Alphavirus polymerase and RNA replication

Alphaviruses are typically arthropod-borne, and many are important pathogens such as chikungunya virus. Alphaviruses encode four nonstructural proteins (nsP1-4), initially produced as a polyprotein P1234. nsP4 is the core RNA-dependent RNA polymerase but all four nsPs are required for RNA synthesis. The early replication complex (RC) formed by the polyprotein P123 and nsP4 synthesizes minus RNA strands, and the late RC composed of fully processed nsP1-nsP4 is responsible for the production of genomic and subgenomic plus strands. Different parts of nsP4 recognize the promoters for minus and plus strands but the binding also requires the other nsPs. The alphavirus polymerase has been purified and is capable of de novo RNA synthesis only in the presence of the other nsPs. The purified nsP4 also has terminal adenylyltransferase activity, which may generate the poly(A) tail at the 3' end of the genome. Membrane association of the nsPs is vital for replication, and alphaviruses induce membrane invaginations called spherules, which form a microenvironment for RNA synthesis by concentrating replication components and protecting double-stranded RNA intermediates. The RCs isolated as crude membrane preparations are active in RNA synthesis in vitro, but high-resolution structure of the RC has not been achieved, and thus the arrangement of viral and possible host components remains unknown. For some alphaviruses, Ras-GTPase-activating protein (Src-homology 3 (SH3) domain)-binding proteins (G3BPs) and amphiphysins have been shown to be essential for RNA replication and are present in the RCs. Host factors offer an additional target for antivirals, as only few aiphavirus polymerase inhibitors have been described. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Lapsella on oikeus osallisuuteen - vammaisuudesta riippumatta

Vammaisilla lapsilla on lähtökohtaisesti samat tarpeet kuin muillakin lapsilla. Vammaisten lasten ihmisoikeuksien perustana ovat sekä lapsen oikeuksien sopimus että vammaissopimus. Lapsen mahdollisuus ilmaista itseään ja saada näkemyksensä huomioon otetuiksi ovat olennaisia edellytyksiä lapsen ihmisoikeuksien toteutumiselle. Kuitenkin siihen, miten ihmisoikeudet tosiasiallisesti lasten elämässä toteutuvat, vaikuttavat useat eri tekijät yhteiskunnassamme. Vammaisia lapsia on kohdeltava nimenomaan lapsina. Aikuisille, edes vammaisille aikuisille, tarkoitetut palvelut eivät läheskään aina ole heille sopivia. Toisaalta vammaiset lapset kuitenkin usein tarvitsevat yleisten lapsille tarkoitettujen palvelujen lisäksi erityispalveluja voidakseen elää normaalia elämää muiden lasten tavoin. Kirjoituksessa käsitellään vammaisten lasten oikeuksia YK:n lapsen oikeuksien sopimuksen, YK:n vammaisten henkilöiden oikeuksia koskevan sopimuksen ja Suomen lainsäädännön pohjalta

Värk och nedstämdhet : samförekomst av muskuloskeletal smärta och depressivitet i Finland

Rapporten omfattar en granskning av samförekomsten av muskuloskeletal smärta och depressivitet i samtliga åldersgrupper över 30 år samt en närmare analys av samförekomsten inom den yrkesverksamma befolkningen i åldern 30−64 år. Med muskuloskeletal smärta avses i denna undersökning förekomst av rygg-, nack-, axel-, armbågs-, handleds-, finger-, höft-, knä-, vrist- eller fotrelaterad smärta, värk eller rörelsesmärta under den senaste månaden. Med depressivitet avses i denna undersökning förekomst av aktuella depressionssymtom

Ache and Melancholy: Co-occurence of musculoskeletal pain and depressive symptoms in Finland

We analysed the co-occurence of musculoskeletal pain and depressive symptoms first in the entire Finnish population 30 years of age or older and then more closely among working people 30–64 years of age. In this study, musculoskeletal pain refers to pain, ache or motion-related soreness that occurred during the past month in the back, neck, shoulder, elbow, wrist, fi ngers, hip, knee, ankle or foot. Depressive symptoms cover mild, moderate and severe symptoms

