An Improved Search Algorithm for Optimal Multiple-Sequence Alignment

Multiple sequence alignment (MSA) is a ubiquitous problem in computational biology. Although it is NP-hard to find an optimal solution for an arbitrary number of sequences, due to the importance of this problem researchers are trying to push the limits of exact algorithms further. Since MSA can be cast as a classical path finding problem, it is attracting a growing number of AI researchers interested in heuristic search algorithms as a challenge with actual practical relevance. In this paper, we first review two previous, complementary lines of research. Based on Hirschbergs algorithm, Dynamic Programming needs O(kN^(k-1)) space to store both the search frontier and the nodes needed to reconstruct the solution path, for k sequences of length N. Best first search, on the other hand, has the advantage of bounding the search space that has to be explored using a heuristic. However, it is necessary to maintain all explored nodes up to the final solution in order to prevent the search from re-expanding them at higher cost. Earlier approaches to reduce the Closed list are either incompatible with pruning methods for the Open list, or must retain at least the boundary of the Closed list. In this article, we present an algorithm that attempts at combining the respective advantages; like A* it uses a heuristic for pruning the search space, but reduces both the maximum Open and Closed size to O(kN^(k-1)), as in Dynamic Programming. The underlying idea is to conduct a series of searches with successively increasing upper bounds, but using the DP ordering as the key for the Open priority queue. With a suitable choice of thresholds, in practice, a running time below four times that of A* can be expected. In our experiments we show that our algorithm outperforms one of the currently most successful algorithms for optimal multiple sequence alignments, Partial Expansion A*, both in time and memory. Moreover, we apply a refined heuristic based on optimal alignments not only of pairs of sequences, but of larger subsets. This idea is not new; however, to make it practically relevant we show that it is equally important to bound the heuristic computation appropriately, or the overhead can obliterate any possible gain. Furthermore, we discuss a number of improvements in time and space efficiency with regard to practical implementations. Our algorithm, used in conjunction with higher-dimensional heuristics, is able to calculate for the first time the optimal alignment for almost all of the problems in Reference 1 of the benchmark database BAliBASE

Autophagy: A cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress

The role of autophagy in the response of human hepatocytes to oxidative stress remains unknown. Understanding this process may have important implications for the understanding of basic liver epithelial cell biology and the responses of hepatocytes during liver disease. To address this we isolated primary hepatocytes from human liver tissue and exposed them ex vivo to hypoxia and hypoxia-reoxygenation (H-R). We showed that oxidative stress increased hepatocyte autophagy in a reactive oxygen species (ROS) and class III PtdIns3K-dependent manner. Specifically, mitochondrial ROS and NADPH oxidase were found to be key regulators of autophagy. Autophagy involved the upregulation of BECN1, LC3A, Atg7, Atg5 and Atg 12 during hypoxia and H-R. Autophagy was seen to occur within the mitochondria of the hepatocyte and inhibition of autophagy resulted in the lowering a mitochondrial membrane potential and onset of cell death. Autophagic responses were primarily observed in the large peri-venular (PV) hepatocyte subpopulation. Inhibition of autophagy, using 3-methyladenine, increased apoptosis during H-R. Specifically, PV human hepatocytes were more susceptible to apoptosis after inhibition of autophagy. These findings show for the first time that during oxidative stress autophagy serves as a cell survival mechanism for primary human hepatocytes

A bovine model of a respiratory Parachlamydia acanthamoebae infection

The aim of this study was to evaluate the pathogenicity of Parachlamydia (P.) acanthamoebae as a potential agent of lower respiratory tract disease in a bovine model of induced lung infection. Intrabronchial inoculation with P.acanthamoebae was performed in healthy calves aged 2-3 months using two challenge doses: 108 and 1010 bacteria per animal. Controls received 108 heat-inactivated bacteria. Challenge with 108 viable Parachlamydia resulted in a mild degree of general indisposition, whereas 1010 bacteria induced a more severe respiratory illness becoming apparent 1-2 days post inoculation (dpi), affecting 9/9 (100%) animals and lasting for 6 days. The extent of macroscopic pulmonary lesions was as high as 6.6 (6.0)% [median (range)] of lung tissue at 2-4 dpi and correlated with parachlamydial genomic copy numbers detected by PCR, and with bacterial load estimated by immunohistochemistry in lung tissue. Clinical outcome, acute phase reactants, pathological findings and bacterial load exhibited an initial dose-dependent effect on severity. Animals fully recovered from clinical signs of respiratory disease within 5 days. The bovine lung was shown to be moderately susceptible to P.acanthamoebae, exhibiting a transient pneumonic inflammation after intrabronchial challenge. Further studies are warranted to determine the precise pathophysiologic pathways of host-pathogen interactio

