381 research outputs found
Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis
© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained
synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and
perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil
and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease
duration and before treatment (VERA).
Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and
established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF)
from RA and osteoarthritis (OA) patients was also analyzed.
Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as
well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In
established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led
to clinical improvement but without an impact on the cytokine pattern.
Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and
neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest
that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and
SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award
Predictability of evolutionary trajectories in fitness landscapes
Experimental studies on enzyme evolution show that only a small fraction of
all possible mutation trajectories are accessible to evolution. However, these
experiments deal with individual enzymes and explore a tiny part of the fitness
landscape. We report an exhaustive analysis of fitness landscapes constructed
with an off-lattice model of protein folding where fitness is equated with
robustness to misfolding. This model mimics the essential features of the
interactions between amino acids, is consistent with the key paradigms of
protein folding and reproduces the universal distribution of evolutionary rates
among orthologous proteins. We introduce mean path divergence as a quantitative
measure of the degree to which the starting and ending points determine the
path of evolution in fitness landscapes. Global measures of landscape roughness
are good predictors of path divergence in all studied landscapes: the mean path
divergence is greater in smooth landscapes than in rough ones. The
model-derived and experimental landscapes are significantly smoother than
random landscapes and resemble additive landscapes perturbed with moderate
amounts of noise; thus, these landscapes are substantially robust to mutation.
The model landscapes show a deficit of suboptimal peaks even compared with
noisy additive landscapes with similar overall roughness. We suggest that
smoothness and the substantial deficit of peaks in the fitness landscapes of
protein evolution are fundamental consequences of the physics of protein
folding.Comment: 14 pages, 7 figure
Worldwide Incidence of Malaria in 2009: Estimates, Time Trends, and a Critique of Methods
Richard Cibulskis and colleagues present estimates of the worldwide incidence of malaria in 2009, together with a critique of different estimation methods, including those based on risk maps constructed from surveys of parasite prevalence, and those based on routine case reports compiled by health ministries
The cdh1 c.1901c>t variant: A founder variant in the portuguese population with severe impact in mrna splicing
Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.This research and its authors were funded by FEDER—Fundo Europeu de Desenvolvi-mento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274) and LEGOH (PTDC/BTM-TEC/6706/2020). This work was also financed by the projects NORTE-01-0145-FEDER-000003 (DOCnet)—supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)—project POCI-01-0145-FEDER-016390 (CancelStem) and PTDC/BTM-TEC/30164/2017 (3DChroMe), funded by ERDF, POCI, and FCT
Analysis of quality raw data of second generation sequencers with Quality Assessment Software
<p>Abstract</p> <p>Background</p> <p>Second generation technologies have advantages over Sanger; however, they have resulted in new challenges for the genome construction process, especially because of the small size of the reads, despite the high degree of coverage. Independent of the program chosen for the construction process, DNA sequences are superimposed, based on identity, to extend the reads, generating contigs; mismatches indicate a lack of homology and are not included. This process improves our confidence in the sequences that are generated.</p> <p>Findings</p> <p>We developed Quality Assessment Software, with which one can review graphs showing the distribution of quality values from the sequencing reads. This software allow us to adopt more stringent quality standards for sequence data, based on quality-graph analysis and estimated coverage after applying the quality filter, providing acceptable sequence coverage for genome construction from short reads.</p> <p>Conclusions</p> <p>Quality filtering is a fundamental step in the process of constructing genomes, as it reduces the frequency of incorrect alignments that are caused by measuring errors, which can occur during the construction process due to the size of the reads, provoking misassemblies. Application of quality filters to sequence data, using the software Quality Assessment, along with graphing analyses, provided greater precision in the definition of cutoff parameters, which increased the accuracy of genome construction.</p
Clinical, demographic, and epidemiologic characteristics of hepatitis B virus-infected patients at a tertiary public hospital in Presidente Prudente, State of São Paulo, Brazil
MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer
Two common mutations, 677 C→T and a1298 A→C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients with a diagnosis of GC, in 37 with a history of GC in first-degree relatives (GC-relatives), and in 454 blood donors. Helicobacter pylori (HP) infection was also determined. An increased risk was found for 677TT in GC patients with respect to blood donors (odds ratio (OR) = 1.98), and statistical significance was sustained when we compared sex–age-matched GC patients and donors (OR = 2.37). The 677TT genotype association with GC was found in women (OR = 3.10), while a reduction in the 667C allele frequency was present in both the sex. No statistically significant association was detected when 677–1298 genotype was stratified by sex and age. Men of GC-relatives showed a higher 1298C allele frequency than donors (OR = 4.38). Between GC and GC-relatives, HP infection frequency was similar. In conclusion, overall findings support the hypothesis that folate plays a role in GC risk. GC-relatives evidence a similar 677TT frequency to that found in the general population
Online dispute resolution: an artificial intelligence perspective
Litigation in court is still the main dispute resolution mode. However, given the amount
and characteristics of the new disputes, mostly arising out of electronic contracting, courts are
becoming slower and outdated. Online Dispute Resolution (ODR) recently emerged as a set of
tools and techniques, supported by technology, aimed at facilitating conflict resolution. In this
paper we present a critical evaluation on the use of Artificial Intelligence (AI) based techniques in
ODR. In order to fulfill this goal, we analyze a set of commercial providers (in this case twenty
four) and some research projects (in this circumstance six). Supported by the results so far
achieved, a new approach to deal with the problem of ODR is proposed, in which we take on some
of the problems identified in the current state of the art in linking ODR and AI.The work described in this paper is included in TIARAC - Telematics and
Artificial Intelligence in Alternative Conflict Resolution Project (PTDC/JUR/71354/2006), which
is a research project supported by FCT (Science & Technology Foundation), Portugal. The work
of Davide Carneiro is also supported by a doctoral grant by FCT (SFRH/BD/64890/2009).Acknowledgments. The work described in this paper is included in TIARAC - Telematics and Artificial Intelligence in Alternative Conflict Resolution Project (PTDC/JUR/71354/2006), which is a research project supported by FCT (Science & Technology Foundation), Portugal. The work of Davide Carneiro is also supported by a doctoral grant by FCT (SFRH/BD/64890/2009)
Effects of carbon dioxide pneumoperitoneum on hepatic and renal morphology of rats after segmental colectomy and colonic anastomosis
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