full text linkMotivation: Constraint-Based Reconstruction and Analysis (COBRA) is a widely used approach for the interrogation and stratification of microbiome samples, yet applications to large-scale cohorts are hampered by limited scalability and efficiency of simulations. Results: We substantially improved the computation speed and scalability of a previous implementation for the construction and interrogation of personalized constraint-based microbiome models as well as implemented additional functionalities for analysis and visualization. Availability and implementation: Microbiome Modelling Toolbox and tutorials are freely available as part of the COBRA Toolbox at https://git.io/microbiomeModelingToolbox
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
