scholarly journals Comparative genomics of global optrA-carrying Enterococcus faecalis uncovers common genetic features and a chromosomal hotspot for optrA acquisition

2019 ◽  
Author(s):  
Ana R. Freitas ◽  
Ana P. Tedim ◽  
Carla Novais ◽  
Luísa Peixe
Keyword(s):  
Enterococcus Faecalis ◽  
De Novo ◽  
Integration Site ◽  
Medium Size ◽  
Multiple Sources ◽  
Animal Reservoir ◽  
Phylogenetic Structure ◽  
Healthy Humans ◽  
Wide Range ◽  
Genetic Features

AbstractLinezolid-resistant Enterococcus faecalis (LREfs) carrying optrA are increasingly reported globally from multiple sources, but we still lack a comprehensive analysis of human and animal optrA-LREfs strains. We investigated the phylogenetic structure, genetic content [antimicrobial resistance (AMR), virulence, prophages, plasmidome] and optrA-containing platforms of 28 publicly available optrA-positive E. faecalis genomes from different hosts in 7 countries. In the genome-level analysis, in house databases with 57 virulence and 391 plasmid replication genes were tested for the first time. Our analysis showed a diversity of clones and adaptive gene sequences related to a wide range of genera, mainly but not exclusive from Firmicutes. The content in AMR and virulence genes was highly identical in contrast to the diversity of phages and plasmids observed. Epidemiologically unrelated clones (ST476-like and ST21-like) obtained from human clinical and animal hosts in different continents over 5 years (2012-2017) were phylogenetically related (3-122 SNPs difference). They also exhibited identical AMR and virulence profiles, highlighting a global spread of optrA-positive strains with relevant adaptive traits in livestock and that they might originate from an animal reservoir. optrA was located on the chromosome within a Tn6674-like element (n=9) or on medium-size plasmids (30-60 kb; n=14) belonging to main plasmid families (RepA_N/Inc18/Rep_3). In most cases, the immediate gene vicinity of optrA was identical in chromosomal (Tn6674) and plasmid (impB-fexA-optrA) backbones. Tn6674 was always inserted in the same ΔradC integration site and embedded in a 32 kb chromosomal platform common to diverse strains from different origins (patients, healthy humans, and animals) in Europe, Africa, and Asia during 2012-2018. This platform is conserved among hundreds of E. faecalis genomes and we here propose a conserved chromosomal hotspot for optrA integration. The finding of optrA in strains sharing identical adaptive features and genetic backgrounds across different hosts and countries suggest the occurrence of common and independent genetic events occurring in distant regions, and might explain the easy de novo generation of optrA-positive strains. It also anticipates a dramatic increase of optrA carriage and spread with a serious impact in the efficacy of linezolid for the treatment of Gram-positive infections.

scholarly journals Comparative genomics of global optrA-carrying Enterococcus faecalis uncovers a common chromosomal hotspot for optrA acquisition within a diversity of core and accessory genomes

2020 ◽  
Vol 6 (6) ◽  
Author(s):  
Ana R. Freitas ◽  
Ana P. Tedim ◽  
Carla Novais ◽  
Val F. Lanza ◽  
Luísa Peixe
Keyword(s):  
Enterococcus Faecalis ◽  
Type Species ◽  
De Novo ◽  
Integration Site ◽  
Medium Size ◽  
Phylogenetic Structure ◽  
Content Type ◽  
Link Type ◽  
Healthy Humans ◽  
Wide Range