Content Development of the Relationships with Alcohol Scale for Late-Adolescents

Level of functioning is an important component of comprehensive assessments of adolescent alcohol use behavior. However, comprehensive adolescent substance use measures fail to provide a clear conceptual framework for understanding how alcohol use impacts functioning. Recent research (Lucey, 2009) suggests that alcohol use does negatively impact late-adolescent functioning and it is important to measure an adolescent\u27s alcohol-use behavior and its consequences in conjunction with level of functioning. Thus, a biopsychosocial measure of the impact of alcohol use on late adolescent functioning entitled the Relationship with Alcohol Scale (RAS) was proposed. Items for the RAS were developed from a review of the adolescent and adult alcohol use literature and interviews with late-adolescents. The purpose of the proposed study was to determine the content domains, domain definitions and item relevance of the RAS. Two sequential studies were conducted. Study I consisted of 20 late-adolescent participants. Participants completed a simple sorting task with the 192 items, in which they were instructed to sort items into piles representing similar areas of life affected by alcohol use. A Multidimensional Scaling analysis and follow-up cluster analysis identified 6 content domains: 1) Social Role Performance, 2) Interpersonal Functioning, 3) Alcohol Use Behavior, 4) Personal Health and Hygiene, 5) Legal-Financial Problems, and 6) Psychological Well-Being. Domain definitions were obtained by reviewing the item clusters obtained from the cluster analysis. Study II consisted of 50 late-adolescent participants. Participants completed a Q-sorting task, where they were instructed to rate each item within the 6 content domains based on how relevant they were to the domain definition. Aiken\u27s (1980) Validity Indexes were used to identify the most relevant items of the content domains. A total of 45 items were removed from the RAS. The results of this study identified 6 content domains (4 level of functioning and 2 alcohol use behavior/consequences domains) for a total of 147 items. The strengths of the RAS are its biopsychosocial framework, its use of late-adolescents as content experts to identify salient content domains and the use of empirical methods to determine content domains and item relevance. Further studies will need to be conducted to reduce the number of items and to evaluate the psychometric properties of the RAS

At the limits of a successful body plan-3D microanatomy, histology and evolution of Helminthope (Mollusca: Heterobranchia: Rhodopemorpha), the most worm-like gastropod

Background: Gastropods are among the most diverse animal clades, and have successfully colonized special habitats such as the marine sand interstitial. Specialized meiofaunal snails and slugs are tiny and worm-shaped. They combine regressive features - argued to be due to progenetic tendencies - with convergent adaptations. Microscopic size and concerted convergences make morphological examination non-trivial and hamper phylogenetic reconstructions. The enigmatic turbellarian-like Rhodopemorpha are a small group that has puzzled systematists for over a century. A preliminary molecular framework places the group far closer to the root of Heterobranchia - one of the major gastropod groups - than previously suggested. The poorly known meiofaunal Helminthope psammobionta Salvini-Plawen, 1991 from Bermuda is the most worm-shaped free-living gastropod and shows apparently aberrant aspects of anatomy. Its study may give important clues to understand the evolution of rhodopemorphs among basal heterobranchs versus their previously thought origin among `higher' euthyneuran taxa. Results: We describe the 3D-microanatomy of H. psammobionta using three-dimensional digital reconstruction based on serial semithin histological sections. The new dataset expands upon the original description and corrects several aspects. Helminthope shows a set of typical adaptations and regressive characters present in other mesopsammic slugs (called `meiofaunal syndrome' herein). The taxonomically important presence of five separate visceral loop ganglia is confirmed, but considerable further detail of the complex nervous system are corrected and revealed. The digestive and reproductive systems are simple and modified to the thread-like morphology of the animal; the anus is far posterior. There is no heart; the kidney resembles a protonephridium. Data on all organ systems are compiled and compared to Rhodope. Conclusions: Helminthope is related to Rhodope sharing unique apomorphies. We argue that the peculiar kidney, configuration of the visceral loop and simplicity or lack of other organs in Rhodopemorpha are results of progenesis. The posterior shift of the anus in Helminthope is interpreted as a peramorphy, i.e. hypertrophy of body length early in ontogeny. Our review of morphological and molecular evidence is consistent with an origin of Rhodopemorpha slugs among shelled `lower Heterobranchia'. Previously thought shared `diagnostic' features such as five visceral ganglia are either plesiomorphic or convergent, while euthyneury and a double-rooted cerebral nerve likely evolved independently in Rhodopemorpha and Euthyneura

Cacicazgos und das Tahuantinsuyu : die imperiale Politik der Inka lokal verhandelt

