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A genome wide approach to identify genetic variants associated with left ventricular mass
Full text linkLeft ventricular mass (LVM) is an important clinical phenotype, whose assessment
can predict adverse cardiovascular events and premature death in all genders,
races, and ages. Increase in LVM defines left ventricular hypertrophy (LVH) with
the thickening of the left ventricle of the heart. In community-based cohorts, the
presence of left ventricular hypertrophy (LVH) and increased LVM predict the
development of coronary heart disease, congestive heart failure, stroke, and
cardiovascular disease. Thus this trait serves not only as measures of cardiac
structure, but also as intermediate phenotype for clinical cardiovascular disease
outcome. Several studies have indicated that LVM is influenced by genetic factors.
Genome wide linkage and association studies in diverse population have been
performed to identify genes influencing LVM, but much of the heritability remains
unexplained, the identity of the underlying gene pathways and functional variants
remain unknown, and the promise of genetically based risk prediction remains
unfulfilled.
The aim of the study was to investigate the association of common genetic variants
with left ventricular mass using a genome wide approach in a large cohort of never
treated mild-to-moderate essential hypertensive subjects. From the linear analysis,
we selected 85 single nucleotide polymorphisms (SNPs), with a suggestive p-value
of association with LVM (≤ 10-5). In particular, some SNPs lying in genes
previously described as having a role in the pathogenesis of cardiac hypertrophy,
such as ROCK1, IGF1, CACNA1D, FGFR1, TRAF5, SOX5, and KSR2. Each of
them might play a putative role in determining the LVM phenotype as well as other
pathophysiological pathways directly or indirectly linked to cardiac pathophysiology.
To assess the risk alleles associated to the most interesting findings in relation to
the phenotype studied, we performed a case-control analysis by dividing our
sample in two subsets according to LVM values. Most of the SNPs associated with
LVM in linear regression presented a significant association, showing that the
carriers of the risk alleles have an odds ratio higher than 1 to have increased LVM,
i.e. to be cases respect to controls. Nevertheless as for most of the complex traits,
the observed odds ratios are modest (except for those biased by the absence of
homozygous risk genotypes), so their relevance for a clinical use is uncertain.
Thus, we defined a weighted genetic risk score using the effect size of the risk
allele (beta value of the linear regression analysis) to account for the strength of
the genetic association with each allele. The possibility to combine more variants in
a global genetic risk score could be interesting and could add relevance to the
results.
In conclusion, our GWAS allowed us to pinpoint genes whose role in heart function
and/or cardiac hypertrophy has been demonstrated in previously publications by
different authors. Moreover, we highlighted the usefulness of an aggregate
measure of risk of LVH to discriminate high-risk subjects. However, the results
must be interpreted within the context of some potential limitations and
perspectives. No SNPs reached a Bonferroni’s significance level probably due to a
limited sample size. However, the phenotypic homogeneity of our cohort and the
absence of previous antihypertensive treatment are prerequisites for the
identification of true genetic effects. A replication in independent cohorts is needed
VII
to further confirm the findings; however an independent cohort with similar criteria
was not available for replication. Moreover, it often happens, as in our study, the
significant SNPs map in non-coding regions, making it difficult to explain their
causative role. These limitations should not reduce the relevance of the genes
identified and confirmed by previously published papers.
Future perspectives of this study should be the replication of the GWAS findings in
independent cohorts and the assessment in independent samples of the prediction
ability of wGRS to correctly classify true positives and true negatives according to
their genetic background
Importanza del mappaggio genetico fine per la definizione farmacogenomica : esempio dell'ACE e risposta a LOSARTAN
No full textRAZIONALE. L'allele D del gene ACE è associato a maggior rischio cardio-renale. I dati sono controversi per la risposta alla terapia antiipertensiva.
Abbiamo eseguito uno studio farmacogenomico tra locus ACE e risposta a Losartan in ipertesi naïve (EH), mai trattati prima, per evitare ogni effetto carry-over.
CASISTICA E METODI. Analisi della struttura di linkage disequilibrium (LD) di ACE per individuare SNPs tagging I/D, su 1013 soggetti etnicamente omogenei, caratterizzati anche per I/D. Gli SNP rs4341, rs4342, rs1987692 sono in LD assoluto con I/D, quindi tag.