Linezolid-resistant Enterococcus faecalis (LREfs) carrying optrA are increasingly reported globally from multiple sources, but we lack a comprehensive analysis of human and animal optrA-LREfs strains. To assess if optrA is dispersed in isolates with varied genetic backgrounds or with common genetic features, we investigated the phylogenetic structure, genetic content [antimicrobial resistance (AMR), virulence, prophages, plasmidome] and optrA-containing platforms of 27 publicly available optrA-positive E. faecalis genomes from different hosts in seven countries. At the genome-level analysis, an in-house database with 64 virulence genes was tested for the first time. Our analysis showed a diversity of clones and adaptive gene sequences related to a wide range of genera from Firmicutes . Phylogenies of core and accessory genomes were not congruent, and at least PAI-associated and prophage genes contribute to such differences. Epidemiologically unrelated clones (ST21, ST476-like and ST489) obtained from human clinical and animal hosts in different continents over eight years (2010–2017) could be phylogenetically related (3–126 SNPs difference). optrA was located on the chromosome within a Tn6674-like element (n=10) or on medium-size plasmids (30–60 kb; n=14) belonging to main plasmid families (RepA_N/Inc18/Rep_3). In most cases, the immediate gene vicinity of optrA was generally identical in chromosomal (Tn6674) or plasmid (impB-fexA-optrA) backbones. Tn6674 was always inserted into the same ∆radC integration site and embedded in a 32 kb chromosomal platform common to strains from different origins (patients, healthy humans, and animals) in Europe, Africa, and Asia during 2012–2017. This platform is conserved among hundreds of E. faecalis genomes and proposed as a chromosomal hotspot for optrA integration. The finding of optrA in strains sharing common adaptive features and genetic backgrounds across different hosts and countries suggests the occurrence of common and independent genetic events occurring in distant regions and might explain the easy de novo generation of optrA-positive strains. It also anticipates a dramatic increase of optrA carriage and spread with a serious impact on the efficacy of linezolid for the treatment of Gram-positive infections.

Museum Preserves in the Sphere of “Cultural Tourism”: Through the Example of the Cultural Preserves of Tatarstan

2019 ◽  
Vol 9 (4) ◽  
pp. 193-198
Author(s):  
Lyudmila S. Timofeeva ◽  
Albina R. Akhmetova ◽  
Liliya R. Galimzyanova ◽  
Roman R. Nizaev ◽  
Svetlana E. Nikitina
Keyword(s):  
19Th Century ◽  
Art Museum ◽  
Medium Size ◽  
Business Elite ◽  
Wide Range ◽  
The Subject ◽  
Tourist Center ◽  
Regional Authorities ◽  
The 19Th Century ◽  
The City

Abstract The article studies the existence experience of historical cities as centers of tourism development as in the case of Elabuga. The city of Elabuga is among the historical cities of Russia. The major role in the development of the city as a tourist center is played by the Elabuga State Historical-Architectural and Art Museum-Reserve. The object of the research in the article is Elabuga as a medium-size historical city. The subject of the research is the activity of the museum-reserve which contributes to the preservation and development of the historical look of Elabuga and increases its attractiveness to tourists. The tourism attractiveness of Elabuga is obtained primarily through the presence of the perfectly preserved historical center of the city with the blocks of integral buildings of the 19th century. The Elabuga State Historical-Architectural and Art Museum-Reserve, which emerged in 1989, is currently an object of historical and cultural heritage of federal importance. Museum-reserves with their significant territories and rich historical, cultural and natural heritage have unique resources for the implementation of large partnership projects. Such projects are not only aimed at attracting a wide range of tourists, but also stimulate interest in the reserve from the business elite, municipal and regional authorities. The most famous example is the Spasskaya Fair which revived in 2008 in Elabuga. It was held in the city since the second half of the 19th century, and was widely known throughout Russia. The process of the revival and successful development of the fair can be viewed as the creation of a special tourist event contributing to the formation of new and currently important tourism products.

Search for mutations of the interferon-induced transmembrane protein 5 (IFITM5) gene in patients with osteogenesis imperfecta

2019 ◽  
pp. 21-29
Author(s):  
А.Р. Зарипова ◽  
Л.Р. Нургалиева ◽  
А.В. Тюрин ◽  
И.Р. Минниахметов ◽  
Р.И. Хусаинова
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Transmembrane Protein ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Heterozygous Mutation ◽  
Type I ◽  
New Genes ◽  
Wide Range ◽  
Type V

