Relationship between global structural parameters and Enzyme Commission hierarchy: Implications for function prediction

In protein databases there is a substantial number of proteins structurally determined but without function annotation. Understanding the relationship between function and structure can be useful to predict function on a large scale. We have analyzed the similarities in global physicochemical parameters for a set of enzymes which were classified according to the four Enzyme Commission (EC) hierarchical levels. Using relevance theory we introduced a distance between proteins in the space of physicochemical characteristics. This was done by minimizing a cost function of the metric tensor built to reflect the EC classification system. Using an unsupervised clustering method on a set of 1025 enzymes, we obtained no relevant clustering formation compatible with EC classification. The distance distributions between enzymes from the same EC group and from different EC groups were compared by histograms. Such analysis was also performed using sequence alignment similarity as a distance. Our results suggest that global structure parameters are not sufficient to segregate enzymes according to EC hierarchy. This indicates that features essential for function are rather local than global. Consequently, methods for predicting function based on global attributes should not obtain high accuracy in main EC classes prediction without relying on similarities between enzymes from training and validation datasets. Furthermore, these results are consistent with a substantial number of studies suggesting that function evolves fundamentally by recruitment, i.e., a same protein motif or fold can be used to perform different enzymatic functions and a few specific amino acids (AAs) are actually responsible for enzyme activity. These essential amino acids should belong to active sites and an effective method for predicting function should be able to recognize them. (C) 2012 Elsevier Ltd. All rights reserved.

Automatic aspect discrimination in data clustering

The attributes describing a data set may often be arranged in meaningful subsets, each of which corresponds to a different aspect of the data. An unsupervised algorithm (SCAD) that simultaneously performs fuzzy clustering and aspects weighting was proposed in the literature. However, SCAD may fail and halt given certain conditions. To fix this problem, its steps are modified and then reordered to reduce the number of parameters required to be set by the user. In this paper we prove that each step of the resulting algorithm, named ASCAD, globally minimizes its cost-function with respect to the argument being optimized. The asymptotic analysis of ASCAD leads to a time complexity which is the same as that of fuzzy c-means. A hard version of the algorithm and a novel validity criterion that considers aspect weights in order to estimate the number of clusters are also described. The proposed method is assessed over several artificial and real data sets.

Average control of Markov decision processes with Feller transition probabilities and general action spaces

This paper studies the average control problem of discrete-time Markov Decision Processes (MDPs for short) with general state space, Feller transition probabilities, and possibly non-compact control constraint sets A(x). Two hypotheses are considered: either the cost function c is strictly unbounded or the multifunctions A(r)(x) = {a is an element of A(x) : c(x, a) <= r} are upper-semicontinuous and compact-valued for each real r. For these two cases we provide new results for the existence of a solution to the average-cost optimality equality and inequality using the vanishing discount approach. We also study the convergence of the policy iteration approach under these conditions. It should be pointed out that we do not make any assumptions regarding the convergence and the continuity of the limit function generated by the sequence of relative difference of the alpha-discounted value functions and the Poisson equations as often encountered in the literature. (C) 2012 Elsevier Inc. All rights reserved.

An analysis of Taguchi's on-line quality monitoring procedure for variables based on the results of a sequence of inspections

In this paper, a procedure for the on-line process control of variables is proposed. This procedure consists of inspecting the m-th item from every m produced items and deciding, at each inspection, whether the process is out-of-control. Two sets of limits, warning (µ0 ± W) and control (µ0 ± C), are used. If the value of the monitored statistic falls beyond the control limits or if a sequence of h observations falls between the warning limits and the control limits, the production is stopped for adjustment; otherwise, production goes on. The properties of an ergodic Markov chain are used to obtain an expression for the average cost per item. The parameters (the sampling interval m, the widths of the warning, the control limits W and C(W < C), and the sequence length (h) are optimized by minimizing the cost function. A numerical example illustrates the proposed procedure.

