Cândida G. Silva

Classification of Systemic Lupus Erythematosus: Systemic Lupus International Collaborating Clinics Versus American College of Rheumatology Criteria. A Comparative Study of 2,055 Patients From a Real-Life, International Systemic Lupus Erythematosus Cohort.

The new Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria aimed to improve the performance of systemic lupus erythematosus (SLE) classification over the American College of Rheumatology (ACR) 1997 criteria. However, the SLICC 2012 criteria need further external validation. Our objective was to compare the sensitivity for SLE classification between the ACR 1997 and the SLICC 2012 criteria sets in a real‐life, multicenter, international SLE population.

Mining approximate motifs in time series

The problem of discovering previously unknown frequent patterns in time series, also called motifs, has been recently introduced. A motif is a subseries pattern that appears a significant number of times. Results demonstrate that motifs may provide valuable insights about the data and have a wide range of applications in data mining tasks. The main motivation for this study was the need to mine time series data from protein folding/unfolding simulations. We propose an algorithm that extracts approximate motifs, i.e. motifs that capture portions of time series with a similar and eventually symmetric behavior. Preliminary results on the analysis of protein unfolding data support this proposal as a valuable tool. Additional experiments demonstrate that the application of utility of our algorithm is not limited to this particular problem. Rather it can be an interesting tool to be applied in many real world problems.

Differential male and female adrenal cortical steroid hormone and cortisol responses to interleukin-6 in humans

Abstract: Evidence from experimental animal studies show that sex hormones influence the glucocorticoid response to a variety of inflammatory and noninflammatory stimuli. In this study we assessed gender differences in the response of ACTH and cortisol in normal young male and female humans following intravenous infusion of human IL‐6 in various dosages. Males presented a significantly stronger ACTH production in response to IL‐6 than females. Peak cortisol response, however, was similar in males and females. Cortisol/ACTH ratios were significantly higher in females than in males, both at baseline and after each of the IL‐6 dosages. These results suggest that an effective glucocorticoid response requires similar levels of IL‐6 in males and females. However, they also suggest that the adrenals of males and females have different sensitivities to ACTH (higher in females) and possibly also to direct IL‐6 stimulation.

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimers, Huntingtons and Creutzfeldt‐Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT‐TTR and L55P‐TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P‐TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α‐helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation‐prone conformations characterized by full displacement of strands C and D from the main β‐sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H‐bond network and consequent destabilization of the CBEF β‐sheet of the β‐sandwich; (v) WT forms aggregation‐compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P‐TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.

Detection of hydrophobic clusters in molecular dynamics protein unfolding simulations using association rules

One way of exploring protein unfolding events associated with the development of Amyloid diseases is through the use of multiple Molecular Dynamics Protein Unfolding Simulations. The analysis of the huge amount of data generated in these simulations is not a trivial task. In the present report, we demonstrate the use of Association Rules applied to the analysis of the variation profiles of the Solvent Accessible Surface Area of the 127 amino-acid residues of the protein Transthyretin, along multiple simulations. This allowed us to identify a set of 28 hydrophobic residues forming a hydrophobic cluster that might be essential in the unfolding and folding processes of Transthyretin.

TRAF1/C5 but Not PTPRC Variants Are Potential Predictors of Rheumatoid Arthritis Response to Anti-Tumor Necrosis Factor Therapy

Background. The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. Methods. We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. Results. No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. Conclusion. This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

P-found: Grid-enabling distributed repositories of protein folding and unfolding simulations for data mining

The P-found protein folding and unfolding simulation repository is designed to allow scientists to perform data mining and other analyses across large, distributed simulation data sets. There are two storage components in P-found: a primary repository of simulation data that is used to populate the second component, and a data warehouse that contains important molecular properties. These properties may be used for data mining studies. Here we demonstrate how grid technologies can support multiple, distributed P-found installations. In particular, we look at two aspects: firstly, how grid data management technologies can be used to access the distributed data warehouses; and secondly, how the grid can be used to transfer analysis programs to the primary repositories - this is an important and challenging aspect of P-found, due to the large data volumes involved and the desire of scientists to maintain control of their own data. The grid technologies we are developing with the P-found system will allow new large data sets of protein folding simulations to be accessed and analysed in novel ways, with significant potential for enabling scientific discovery.

Predictors of damage progression in Portuguese patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have a longer life expectancy. The occurrence of irreversible damage has become a major concern. The present study assessed damage progression in patients with SLE over a 2‐year period and identified baseline features associated with damage accrual. Two hundred and twenty‐one patients that fulfilled criteria for SLE and had a follow‐up longer than 6 months were enrolled. Demographic, clinical, and immunological data were collected at baseline. Accumulated organ damage was scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Patients were prospectively followed and SDI assessment repeated at 2 years. At baseline 72 patients (33%) presented some irreversible damage, and after 2 years 53 had accrued new damage. The mean SDI for the whole cohort increased from 0.582 to 0.980. Damage progression was higher in ocular, cardiovascular, and musculoskeletal systems. Older age [OR = 1.045; 95% confidence interval (CI) 1.021–1.069; P= 0.03], presence of antiphospholipid antibodies (OR = 3.047; 95% CI 1.169–7.941; P= 0.02), steroid use (OR = 6.401; 95% CI 1.601–25.210; P= 0.008), azathioprine use (OR = 3.501; CI 1.224–10.012; P= 0.01), and hypertension (OR = 3.825; 95% CI 1.490–9.820; P= 0.005) were predictors of damage progression in multivariate analysis. Overall SDI increased over time, with some systems being affected more frequently. Demographic and clinical characteristics, co‐morbidity, and treatment options may contribute to irreversible damage. It is necessary to determine whether the control of modifiable factors (e.g., hypertension and judicious use of medications) might prevent damage progression in SLE patients.

P-found: The Protein Folding and Unfolding Simulation Repository

One of the central challenges in structural molecular biology today is the protein folding problem, i.e. the acquisition of the 3D structure of a protein from its linear sequence of amino-acids. Different computational approaches to study protein folding and protein unfolding have recently become common tools available to the researcher. However, due to the lack of appropriate infrastructures, it is very difficult to directly compare simulations performed by different groups, with different methods, in different experimental conditions or for different proteins. Thus, we set out to create a public data repository with the goal of addressing the problem of comparison, analysis and sharing of information and data on protein folding and protein unfolding simulations. The P-found system for protein folding and protein unfolding simulations is presented. At the moment, the data repository allows uploading of molecular dynamics (MD) protein folding and unfolding simulations, calculates and stores several time series with the variation over time of pre-defined molecular properties, and allows searching and downloading of these data. In the near future, simulations performed by other than MD methods may be uploaded, and data mining techniques for analysis and comparison of multiple simulations will be implemented. The home page for the P-found system is accessible at http://www.p-found.org

Spatial Clustering of Molecular Dynamics Trajectories in Protein Unfolding Simulations

Molecular dynamics simulations is a valuable tool to study protein unfolding in silico . Analyzing the relative spatial position of the residues during the simulation may indicate which residues are essential in determining the protein structure. We present a method, inspired by a popular data mining technique called Frequent Itemset Mining, that clusters sets of amino acid residues with a synchronized trajectory during the unfolding process. The proposed approach has several advantages over traditional hierarchical clustering.