Проведено исследование гена интерферон индуцированного трансмембранного белка 5 (IFITM5) у 99 пациентов с несовершенным остеогенезом (НО) из 86 неродственных семей. НО - клинически и генетически гетерогенное наследственное заболевание соединительной ткани, основное клиническое проявление которого - множественные переломы, начиная с неонатального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам НО относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушения роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. НО встречается как у мужчин, так и у женщин. До сих пор не определена степень генетической гетерогенности заболевания. На сегодняшний день известно 20 генов, вовлеченных в патогенез НО, и исследователи разных стран продолжают искать новые гены. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-сцепленные мутации в широком спектре генов, кодирующих белки, которые участвуют в синтезе коллагена I типа, его процессинге, секреции и посттрансляционной модификации, а также в белках, которые регулируют дифференцировку и активность костеобразующих клеток, вызывают НО. Мутации в гене IFITM5, также называемом BRIL (bone-restricted IFITM-like protein), участвующем в формировании остеобластов, приводят к развитию НО типа V. До 5% пациентов имеют НО типа V, который характеризуется образованием гиперпластического каллуса после переломов, кальцификацией межкостной мембраны предплечья и сетчатым рисунком ламелирования, наблюдаемого при гистологическом исследовании кости. В 2012 г. гетерозиготная мутация (c.-14C> T) в 5’-нетранслируемой области (UTR) гена IFITM5 была идентифицирована как основная причина НО V типа. В представленной работе проведен анализ гена IFITM5 и идентифицирована мутация c.-14C>T, возникшая de novo, у одного пациента с НО, которому впоследствии был установлен V тип заболевания. Также выявлены три известных полиморфных варианта: rs57285449; c.80G>C (p.Gly27Ala) и rs2293745; c.187-45C>T и rs755971385 c.279G>A (p.Thr93=) и один ранее не описанный вариант: c.128G>A (p.Ser43Asn) AGC>AAC (S/D), которые не являются патогенными. В статье уделяется внимание особенностям клинических проявлений НО V типа и рекомендуется определение мутации c.-14C>T в гене IFITM5 при подозрении на данную форму заболевания. A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

Cerebellotrigeminal Dermal Dysplasia (Gómez-López-Hernández Syndrome)

2018 ◽  
Vol 16 (05) ◽  
pp. 362-368 ◽  
Author(s):  
Federica Sullo ◽  
Agata Polizzi ◽  
Stefano Catanzaro ◽  
Selene Mantegna ◽  
Francesco Lacarrubba ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Number Of Patients ◽  
Wide Range ◽  
Visual Problems ◽  
Neurodevelopmental Abnormalities ◽  
Clinical Triad ◽  
High Degree ◽  
Motor Handicap

Cerebellotrigeminal dermal (CTD) dysplasia is a rare neurocutaneous disorder characterized by a triad of symptoms: bilateral parieto-occipital alopecia, facial anesthesia in the trigeminal area, and rhombencephalosynapsis (RES), confirmed by cranial magnetic resonance imaging. CTD dysplasia is also known as Gómez-López-Hernández syndrome. So far, only 35 cases have been described with varying symptomatology. The etiology remains unknown. Either spontaneous dominant mutations or de novo chromosomal rearrangements have been proposed as possible explanations. In addition to its clinical triad of RES, parietal alopecia, and trigeminal anesthesia, CTD dysplasia is associated with a wide range of phenotypic and neurodevelopmental abnormalities.Treatment is symptomatic and includes physical rehabilitation, special education, dental care, and ocular protection against self-induced corneal trauma that causes ulcers and, later, corneal opacification. The prognosis is correlated to the mental development, motor handicap, corneal–facial anesthesia, and visual problems. Follow-up on a large number of patients with CTD dysplasia has never been reported and experience is limited to few cases to date. High degree of suspicion in a child presenting with characteristic alopecia and RES has a great importance in diagnosis of this syndrome.

scholarly journals R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

2021 ◽  
pp. 123-130
Author(s):  
Anker Stubberud ◽  
Emer O’Connor ◽  
Erling Tronvik ◽  
Henry Houlden ◽  
Manjit Matharu
Keyword(s):  
Mental Retardation ◽  
Case Report ◽  
Genetic Testing ◽  
Head Trauma ◽  
Cerebral Oedema ◽  
De Novo ◽  
Minor Head Trauma ◽  
Hemiplegic Migraine ◽  
Wide Range ◽  
History Of

Mutations in the <i>CACNA1A</i> gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the <i>CACNA1A</i> gene (c.4055G&#x3e;A, p.R1352Q). The R1352Q <i>CACNA1A</i> variant shares the phenotype with other described <i>CACNA1A</i> mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

scholarly journals Discovery of novel community-relevant small proteins in a simplified human intestinal microbiome

