35,319 research outputs found
T Cell responses to whole SARS Coronavirus in humans
No full textEffective vaccines should confer long-term protection against future outbreaks of severe acute respiratory syndrome (SARS) caused by a novel zoonotic coronavirus (SARS-CoV) with unknown animal reservoirs. We conducted a cohort study examining multiple parameters of immune responses to SARS-CoV infection, aiming to identify the immune correlates of protection. We used a matrix of overlapping peptides spanning whole SARS-CoV proteome to determine T cell responses from 128 SARS convalescent samples by ex vivo IFN-γ ELISPOT assays. Approximately 50% of convalescent SARS patients were positive for T cell responses, and 90% possessed strongly neutralizing Abs. Fifty-five novel T cell epitopes were identified, with spike protein dominating total T cell responses. CD8+ T cell responses were more frequent and of a greater magnitude than CD4+ T cell responses (p < 0.001).
Polychromatic cytometry analysis indicated that the virus-specific T cells from the severe group tended to be a central memory phenotype (CD27+/CD45RO+) with a significantly higher frequency of polyfunctional CD4+ T cells producing IFN-γ, TNF-α, and IL-2, and CD8+ T cells producing IFN-γ, TNF-α, and CD107a (degranulation), as compared with the mild-moderate group. Strong T cell responses correlated significantly (p < 0.05) with higher neutralizing Ab. The serum cytokine profile during acute infection indicated a significant elevation of innate immune responses. Increased Th2 cytokines were observed in patients with fatal infection. Our study provides a roadmap for the immunogenicity of SARS-CoV and types of immune responses that may be responsible for the virus clearance, and should serve as a benchmark for SARS-CoV vaccine design and evaluation
An unusual dark macular lesion in the plantar region of a child
No full textUniv Estadual Paulista, Fac Med, Botucatu, SP, BrazilPhoto Nat, Bonito, MS, BrazilUniv Estadual Paulista, Fac Med, Botucatu, SP, Brazi
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
No full textElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets
Pharmacogenetics of ophthalmic topical β-blockers
No full textGlaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical β-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical β-blockers. This review summarizes clinically significant polymorphisms that have been identified in the β-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical β-blockers may advance individualized treatment at a lower cost
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
No full textUsing the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
Severe chronic neck injury caused by a snare in a Coyote, Canis latrans
No full textA two-year-old male Coyote, Canis latrans, in poor body condition was found in a moribund state with a snare deeply embedded in the ventral portion of its neck, more than a month after the official end of the trapping season on Prince Edward Island. This snare had presumably malfunctioned, and the cable had cut through the soft tissues of the neck as well as the trachea and had obstructed both jugular veins and both common carotid arteries but had largely spared both vagosympathetic trunks. Cases like this illustrate the need to continue to work on improving the efficiency of trapping methods, through research and trapper education.PT: J; CR: *DEP FOR AFF INT T, 1997, AGR INT HUM TRAPP ST, P31 ANDREWS PLR, 1992, NEUROANATOMY PHYSL A, P280 BENZ GW, 2001, CAN FIELD NAT, V115, P506 BODDICKER ML, 1982, P VERT PEST C, V10, P50 ESLER M, 1992, CLIN AUTON RES, V2, P133 EVANS HE, 1993, MILLERS ANATOMY DOG, P219 GUTHERY FS, 1978, J WILDLIFE MANAGE, V42, P457 GUYTON AC, 1996, TXB MED PHYSL, P107 PHILLIPS RL, 1996, WILDLIFE SOC B, V24, P107 PROULX G, 1990, WILDLIFE SOC B, V18, P27 PROULX G, 1991, N AM WILDLIFE NATURA, V56, P387 SCOTT DW, 2001, MULLER KIRKS SMALL A, P1 WHISNANT JP, 1956, AM J PHYSIOL, V186, P275; NR: 13; TC: 0; J9: CAN FIELD-NATUR; PG: 4; GA: 927NLSource type: Electronic(1
Ny tid
No full textVi har nå lagt bak oss det vanskelige året 2020, og vi går – forhåpentligvis – inn i en mer normal tid. Noen arbeidsmåter som ble endret under pandemien, tar vi med oss videre. Et eksempel er at mange møter og konferanser nå vil skje digitalt eller hybrid. NAT er intet unntak, og redaksjonen hadde det første digitale møte våren 2021. Det vil redaksjonen fortsette med i form av digitale redaksjonsmøter hvert halvår.