Farmacogenomica: 388 EH caucasici, genotipizzati con ILLUMINA 1MDuo. Imputazione con aplotipi CEU 1000Genomes.
Fenotipo: caduta pressoria sistolica dopo 4 settimane di terapia con Losartan (ΔSBP), analizzata con regressione lineare, modello additivo, correggendo per età, sesso ed etnia.
RISULTATI. I tre tag SNP sono significativamente associati a ΔSBP (p=3x10). Estendendo l'analisi a tutto il locus (400 kbp), abbiamo analizzato 110 SNP, notando un progressivo aumento di significatività
alla regione flanking-3’ del gene (rs4461142, p=5.86x10
-2
) a
circa 2.000 bp dal codone di stop di ACE, associato a una caduta
pressoria di 3.7 mmHg nei CC rispetto ai portatori dell’allele T. Il polimorfismo
è solo in debole LD con I/D (r
=0.6).
A conferma della specificità per Losartan, ripetendo lo stesso espe-
2
rimento in 180 EH trattati con placebo e 660 con idroclorotiazide,
-3
non è stato osservato nessun effetto attribuibile al genotipo (p=0.84
e p=0.97).
CONCLUSIONI. Nonostante siano passati più di 20 anni dalla prima
segnalazione, è probabile che il polimorfismo I/D non abbia un ruolo
funzionale ma che sia solo un proxy di altri non ancora identificati.
Questo studio di mappaggio fine punta alla regione flanking-3’ che
potrebbe essere connessa a un sito regolatore per il gene ACE, localizzata
a circa 6.000 bp dallo pseudogene
ACE3p
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
Ipotiroidismo congenito causato da una nuova mutazione omozigote del gene della tireoglobulina
No full textL’ipotiroidismo congenito dovuto a deficit di tireoglobulina (TG) è una malattia
autosomica recessiva con una prevalenza di 1:4000091:100000 nati vivi e
caratterizzata da gozzo, bassi livelli sierici di TG, elevati livelli di TSH con bassi
livelli di ormoni tiroidei e test al perclorato negativo. La TG umana, una
proteina di 2768 aminoacidi, è codificata da un grosso gene con 48 esoni
localizzato su cromosoma 8q24. Mutazioni del gene della TG sono associate a
gozzo congenito con ipotiroidismo o eutiroidismo. Ad oggi sono state descritte
e caratterizzate 50 mutazioni del gene della TG umana. Lo scopo del nostro
studio è stato quello di eseguire l’analisi del gene della TG in due sorelle nate
da genitori consanguinei affette da ipotiroidismo congenito. Le due sorelle
sono state identificate allo screening neonatale e trattate dopo la conferma di
ipotiroidismo con L9Tiroxina. Alla età di 7 anni, una sorella, dopo sospensione
della L9tiroxina presentava un franco ipotiroidismo, TG indosabile; alla
scintigrafia era presente una tiroide in sede con captazione del 12% dopo 24
ore; la ecografia dimostrava la presenza di una ghiandola in sede di normali
dimensioni. La seconda sorella, nonostante il precoce trattamento con L9
tiroxina, era anche affetta da ritardo mentale. La ecografia confermava la
presenza di una tiroide in sede di normali dimensioni, e la tireoglobulina era
indosabile. Il DNA genomico è stato estratto dal sangue delle pazienti e da
quello del padre, unico genitore in vita, utilizzando un kit commerciale. Tutti i
48 esoni che compongono il gene della TG sono stati amplificati per PCR,
sequenziati con BigDye Terminator Kit e analizzati su 3130xl genetic analyzer.
Nel sangue di entrambe le pazienti è stata identificata una mutazione
puntiforme omozigote a livello dell’esone 10 del gene della TG (CGA/TGA) che
determina la formazione di un codone di stop in posizione 768 (R768X). Il
risultato è quindi la presenza di una proteina precocemente troncata e quindi
non funzionante. Erano inoltre presenti varianti alleliche già descritte in
letteratura. In conclusione, abbiamo identificato due sorelle con ipotiroidismo
congenito e tiroide in sede di normali dimensioni e TG indosabile. L’analisi
genetica ha dimostrato una alterazione della Tireoglobulina come causa
dell’ipotiroidismo
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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