Functional Characterisation of Alpha-Galactosidase A Mutations as a Basis for a New Classification System in Fabry Disease

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The study has been supported partially by an unrestricted scientific grant from Shire Human Genetic Therapies (Germany

Rationality as the Rule of Reason

The demands of rationality are linked both to our subjective normative perspective (given that rationality is a person-level concept) and to objective reasons or favoring relations (given that rationality is non-contingently authoritative for us). In this paper, I propose a new way of reconciling the tension between these two aspects: roughly, what rationality requires of us is having the attitudes that correspond to our take on reasons in the light of our evidence, but only if it is competent. I show how this view can account for structural rationality on the assumption that intentions and beliefs as such involve competent perceptions of downstream reasons, and explore various implications of the account

Convergent algorithms for protein structural alignment

<p>Abstract</p> <p>Background</p> <p>Many algorithms exist for protein structural alignment, based on internal protein coordinates or on explicit superposition of the structures. These methods are usually successful for detecting structural similarities. However, current practical methods are seldom supported by convergence theories. In particular, although the goal of each algorithm is to maximize some scoring function, there is no practical method that theoretically guarantees score maximization. A practical algorithm with solid convergence properties would be useful for the refinement of protein folding maps, and for the development of new scores designed to be correlated with functional similarity.</p> <p>Results</p> <p>In this work, the maximization of scoring functions in protein alignment is interpreted as a Low Order Value Optimization (LOVO) problem. The new interpretation provides a framework for the development of algorithms based on well established methods of continuous optimization. The resulting algorithms are convergent and <it>increase the scoring functions at every iteration</it>. The solutions obtained are critical points of the scoring functions. Two algorithms are introduced: One is based on the maximization of the scoring function with Dynamic Programming followed by the continuous maximization of <it>the same </it>score, with respect to the protein position, using a smooth Newtonian method. The second algorithm replaces the Dynamic Programming step by a fast procedure for computing the correspondence between C<it>α </it>atoms. The algorithms are shown to be very effective for the maximization of the STRUCTAL score.</p> <p>Conclusion</p> <p>The interpretation of protein alignment as a LOVO problem provides a new theoretical framework for the development of convergent protein alignment algorithms. These algorithms are shown to be very reliable for the maximization of the STRUCTAL score, and other distance-dependent scores may be optimized with same strategy. The improved score optimization provided by these algorithms provide means for the refinement of protein fold maps and also for the development of scores designed to match biological function. The LOVO strategy may be also used for more general structural superposition problems such as flexible or non-sequential alignments. The package is available on-line at http://www.ime.unicamp.br/~martinez/lovoalign.</p

Sexual Dysfunction in Jordanian Diabetic Women

OBJECTIVE—To estimate the prevalence of female sexual dysfunction (FSD) in diabetic and nondiabetic Jordanian women

Nuclear medicine procedures and the evaluation of male sexual organs: a short review

Sexuality consists of three aspects that are interrelated and inseparable, biological, physiological and social. The biological aspect considers the individual's capability to give and to receive pleasure. In consequence, it covers the functionality of the sexual organs and the physiology of human sexual response cycle. Diagnostic imaging modalities, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have been used to evaluate clinical disorders of the male reproductive system. PET and SPECT procedures basically involve the administration of a radiopharmaceutical that has a higher uptake in a specific tumor or tissue. The aim of this brief review is to present some radiopharmaceuticals that have been used in the clinical evaluation of the male sexual organs (testes, prostate, seminal vesicles, penis) related with male sexuality. This information could be useful in better understanding the male sexual response cycle, as well as the sexual disorders, when considering the male sexual organs and the pelvic floor. Moreover, the findings obtained with PET and SPECT imaging could help to evaluate the efficacy of clinical results of therapeutic procedures. In conclusion, the knowledge from these images could aid in better understanding the physiology of the different organs related with sexuality. Furthermore, they could be important tools to evaluate the physiological integrity of the involved organs, to improve clinical strategies and to accompany the patients under treatment

R3D-BLAST: a search tool for similar RNA 3D substructures

R3D-BLAST is a BLAST-like search tool that allows the user to quickly and accurately search against the PDB for RNA structures sharing similar substructures with a specified query RNA structure. The basic idea behind R3D-BLAST is that all the RNA 3D structures deposited in the PDB are first encoded as 1D structural sequences using a structural alphabet of 23 distinct nucleotide conformations, and BLAST is then applied to these 1D structural sequences to search for those RNA substructures whose 1D structural sequences are similar to that of the query RNA substructure. R3D-BLAST takes as input an RNA 3D structure in the PDB format and outputs all substructures of the hits similar to that of the query with a graphical display to show their structural superposition. In addition, each RNA substructure hit found by R3D-BLAST has an associated E-value to measure its statistical significance. R3D-BLAST is now available online at http://genome.cs.nthu.edu.tw/R3D-BLAST/ for public access