Et tema som redaksjonen diskuterte, var hvilke språk NAT skal publisere sine artikler på. De fleste skandinaver kan lese og forstå andre skandinaviske språk. Norden er i dag ikke et språkfellesskap. Svensk var forholdsvis utbredt i Finland tidligere, og på Island og Færøyene er det vanlig å kunne et skandinavisk språk i tillegg til morsmålet. NAT vil fortsatt først og fremst publisere på de skandinaviske språkene dansk, norsk og svensk for forfattere som bruker disse språkene. For forfattere som ikke bruker dansk, norsk eller svensk, vil NAT kunne publisere deres artikler på engelsk.
Vi oppfordrer NAFs medlemsforeninger og NATs lesere til å vurdere aktuelle foredrag, notater og vitenskapelige rapporter som manuskripter til NAT. Vi minner om at NAT publiserer ulike typer artikler. Vi tror for eksempel mange flere bokomtaler, foredrag, utredningsrapporter og fremragende studentarbeider fra mange av våre masterstudenter, også bør bli spennende artikler i NAT.
Redaksjonen takker Justitieråd Ulrik von Essen ved Högsta förvaltningsdomstolen for hans bidrag i redaksjonen i NAT inntil ny svensk landredaktør ble utnevnt, og vi ønsker biträdande lektor Marta Reuter fra Statsvetenskapliga institutionen ved Stockholms universitet hjertelig velkommen som ny, svensk landredaktør. Takk til alle som har bidratt ved å sende sine manuskripter til tidsskriftet og til våre anonyme konsulenter for deres vurderinger. Takk også til Eirik Hanssen ved OsloMet for støtten ved omleggingen av NAT til ny portal i fjor og teknisk støtte ved utgivelsen av dette nummeret.
Vi ønsker alle god lesning og god sommer!
Åge Johnsen
Hovedredaktø
Ny tid
No full textVi har nå lagt bak oss det vanskelige året 2020, og vi går – forhåpentligvis – inn i en mer normal tid. Noen arbeidsmåter som ble endret under pandemien, tar vi med oss videre. Et eksempel er at mange møter og konferanser nå vil skje digitalt eller hybrid. NAT er intet unntak, og redaksjonen hadde det første digitale møte våren 2021. Det vil redaksjonen fortsette med i form av digitale redaksjonsmøter hvert halvår.
Et tema som redaksjonen diskuterte, var hvilke språk NAT skal publisere sine artikler på. De fleste skandinaver kan lese og forstå andre skandinaviske språk. Norden er i dag ikke et språkfellesskap. Svensk var forholdsvis utbredt i Finland tidligere, og på Island og Færøyene er det vanlig å kunne et skandinavisk språk i tillegg til morsmålet. NAT vil fortsatt først og fremst publisere på de skandinaviske språkene dansk, norsk og svensk for forfattere som bruker disse språkene. For forfattere som ikke bruker dansk, norsk eller svensk, vil NAT kunne publisere deres artikler på engelsk.
Vi oppfordrer NAFs medlemsforeninger og NATs lesere til å vurdere aktuelle foredrag, notater og vitenskapelige rapporter som manuskripter til NAT. Vi minner om at NAT publiserer ulike typer artikler. Vi tror for eksempel mange flere bokomtaler, foredrag, utredningsrapporter og fremragende studentarbeider fra mange av våre masterstudenter, også bør bli spennende artikler i NAT.
Redaksjonen takker Justitieråd Ulrik von Essen ved Högsta förvaltningsdomstolen for hans bidrag i redaksjonen i NAT inntil ny svensk landredaktør ble utnevnt, og vi ønsker biträdande lektor Marta Reuter fra Statsvetenskapliga institutionen ved Stockholms universitet hjertelig velkommen som ny, svensk landredaktør. Takk til alle som har bidratt ved å sende sine manuskripter til tidsskriftet og til våre anonyme konsulenter for deres vurderinger. Takk også til Eirik Hanssen ved OsloMet for støtten ved omleggingen av NAT til ny portal i fjor og teknisk støtte ved utgivelsen av dette nummeret.
Vi ønsker alle god lesning og god sommer!
Åge Johnsen
Hovedredaktø
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
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