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Hannes Petruschke ◽  
Christian Schori ◽  
Sebastian Canzler ◽  
Sarah Riesbeck ◽  
Anja Poehlein ◽  
...  
Keyword(s):  
Microbial Communities ◽  
Intestinal Microbiota ◽  
De Novo ◽  
Bacterial Species ◽  
Intestinal Microbiome ◽  
Single Strain ◽  
Small Proteins ◽  
Human Intestinal Microbiota ◽  
Wide Range

Abstract Background The intestinal microbiota plays a crucial role in protecting the host from pathogenic microbes, modulating immunity and regulating metabolic processes. We studied the simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species with a particular focus on the discovery of novel small proteins with less than 100 amino acids (= sProteins), some of which may contribute to shape the simplified human intestinal microbiota. Although sProteins carry out a wide range of important functions, they are still often missed in genome annotations, and little is known about their structure and function in individual microbes and especially in microbial communities. Results We created a multi-species integrated proteogenomics search database (iPtgxDB) to enable a comprehensive identification of novel sProteins. Six of the eight SIHUMIx species, for which no complete genomes were available, were sequenced and de novo assembled. Several proteomics approaches including two earlier optimized sProtein enrichment strategies were applied to specifically increase the chances for novel sProtein discovery. The search of tandem mass spectrometry (MS/MS) data against the multi-species iPtgxDB enabled the identification of 31 novel sProteins, of which the expression of 30 was supported by metatranscriptomics data. Using synthetic peptides, we were able to validate the expression of 25 novel sProteins. The comparison of sProtein expression in each single strain versus a multi-species community cultivation showed that six of these sProteins were only identified in the SIHUMIx community indicating a potentially important role of sProteins in the organization of microbial communities. Two of these novel sProteins have a potential antimicrobial function. Metabolic modelling revealed that a third sProtein is located in a genomic region encoding several enzymes relevant for the community metabolism within SIHUMIx. Conclusions We outline an integrated experimental and bioinformatics workflow for the discovery of novel sProteins in a simplified intestinal model system that can be generically applied to other microbial communities. The further analysis of novel sProteins uniquely expressed in the SIHUMIx multi-species community is expected to enable new insights into the role of sProteins on the functionality of bacterial communities such as those of the human intestinal tract.

scholarly journals Genome-wide integration site detection using Cas9 enriched amplification-free long-range sequencing

2020 ◽  
Author(s):  
Joost van Haasteren ◽  
Altar M Munis ◽  
Deborah R Gill ◽  
Stephen C Hyde
Keyword(s):  
Long Range ◽  
Insertional Mutagenesis ◽  
Lentiviral Vector ◽  
Integration Site ◽  
Low Cost ◽  
Safety Evaluation ◽  
Read Length ◽  
Chromosomal Dna ◽  
Wide Range

Abstract The gene and cell therapy fields are advancing rapidly, with a potential to treat and cure a wide range of diseases, and lentivirus-based gene transfer agents are the vector of choice for many investigators. Early cases of insertional mutagenesis caused by gammaretroviral vectors highlighted that integration site (IS) analysis was a major safety and quality control checkpoint for lentiviral applications. The methods established to detect lentiviral integrations using next-generation sequencing (NGS) are limited by short read length, inadvertent PCR bias, low yield, or lengthy protocols. Here, we describe a new method to sequence IS using Amplification-free Integration Site sequencing (AFIS-Seq). AFIS-Seq is based on amplification-free, Cas9-mediated enrichment of high-molecular-weight chromosomal DNA suitable for long-range Nanopore MinION sequencing. This accessible and low-cost approach generates long reads enabling IS mapping with high certainty within a single day. We demonstrate proof-of-concept by mapping IS of lentiviral vectors in a variety of cell models and report up to 1600-fold enrichment of the signal. This method can be further extended to sequencing of Cas9-mediated integration of genes and to in vivo analysis of IS. AFIS-Seq uses long-read sequencing to facilitate safety evaluation of preclinical lentiviral vector gene therapies by providing IS analysis with improved confidence.

Gearbox (China) Ltd.: Will the Company's ERP System Support its Ambitious Growth Strategy?

