scholarly journals Identification of site-specific evolutionary trajectories shared across human betacoronaviruses

2021 ◽  
Author(s):  
Marina Escalera-Zamudio ◽  
Sergei L Kosakovsky Pond ◽  
Natalia Martinez de la Vina ◽  
Bernardo Gutierrez ◽  
Julien Theze ◽  
...  
Keyword(s):  
Protein Structures ◽  
Comparative Approach ◽  
New Host ◽  
Functional Sites ◽  
The Past ◽  
Adaptive Processes ◽  
Evolutionary Trajectories ◽  
Stepwise Evolution ◽  
Protein Structure Data ◽  
S Genes

Comparison of evolution among related viruses can provide insights into shared adaptive processes, for example following host switching to a mutual host species. Whilst phylogenetic methods can help identify mutations that may be important for evolutionary processes such as adaptation to a new host, these can be enhanced by positioning candidate mutations to known functional sites on protein structures. Over the past two decades, three zoonotic betacoronaviruses have significantly impacted human public health: SARS-CoV-1, MERS-CoV and SARS-CoV-2, whilst two other betacoronaviruses, HKU1 and OC43, have circulated endemically in the human population for over 100 years. In this study, we use a comparative approach to prospectively search for potentially evolutionarily-relevant mutations within the Orf1ab and S genes across betacoronavirus species that have demonstrated sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2). We used a combination of molecular evolution methods to identify 30 sites that display evidence of homoplasy and/or stepwise evolution, that may be suggestive of adaptation across emerging and endemic betacoronaviruses. Of these, seven sites also display evidence of being selectively relevant. Drawing upon known protein structure data, we find that four of the identified mutations [18121 (exonuclease/27), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796), in SARS-CoV-2 genome coordinates] are proximal to regions of known functionality. Our results provide a molecular-level context for common evolutionary pathways that betacoronaviruses may undergo during adaptation to the human host.

The Oxford History of Historical Writing

2018 ◽  
Keyword(s):  
Early Modern ◽  
Korean Peninsula ◽  
Comparative Approach ◽  
Modern World ◽  
Historical Writing ◽  
North West ◽  
The Past ◽  
History Of

How was history written in Europe and Asia between 400–1400? How was the past understood in religious, social, and political terms? And in what ways does the diversity of historical writing in this period mask underlying commonalities in narrating the past? The volume tackles these and other questions. Part I provides comprehensive overviews of the development of historical writing in societies that range from the Korean Peninsula to north-west Europe, which together highlight regional and cultural distinctiveness. Part II complements the first part by taking a thematic and comparative approach; it includes chapters on genre, warfare, and religion (amongst others) which address common concerns of historians working in this liminal period before the globalizing forces of the early modern world.

scholarly journals Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae

2021 ◽  
Vol 8 ◽  
Author(s):  
Sundeep Chaitanya Vedithi ◽  
Sony Malhotra ◽  
Marta Acebrón-García-de-Eulate ◽  
Modestas Matusevicius ◽  
Pedro Henrique Monteiro Torres ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Schwann Cells ◽  
Protein Structures ◽  
Mycobacterium Leprae ◽  
Data Bank ◽  
Nerve Damage ◽  
Structural Proteomics ◽  
Bacterial Survival ◽  
Functional Sites

Leprosy, caused by Mycobacterium leprae (M. leprae), is treated with a multidrug regimen comprising Dapsone, Rifampicin, and Clofazimine. These drugs exhibit bacteriostatic, bactericidal and anti-inflammatory properties, respectively, and control the dissemination of infection in the host. However, the current treatment is not cost-effective, does not favor patient compliance due to its long duration (12 months) and does not protect against the incumbent nerve damage, which is a severe leprosy complication. The chronic infectious peripheral neuropathy associated with the disease is primarily due to the bacterial components infiltrating the Schwann cells that protect neuronal axons, thereby inducing a demyelinating phenotype. There is a need to discover novel/repurposed drugs that can act as short duration and effective alternatives to the existing treatment regimens, preventing nerve damage and consequent disability associated with the disease. Mycobacterium leprae is an obligate pathogen resulting in experimental intractability to cultivate the bacillus in vitro and limiting drug discovery efforts to repositioning screens in mouse footpad models. The dearth of knowledge related to structural proteomics of M. leprae, coupled with emerging antimicrobial resistance to all the three drugs in the multidrug therapy, poses a need for concerted novel drug discovery efforts. A comprehensive understanding of the proteomic landscape of M. leprae is indispensable to unravel druggable targets that are essential for bacterial survival and predilection of human neuronal Schwann cells. Of the 1,614 protein-coding genes in the genome of M. leprae, only 17 protein structures are available in the Protein Data Bank. In this review, we discussed efforts made to model the proteome of M. leprae using a suite of software for protein modeling that has been developed in the Blundell laboratory. Precise template selection by employing sequence-structure homology recognition software, multi-template modeling of the monomeric models and accurate quality assessment are the hallmarks of the modeling process. Tools that map interfaces and enable building of homo-oligomers are discussed in the context of interface stability. Other software is described to determine the druggable proteome by using information related to the chokepoint analysis of the metabolic pathways, gene essentiality, homology to human proteins, functional sites, druggable pockets and fragment hotspot maps.