Die vorliegende Arbeit beschäftigt sich auf der Basis von spanischsprachigen Schriftquellen des 16. und 17. Jahrhunderts, die im Kontext der europäischen Kolonisierung des Andengebietes verfasst worden waren, mit der Frage der Beziehung zwischen dem inkaischen Machtzentrum Cuzco und den andinen Lokalgruppen mit ihren politischen Autoritäten. Thema des ersten Teils ist die Eroberung und Eingliederung der Lokalgruppen in den expandierenden Inkastaat. Hierbei wird versucht, das komplexe Zusammenwirken von militärischer Gewalt, Diplomatie und Staatsideologie aufzuschlüsseln. Anhand der Frage nach dem Beginn inkaischer Expansion wird zudem exemplarisch die Problematik einer wörtlichen Lesart der Chroniken aufgezeigt. Rückbezüge zu archäologischen Untersuchungen zeigen, welche Bedeutung der Archäologie als komplementärer Wissenschaft zur Ethnohistorie zukommt. Im zweiten Teil der Arbeit liegt der methodische Schwerpunkt vor allem in der Einarbeitung regionalspezifischer Dokumente, die eine Annäherung an die lokale Perspektive der curacas ermöglichen soll. Auf den Ebenen von Politik, Wirtschaft und Religion wird untersucht, wie sich die Situation der Lokalherrscher nach ihrer Unterwerfung unter die inkaische Obrigkeit gestaltete. Wie auf allen drei Ebenen gleichermaßen deutlich wird, waren die Handlungen nicht nur von einer Seite aus bestimmt, d.h. von Cuzco zu den Lokalherrschern. In diesem Falle hätten die curacas nur eine passive Rolle gegenüber einer eingreifenden Staatsmacht erfüllt. Stattdessen zeigt sich, dass es in politischer, wirtschaftlicher wie religiöser Hinsicht ‚Verhandlungen’ gab, in denen sich immer wieder Spielraum für die Interessen der curacas bot. Durch Demonstration ihrer Kooperationsbereitschaft mit Cuzco konnten sie aktiv an der Ausdehnung ihrer politischen Autorität und der Erweiterung ihrer Privilegien arbeiten. Insofern wird argumentiert, dass die curacas in der Arena der imperialen Politik der Inka auch selbst als ‚Akteure’ mitwirkten

Pulmonary rehabilitation and severe exacerbations of COPD: solution or white elephant?

Hospitalisations for severe exacerbations of chronic obstructive pulmonary disease are associated with significant physical and psychological consequences including an increase in symptom severity, severe reductions in physical activity, a deleterious effect on skeletal muscle, impaired exercise tolerance/ability to self-care, decline in quality of life, and increased anxiety and depression. As these consequences are potentially amenable to exercise training, there is a clear rationale for pulmonary rehabilitation in the peri/post-exacerbation setting. Although a 2011 Cochrane review was overwhelmingly positive, subsequent trials have shown less benefit and real-life observational studies have revealed poor acceptability. Qualitative studies have demonstrated that the patient experience is a determining factor while the presence of comorbidities may influence referral, adherence and response to pulmonary rehabilitation. Systematic reviews of less supervised interventions, such as self-management, have shown limited benefits in the post-exacerbation setting. The recent update of the Cochrane review of peri-exacerbation pulmonary rehabilitation showed that benefits were associated with the “comprehensive” nature of the intervention (the number of sessions received, the intensity of exercise training and education delivered, and the degree of supervision) but implementation is demanding. The challenge is to develop interventions that are deliverable and acceptable around the time of an acute exacerbation but also deliver the desired clinical impact

Towards a Consumer Cloud Computing Maturity Model - Proposition of Development Guidelines, Maturity Domains and Maturity Levels

In recent years, Cloud Computing (CC) has transformed from a new trend to IT management reality. Its potential promises to significantly change computing and benefit many organisations but at the same time uncertainty and the need for managerial guidance prevail. To benefit from the opportunities that CC promises, organisations need to adapt to the new circumstances that this phenomenon triggers and develop new capabilities. Maturity models have shown to be an excellent and easily applicable tool for the assessment and improvement of capabilities. However, there is no fully developed and universally accepted CC maturity model (CCMM) so far. Through the execution of a maturity model development process, this contribution is aiming at deriving development guidelines for the future development of a holistic consumer CCMM. Additionally, content and structure in the form of maturity domains and maturity levels are proposed throughout the development process, the combination of which represents the first steps towards a holistic consumer CCMM

Condition monitoring approach for permanent magnet synchronous motor drives based on the INFORM method

This paper proposes a monitoring scheme based on saliency tracking to assess the health condition of PMSM drives operating under non stationary conditions. The evaluated scheme is based on the INFORM methodology, which is associated to the accurate sensorless control of PM drives without zero speed limitation. The result is a monitoring scheme that is able to detect faults that would be very difficult to evaluate under nonstationary conditions. A relevant aspect of the proposed scheme is that it remains valid for full speed range, and can be used for standstill operation. Additionally, the approach is insensitive to the inverter nonlinearities which enhance the detection capabilities further respect to similar topologies. In this work the proposed approach is evaluated numerically and experimentally in the presence of incipient winding faults and inter-turn short circuits in a PM conventional drive. The obtained results show quick response and excellent detection capabilities not only in the detection of faults, but to determine their magnitude which is vital to avoid further degradation