TOPS++FATCAT: Fast flexible structural alignment using constraints derived from TOPS+ Strings Model

<p>Abstract</p> <p>Background</p> <p>Protein structure analysis and comparison are major challenges in structural bioinformatics. Despite the existence of many tools and algorithms, very few of them have managed to capture the intuitive understanding of protein structures developed in structural biology, especially in the context of rapid database searches. Such intuitions could help speed up similarity searches and make it easier to understand the results of such analyses.</p> <p>Results</p> <p>We developed a TOPS++FATCAT algorithm that uses an intuitive description of the proteins' structures as captured in the popular TOPS diagrams to limit the search space of the aligned fragment pairs (AFPs) in the flexible alignment of protein structures performed by the FATCAT algorithm. The TOPS++FATCAT algorithm is faster than FATCAT by more than an order of magnitude with a minimal cost in classification and alignment accuracy. For beta-rich proteins its accuracy is better than FATCAT, because the TOPS+ strings models contains important information of the parallel and anti-parallel hydrogen-bond patterns between the beta-strand SSEs (Secondary Structural Elements). We show that the TOPS++FATCAT errors, rare as they are, can be clearly linked to oversimplifications of the TOPS diagrams and can be corrected by the development of more precise secondary structure element definitions.</p> <p>Software Availability</p> <p>The benchmark analysis results and the compressed archive of the TOPS++FATCAT program for Linux platform can be downloaded from the following web site: <url>http://fatcat.burnham.org/TOPS/</url></p> <p>Conclusion</p> <p>TOPS++FATCAT provides FATCAT accuracy and insights into protein structural changes at a speed comparable to sequence alignments, opening up a possibility of interactive protein structure similarity searches.</p

Fabry Disease in Latin America: Data from the Fabry Registry

The purpose of these analyses was to characterize demographic and baseline clinical characteristics of Latin American patients with Fabry disease compared to that of patients in the rest of the world. Observational data reported to the Fabry Registry were obtained from untreated patients or prior to treatment with enzyme replacement therapy. As of October 1, 2010, 3,752 patients were enrolled in the Fabry Registry worldwide, including 333 patients within Latin America. Latin American patients tended to be younger than Fabry Registry patients enrolled in the rest of the world: mean current age 35.5 years versus 39.2 years for men (p < 0.05 by t-test), mean age 37.8 years versus 43.6 years for women (p < 0.05 by t-test). A smaller percentage of Latin American patients have received enzyme replacement therapy, compared to patients in the rest of the world: 67% versus 80% for men, and 19% versus 39% of women, respectively. Thirty-one percent of men and 22% of women in Latin America reported experiencing a significant cardiovascular, renal, or cerebrovascular event, at a mean age of 35 ± 12.6 years in men and 44 ± 12.3 years in women. Cardiovascular events were the most common type of initial clinical event among men and women in Latin America. The medical community in Latin America should be aware of Fabry disease as a possible cause of renal or cardiac dysfunction. Increased awareness will facilitate prompt diagnosis and initiation of treatment

Reporting conditionals with modals

Conditionals and modals work in tandem in some instances of practical reasoning, or decision making. Consider the following example (from Kratzer 2012): a. I want to become a mayor. b. (q) I will become a mayor only if (p) I go to the pub. c. Therefore, I should go to the pub. Given what the cogniser wants (a) and the relevant circumstances (b), the conclusion that the cogniser goes to the pub comes out as necessary. Hence, the presence of the necessity modal should in (c). Indeed, given the context of (a), the necessity modal in (c) is simply a reflection of the necessity of p for q, which is overtly represented by the use of the ‘only if p, q’ construction. This chapter looks into whether indirect reports of conditionals – in particular, indirect reports which involve the use of a modal verb – are sensitive to the necessity of p for q in cases where necessity is not overtly represented in a conditional, as in ‘if p, q’ formulations. We report on two online experiments into the relation between (i) perceived necessity or sufficiency of the truth of a conditional antecedent for the truth of the consequent, and (ii) the formulation of an indirect report of a conditional with necessity or possibility modals (have to, should, could). In Experiment 1, the ‘necessity/sufficiency of p for q’ variable was manipulated by contextually altering the number of alternative antecedents (e.g. Cummins et al. 1991; Thompson 1994; Politzer 2003). It was found that modals used in indirect reports of ‘if p, q’ conditionals co-vary with the number of alternative antecedents in predictable ways. This suggests that modals used in indirect reports of ‘if p, q’ conditionals may be a diagnostic for biconditional versus material interpretations of conditionals. The aim of Experiment 2 was to find out whether the results of Experiment 1 could be replicated in contexts which lower/eliminate the believability of the conditionals. It was found that manipulating the believability variable has no reliable effect on the results