High-Performance Liquid Chromatography Under Partially Denaturing Conditions (dHPLC) is a Fast and Cost-Effective Method for Screening Molecular Defects: Four Novel Mutations Found in X-Linked Chronic Granulomatous Disease

Implementing precise techniques in routine diagnosis of chronic granulomatous disease (CGD), which expedite the screening of molecular defects, may be critical for a quick assumption of patient prognosis. This study compared the efficacy of single-strand conformation polymorphism analysis (SSCP) and high-performance liquid chromatography under partially denaturing conditions (dHPLC) for screening mutations in CGD patients. We selected 10 male CGD patients with a clinical history of severe recurrent infections and abnormal respiratory burst function. gDNA, mRNA and cDNA samples were prepared by standard methods. CYBB exons were amplified by PCR and screened by SSCP or dHPLC. Abnormal DNA fragments were sequenced to reveal the nature of the mutations. The SSCP and dHPLC methods showed DNA abnormalities, respectively, in 55% and 100% of the cases. Sequencing of the abnormal DNA samples confirmed mutations in all cases. Four novel mutations in CYBB were identified which were picked up only by the dHPLC screening (c.904 insC, c.141+5 g>t, c.553 T>C, and c.665 A>T). This work highlights the relevance of dHPLC, a sensitive, fast, reliable and cost-effective method for screening mutations in CGD, which in combination with functional assays assessing the phagocyte respiratory burst will contribute to expedite the definitive diagnosis of X-linked CGD, direct treatment, genetic counselling and to have a clear assumption of the prognosis. This strategy is especially suitable for developing countries.

Cost-Effectiveness Analysis for Surgical, Angioplasty, or Medical Therapeutics for Coronary Artery Disease 5-Year Follow-Up of Medicine, Angioplasty, or Surgery Study (MASS) II Trial

Background-The Second Medicine, Angioplasty, or Surgery Study (MASS II) included patients with multivessel coronary artery disease and normal systolic ventricular function. Patients underwent coronary artery bypass graft surgery (CABG, n = 203), percutaneous coronary intervention (PCI, n = 205), or medical treatment alone (MT, n = 203). This investigation compares the economic outcome at 5-year follow-up of the 3 therapeutic strategies. Methods and Results-We analyzed cumulative costs during a 5-year follow-up period. To analyze the cost-effectiveness, adjustment was made on the cumulative costs for average event-free time and angina-free proportion. Respectively, for event-free survival and event plus angina-free survival, MT presented 3.79 quality-adjusted life-years and 2.07 quality-adjusted life-years; PCI presented 3.59 and 2.77 quality-adjusted life-years; and CABG demonstrated 4.4 and 2.81 quality-adjusted life-years. The event-free costs were $9071.00 for MT; $19 967.00 for PCI; and $18 263.00 for CABG. The paired comparison of the event-free costs showed that there was a significant difference favoring MT versus PCI (P<0.01) and versus CABG (P<0.01) and CABG versus PCI (P<0.01). The event-free plus angina-free costs were $16 553.00, $25 831.00, and $24 614.00, respectively. The paired comparison of the event-free plus angina-free costs showed that there was a significant difference favoring MT versus PCI (P=0.04), and versus CABG (P<0.001); there was no difference between CABG and PCI (P>0.05). Conclusions-In the long-term economic analysis, for the prevention of a composite primary end point, MT was more cost effective than CABG, and CABG was more cost-effective than PCI.

Dual function of egg-covering in the Kentish plover Charadrius alexandrinus

Many bird species take recesses during incubation, and while the nests are unattended, the eggs may both be vulnerable to predation and reach suboptimal temperatures for embryo development. Perhaps to avoid these negative possibilities, some birds cover their eggs with materials when they depart from nests. We examined experimentally, using the ground-nesting Kentish plover as model species, whether egg-covering allows egg temperatures to remain within optimal limits for embryogenesis in unattended nests, thus reducing the requirements of contact incubation, and simultaneously maintain the eggs' camouflage. There was a negative relationship between nest attendance and ambient temperature, but only during mid-morning, the period of the day when egg-covering was most frequent. Indeed, during mid-morning egg-covering not only served to better camouflage the eggs, but also to maintain egg temperatures within optimal thermal thresholds for embryogenesis while the nests remained unattended. During other periods of the day, covered eggs in unattended nests overheated (e.g., afternoon) or did not reach the optimal temperature for embryogenesis (e.g., early morning). During periods in which eggs may be uncovered to alleviate overheating, unattended nests may be easier to locate by predators, because the eggs are less well camouflaged. Therefore, camouflage and appropriate thermal environment are inseparable functions of egg-covering in the ground-nesting Kentish plover.