scholarly journals A60 Revealing the evolution of virulence in RNA viruses

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
Marina Escalera-Zamudio ◽  
Bernardo Gutiérrez ◽  
Julien Thézé ◽  
Oliver G Pybus
Keyword(s):  
Influenza A ◽  
Hepatitis A Virus ◽  
Rna Viruses ◽  
Phenotypic Diversity ◽  
Severe Disease ◽  
Protein Structures ◽  
Viral Fitness ◽  
Lassa Virus ◽  
Virulence Determinants ◽  
New Host

Abstract A combination of high rates of mutation and replication, coupled with strong natural selection, ensures that RNA viruses experience rapid genotypic and phenotypic evolution. Such a ‘fast-forward’ evolution enables viruses to rapidly adapt to new host species, evade host immune responses, and to develop resistance to anti-viral drugs. Similarly, rapid evolution allows viruses to attain new levels of virulence, defined as the ability to cause severe disease in hosts. We hypothesize that distinct viral groups share genetic determinants that modulate virulence that have been acquired through convergent evolution. Thus, common patterns reflecting changing virulence-related specific viral groups could be detected. The main goals for this project are (1) to understand how genetic and phenotypic diversity can be generated among different viral groups by analyzing the variation patterns and determining the selective forces behind them (impact in viral fitness) and (2) to understand how fixed mutations can modulate virulence within different viral groups by performing comparison of strains with differing virulence within a longitudinal timescale. The subject of the study is key emerging and re-emerging virus families of medical importance. Such groups include: Coronaviridae (severe acute respiratory syndrome and Middle East respiratory syndrome-associated coronaviruses), Picornaviridae (Hepatitis A virus), Flaviviridae (Yellow fever, West Nile, Hepatitis C, Dengue, and Zika viruses), Togaviridae (Rubella and Chikungunya virus), Bornaviridae (Borna-disease virus), Filoviridae (Ebola and Marburg viruses), Paramyxoviridae (Measles, Nipah, and Hendra viruses), Rhabdoviridae (Lyssaviruses), Arenaviridae (Lassa virus), Bunyaviridae (Hanta- and Crimean-Congo hemorrhagic fever viruses), and Orthomyxoviridae (Influenza A viruses). Viral genomes collected at different time points, different hosts (human and their most closely related animal reservoirs) and different locations will be compiled. Extensive molecular evolutionary analyses will be carried out to infer gene expansion/contraction within groups, rates of evolution, and changes in selection pressure, including the detection of positive selected genes and sites (adaptive evolution). Positively selected sites will be mapped onto the viral protein structures to reveal their impact on function, and hence the location of potential virulence determinants. Virulence changes among particular viral strains and types will be defined and measured according to definitions based on an increase in: (1) transmissibility, (2) host tropism, (3) immune evasion, (4) morbidity and mortality, (5) drug resistance, and by the incorporation of epidemiological data to determine whether high or low virulence strains within different hosts and localities are spreading most efficiently in nature.

RECOGNIZING COMPLEX, ASYMMETRIC FUNCTIONAL SITES IN PROTEIN STRUCTURES USING A BAYESIAN SCORING FUNCTION

2003 ◽  
Vol 01 (01) ◽  
pp. 119-138 ◽  
Author(s):  
LIPING WEI ◽  
RUSS B. ALTMAN
Keyword(s):  
Binding Sites ◽  
Calcium Binding ◽  
Active Sites ◽  
Large Scale ◽  
Protein Structures ◽  
Scoring Function ◽  
Chemical Properties ◽  
Data Bank ◽  
Functional Sites ◽  
Calcium Binding Sites