Särkyä ja alakuloa – tuki- ja liikuntaelinten kivun ja masentuneisuuden yhteisesiintyvyys Suomessa

Raportin tavoitteena on kuvata väestössä yleisten terveysongelmien, tuki- ja liikuntaelinten kipuoireiden ja masentuneisuuden samanaikaisuutta. Raportin avulla halutaan myös saattaa lukijoiden tietoon tämän ilmiön merkityksen yksilön työkyvyn ja terveyspalveluiden käytön kannalta. Kirjoittajien tavoitteena on, että raportin tulosten avulla suomalaisessa terveydenhuollossa tehostettaisiin entisestään fyysisen vaivan hyvän hoitamisen lisäksi myös mielenterveyden ongelmien varhaisempaa huomioimista ja hoitoa

Vaikuttava työuupumusinterventio : Systemaattinen katsaus ja toimintaohjeita

Liiallinen työkuormitus voi johtaa työntekijän uupumiseen, joka lisää työkyvyttömyyden riskiä. Työuupumuksen käsittelemiseksi ei kuitenkaan ole luotu yhtenäistä käytäntöä työterveyshuoltoon ja työpaikoille. Kokosimme tiedon työuupumuksen lievittämiseksi toteutetuista interventiosta systemaattiseen katsaukseen ja arvioimme interventioiden vaikuttavuutta meta-analyysin avulla. Lisäksi kokosimme työuupumuksesta toipumista kartoittaneiden laadullisten tutkimusten antia. Tulosten perusteella työuupuneille suunnattuja arviointitutkimuksia oli tehty melko vähän. Arvioidut interventiot olivat suuntautuneet pääosin yksilön tukemiseen. Meta-analyysin perusteella yksilöön suuntautuva interventio ei kuitenkaan takaa oireiden lievittymistä. Laadimme laadullisten tutkimusten tulosten perusteella suosituksia siitä, miten työuupumuksesta toipumista voidaan edistää työterveyshuollon ja työpaikan toimin

Partially Uncleaved Alphavirus Replicase Forms Spherule Structures in the Presence and Absence of RNA Template

Alphaviruses are positive-strand RNA viruses expressing their replicase as a polyprotein, P1234, which is cleaved to four final products, nonstructural proteins nsP1 to nsP4. The replicase proteins together with viral RNA and host factors form membrane invaginations termed spherules, which act as the replication complexes producing progeny RNAs. We have previously shown that the wild-type alphavirus replicase requires a functional RNA template and active polymerase to generate spherule structures. However, we now find that specific partially processed forms of the replicase proteins alone can give rise to membrane invaginations in the absence of RNA or replication. The minimal requirement for spherule formation was the expression of properly cleaved nsP4, together with either uncleaved P123 or with the combination of nsP1 and uncleaved P23. These inactive spherules were morphologically less regular than replication-induced spherules. In the presence of template, nsP1 plus uncleaved P23 plus nsP4 could efficiently assemble active replication spherules producing both negative-sense and positive-sense RNA strands. P23 alone did not have membrane affinity, but could be recruited to membrane sites in the presence of nsP1 and nsP4. These results define the set of viral components required for alphavirus replication complex assembly and suggest the possibility that it could be reconstituted from separately expressed nonstructural proteins. IMPORTANCE All positive-strand RNA viruses extensively modify host cell membranes to serve as efficient platforms for viral RNA replication. Alphaviruses and several other groups induce protective membrane invaginations (spherules) as their genome factories. Most positive-strand viruses produce their replicase as a polyprotein precursor, which is further processed through precise and regulated cleavages. We show here that specific cleavage intermediates of the alphavirus replicase can give rise to spherule structures in the absence of viral RNA. In the presence of template RNA, the same intermediates yield active replication complexes. Thus, partially cleaved replicase proteins play key roles that connect replication complex assembly, membrane deformation, and the different stages of RNA synthesis.Peer reviewe

Periodontitis in early and chronic rheumatoid arthritis : a prospective follow-up study in Finnish population

Objectives To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Design Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16months later. Controls were examined once. Settings and participants The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) na1ve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Outcome measures Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Results Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth 4mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Conclusions Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters.Peer reviewe