2004 ◽  
Vol 19 (2) ◽  
pp. 140-148 ◽  
Author(s):  
Kai Reimers
Keyword(s):  
Operations Management ◽  
Emerging Market ◽  
Growth Strategy ◽  
Medium Size ◽  
Cultural Issues ◽  
Erp System ◽  
Organizational Behaviour ◽  
Main Challenge ◽  
Wide Range ◽  
Mechanical Devices

This case describes the experience of a wholly foreign-owned manufacturing company in Tianjin/China regarding the use of its ERP system in its main functional departments, purchasing, production planning, sales/distribution, and finance. The company is part of a group which is a global leader in the manufacturing and distribution of mechanical devices, called gearboxes, that are needed to drive a wide range of facilities such as escalators and baggage conveyor belts in airports. It has entered China in 1995 and the Tianjin manufacturing facility has soon become a hub for the Asian market. The main challenge confronting the management team is to support the breakneck growth rate of this young company. The company's ERP system plays a crucial role in this task. However, it seems that middle managers are frequently hitting an invisible wall when trying to expand the use of the ERP system in order to cope with ever-increasing workloads and coordination tasks. This case serves to illustrate cultural issues implicated in the use of an enterprise wide information system in a medium size company operating in an emerging market economy. In addition, issues of operations management, global management, and organizational behaviour are addressed.

A New Type of Gas Turbine Based-Hybrid Propulsion System: Part 1—Concept Development, Definition of Mission Parameters and Preliminary Sizing

2000 ◽  
Author(s):  
Emiliano Cioffarelli ◽  
Enrico Sciubba
Keyword(s):  
Gas Turbine ◽  
Combustion Engine ◽  
Development Program ◽  
Propulsion System ◽  
Medium Size ◽  
Passenger Cars ◽  
Worst Case ◽  
Hybrid Propulsion ◽  
Wide Range ◽  
Definition Of

Abstract A hybrid propulsion system of new conception for medium-size passenger cars is described and its preliminary design developed. The system consists of a turbogas set operating at fixed rpm, and a battery-operated electric motor that constitutes the actual “propulsor”. The battery pack is charged by the thermal engine which works in an electronically controlled on/off mode. Though the idea is not entirely new (there are some concept cars with similar characteristics), the present study has important new aspects, in that it bases the sizing of the thermal engine on the foreseen “worst case” vehicle mission (derived from available data on mileage and consumption derived from road tests and standard EEC driving mission cycles) that they can in fact be accomplished, and then proceeds to develop a control strategy that enables the vehicle to perform at its near–peak efficiency over a wide range of possible missions. To increase the driveability of the car, a variable-inlet vane system is provided for the gas turbine. After developing the mission concept, and showing via a thorough set of energy balances (integrated over various mission profiles), a preliminary sizing of the turbogas set is performed. The results of this first part of the development program show that the concept is indeed feasible, and that it has important advantages over both more traditional (Hybrid Vehicles powered by an Internal Combustion Engine) and novel (All-Electric Vehicle) propulsion systems.

Memories of Tiananmen

2021 ◽  
Author(s):  
Francis Lee ◽  
Joseph Man Chan
Keyword(s):  
Hong Kong ◽  
Collective Memory ◽  
Digital Media ◽  
Political Communication ◽  
Civil Liberties ◽  
Significant Degree ◽  
Historical Period ◽  
Multiple Sources ◽  
News Reports ◽  
Wide Range

This book analyzes how collective memory regarding the 1989 Beijing student movement and the Tiananmen crackdown was produced, contested, sustained, and transformed in Hong Kong between 1989 and 2019. Drawing on data gathered through multiple sources such as news reports, digital media content, vigil onsite surveys, population surveys, and in-depth interviews with activists, rally participants, and other stakeholders, it identifies six key processes in the dynamics of social remembering: memory formation, memory mobilization, memory institutionalization, intergenerational transfer, memory repair, and memory balkanization. Memories of Tiananmen demonstrates how a socially dominant collective memory, even one the state finds politically irritable, can be generated and maintained through constant negotiation and efforts by a wide range of actors. While the book mainly focuses on the interplay between political changes and Tiananmen commemoration in the historical period within which the society enjoyed a significant degree of civil liberties, it also discusses how the trajectory of the collective memory may take a drastic turn as Hong Kong's autonomy is abridged. The book promises to be a key reference for anyone interested in collective memory studies, social movement research, political communication, and China and Hong Kong studies.

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