1,720,977 research outputs found
Neurodegenerative disorders: From clinicopathology convergence to systems biology divergence
No full text: Neurodegenerative diseases are multifactorial. This means that several genetic, epigenetic, and environmental factors contribute to their emergence. Therefore, for the future management of these highly prevalent diseases, it is necessary to change perspective. If a holistic viewpoint is assumed, the phenotype (the clinicopathological convergence) emerges from the perturbation of a complex system of functional interactions among proteins (systems biology divergence). The systems biology top-down approach starts with the unbiased collection of sets of data generated through one or more -omics techniques and has the aim to identify the networks and the components that participate in the generation of a phenotype (disease), often without any available a priori knowledge. The principle behind the top-down method is that the molecular components that respond similarly to experimental perturbations are somehow functionally related. This allows the study of complex and relatively poorly characterized diseases without requiring extensive knowledge of the processes under investigation. In this chapter, the use of a global approach will be applied to the comprehension of neurodegeneration, with a particular focus on the two most prevalent ones, Alzheimer's and Parkinson's diseases. The final purpose is to distinguish disease subtypes (even with similar clinical manifestations) to launch a future of precision medicine for patients with these disorders
Proteostasis and proteotoxicity in the network medicine era
No full textNeurodegenerative proteinopathies are complex diseases that share some pathogenetic processes. One of these is the failure of the proteostasis network (PN), which includes all components involved in the synthesis, folding, and degradation of proteins, thus leading to the aberrant accumulation of toxic protein aggregates in neurons. The single components that belong to the three main modules of the PN are highly interconnected and can be considered as part of a single giant network. Several pharmacological strategies have been proposed to ameliorate neurodegeneration by targeting PN components. Nevertheless, effective disease-modifying therapies are still lacking. In this review article, after a general description of the PN and its failure in proteinopathies, we will focus on the available pharmacological tools to target proteostasis. In this context, we will discuss the main advantages of systems-based pharmacology in contrast to the classical targeted approach, by focusing on network pharmacology as a strategy to innovate rational drug design
Mitochondrial Proteins in the Development of Parkinson’s Disease
No full textParkinson’s disease (PD) is a multifactorial disorder whose etiology is not completely understood. Strong evidences suggest that mitochondrial impairment and altered mitochondrial disposal play a key role in the development of this pathology. Here we show this association in both genetic and sporadic forms of the disease. Moreover, we describe the mitochondrial dysfunctions in toxin-induced models of PD, thus highlighting the importance of environmental factors in the onset of this pathology. In particular, we focus our attention on mitochondrial dynamics, mitochondrial biogenesis, and mitophagy and explain how their impairment could have a negative impact on dopaminergic neurons function and survival. Lastly, we aim at clarifying the important role played by proteomics in this field of research, proteomics being a global and unbiased approach suitable to unravel alterations of the molecular pathways in multifactorial diseases
Proteomics turns functional
No full textProteomics is acquiring a pivotal role in the comprehensive understanding of human biology. Biochemical processes involved in complex diseases, such as neurodegenerative diseases, diabetes and cancer, can be identified by combining proteomics analysis and bioinformatics tools. In the last ten years, the main output of differential proteomics investigations evolved from long lists of proteins to the generation of new hypotheses and their functional verification. The Journal of Proteomics participated to this progress, reporting more and more biologically-oriented papers with functional interpretation of proteomics data. This change in the field was due to both technological development and novel strategies in exploiting the deep characterization of proteomes. In this review, we explore several approaches that allow proteomics to turn functional. In particular, systems biology tools for data analysis are now routinely used to interpret results, thus defining the biological meaning of differentially abundant proteins. Moreover, by considering the importance of protein-protein interactions and the composition of macromolecular complexes, interactomics is complementing the information given by differential quantitative proteomics. Eventually, terminomics is unveiling new functions for cleaved proteoforms, by analyzing the effect of proteolysis globally. Significance: Proteomics is rapidly evolving not only technologically but also strategically. The correct interpretation of proteomics data can reveal new functions of proteins in several biological backgrounds. Systems biology tools allow researchers to formulate new hypotheses to be further functionally tested. Interactomics is shedding new light on protein complexes truly involved in biochemical pathways and how their alteration can lead to dysfunctionality (in disease pathogenesis, for example). Terminomics is revealing the function of new discovered proteoforms and attributing a novel role to proteolysis. This review would provide the biologist important insights into current applications of several proteomic approaches that could offer new strategies to investigate biological systems
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
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
Molecular phylogenetic analyses of albuminoids reveal the molecular evolution of allosteric properties
No full textSerum albumin, α-fetoprotein, afamin (also named α-albumin and vitamin E binding protein), and vitamin D binding protein are members of the albuminoid superfamily. Albuminoids are plasma proteins characterized by a marked ability for ligand binding and transport. Here, a focused phylogenetic analysis of sequence evolution by maximum likelihood of fatty acid binding sites FA1-FA7 of mammalian albuminoids reveals that the FA1, FA2, and FA3+FA4 sites in serum albumins have evolved from the most recent common ancestor through an intermediate that has originated the α-fetoprotein and afamin clades. The same topology has been observed for the whole protein sequences, for the sequences of all the fatty acid binding sites (FA1-FA7) taken together, and for the allosteric core corresponding to residues 1-303 of human serum albumin. The quantitative divergence analysis indicates that the ligand binding cleft corresponding to the FA2 site could be the main determinant of allosteric properties of serum albumins only. In fact, this binding cleft is structurally not effective in vitamin D binding proteins, whereas key residues that serve to allocate the allosteric effectors are not present in afamins and α-fetoproteins
Discovery and verification of panels of T-lymphocyte proteins as biomarkers of Parkinson’s disease
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