The increase in known three-dimensional protein structures enables us to build statistical profiles of important functional sites in protein molecules. These profiles can then be used to recognize sites in large-scale automated annotations of new protein structures. We report an improved FEATURE system which recognizes functional sites in protein structures. FEATURE defines multi-level physico-chemical properties and recognizes sites based on the spatial distribution of these properties in the sites' microenvironments. It uses a Bayesian scoring function to compare a query region with the statistical profile built from known examples of sites and control nonsites. We have previously shown that FEATURE can accurately recognize calcium-binding sites and have reported interesting results scanning for calcium-binding sites in the entire Protein Data Bank. Here we report the ability of the improved FEATURE to characterize and recognize geometrically complex and asymmetric sites such as ATP-binding sites and disulfide bond-forming sites. FEATURE does not rely on conserved residues or conserved residue geometry of the sites. We also demonstrate that, in the absence of a statistical profile of the sites, FEATURE can use an artificially constructed profile based on a priori knowledge to recognize the sites in new structures, using redoxin active sites as an example.

scholarly journals UET: a database of evolutionarily-predicted functional determinants of protein sequences that cluster as functional sites in protein structures

2015 ◽  
Vol 44 (D1) ◽  
pp. D308-D312 ◽  
Author(s):  
Rhonald C. Lua ◽  
Stephen J. Wilson ◽  
Daniel M. Konecki ◽  
Angela D. Wilkins ◽  
Eric Venner ◽  
...  
Keyword(s):  
Protein Structures ◽  
Protein Sequences ◽  
Functional Sites

The Origins of Study of the Past: A Comparative Approach

1962 ◽  
Vol 4 (2) ◽  
pp. 209-246 ◽  
Author(s):  
J. G. A. Pocock
Keyword(s):  
Comparative Approach ◽  
The Past ◽  
History Of

In this paper I shall attempt to consider how far the history of historiography can be treated as the history of the problems occasioned by men's awareness of the past in different societies, and of their attempts to deal with these problems. This kind of approach has not, so far as I know, been made before. That is to say, the history of historiography has not been approached as primarily a part of the history of social man's awareness of his past and his relations with it; and this is understandable enough, as the historical phenomena we call by the collective name of historiography have been by no means limited to the attempts made by historians and other thinkers to understand the past and its relationship to the present.

scholarly journals Matching of PDB chain sequences to information in public databases as a prerequisite for 3D functional site visualization

2004 ◽  
Vol 1 (1) ◽  
pp. 80-89
Author(s):  
Guido Dieterich ◽  
Dirk W. Heinz ◽  
Joachim Reichelt
Keyword(s):  
Genetic Disorders ◽  
Protein Structures ◽  
3D Structure ◽  
Data Bank ◽  
Mendelian Inheritance ◽  
Biological Information ◽  
Structure Comparison ◽  
3D Structures ◽  
Functional Sites ◽  
And Function

Abstract The 3D structures of biomacromolecules stored in the Protein Data Bank [1] were correlated with different external, biological information from public databases. We have matched the feature table of SWISS-PROT [2] entries as well InterPro [3] domains and function sites with the corresponding 3D-structures. OMIM [4] (Online Mendelian Inheritance in Man) records, containing information of genetic disorders, were extracted and linked to the structures. The exhaustive all-against-all 3D structure comparison of protein structures stored in DALI [5] was condensed into single files for each PDB entry. Results are stored in XML format facilitating its incorporation into related software. The resulting annotation of the protein structures allows functional sites to be identified upon visualization.

Balkan Countries in the World: Aging Process within the Age Structural Transition

2018 ◽  
Vol 42 (2) ◽  
pp. 177-198
Author(s):  
Maria Carella ◽  
Sara Grubanov-Bošković
Keyword(s):  
Structural Transition ◽  
Population Aging ◽  
Population Projections ◽  
Dissimilarity Index ◽  
The Past ◽  
Balkan Country ◽  
Balkan Countries ◽  
Specific Index ◽  
Evolutionary Trajectories ◽  
Scalogram Analysis

This article intends to approach the phenomenon of population aging within the conceptual framework of structural transition. In this work the authors put forward a method of defining the variety of evolutionary trajectories – the result of different sets of fertility-mortality interactions – on the global level and hence identify the position of each Balkan country within the worldwide demographic order of the past four decades (1971–2015). The authors then propose a specific index – the structural dissimilarity index – to measure the corresponding transformations inherent to the population age structure and link the results with the prospects that emerge on the basis of the interaction between fertility and mortality. This has finally enabled the authors to formulate some broad assumptions regarding the current and future intensity and trends of structural transformations. For this purpose, the authors have gathered a sample of 142 national populations, including all Balkan countries, with the exception of Montenegro, and employed different techniques such as Partial Order Structuple (Scalogram) Analysis with Coordinates (POSAC) and the cohort-component population projections for the timeframes 1971–2015 and 2015–2060.

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