An experimental study of Quartets MaxCut and other supertree methods

<p>Abstract</p> <p>Background</p> <p>Supertree methods represent one of the major ways by which the Tree of Life can be estimated, but despite many recent algorithmic innovations, matrix representation with parsimony (MRP) remains the main algorithmic supertree method.</p> <p>Results</p> <p>We evaluated the performance of several supertree methods based upon the Quartets MaxCut (QMC) method of Snir and Rao and showed that two of these methods usually outperform MRP and five other supertree methods that we studied, under many realistic model conditions. However, the QMC-based methods have scalability issues that may limit their utility on large datasets. We also observed that taxon sampling impacted supertree accuracy, with poor results obtained when all of the source trees were only sparsely sampled. Finally, we showed that the popular optimality criterion of minimizing the total topological distance of the supertree to the source trees is only weakly correlated with supertree topological accuracy. Therefore evaluating supertree methods on biological datasets is problematic.</p> <p>Conclusions</p> <p>Our results show that supertree methods that improve upon MRP are possible, and that an effort should be made to produce scalable and robust implementations of the most accurate supertree methods. Also, because topological accuracy depends upon taxon sampling strategies, attempts to construct very large phylogenetic trees using supertree methods should consider the selection of source tree datasets, as well as supertree methods. Finally, since supertree topological error is only weakly correlated with the supertree's topological distance to its source trees, development and testing of supertree methods presents methodological challenges.</p

Outcomes of Operatively Treated Acute Knee Dislocations

Knee dislocation is a complex and rare injury often presenting in the context of high velocity trauma. The aim of this study is to establish the subjective outcomes of surgically treated knee dislocations. A total of 20 knees dislocations treated by open repair were reviewed. Their progress and outcomes were assessed by using a modified Lysholm score questionnaire. Data was obtained on patient demographics, details of injury, investigation, treatment, rehabilitation, 24 months objective outcome and subjective outcomes. Six patients had a vascular deficit and six had neurological deficits. The median range of motion was 0°-100°. Patients with an initially lower pre-injury level of function were able to return an activity level comparable to their pre-injury status. 22% of competitive athletes retuned to competitive sports. 38% of patients undertaking heavy activity returned to comparable pre-injury level of activity and 67% of patients undertaking moderate level of activity before injury returned to a comparable level after repair. 68% regularly had problems running, 70% problem squatting, 40% swelling and 42% problem with stairs. Most patients however did not have locking of the knee or problems with knees giving way. Patients pain scores decreased over time to an acceptable level. Despite the severity of the injury, majority of patients achieved a satisfactory outcome, although none of the patients reached the same level of function as before the injury. 80% of the patients were satisfied with their outcome. All dissatisfied patients suffered postoperative complications

Interaction Between Convection and Pulsation

This article reviews our current understanding of modelling convection dynamics in stars. Several semi-analytical time-dependent convection models have been proposed for pulsating one-dimensional stellar structures with different formulations for how the convective turbulent velocity field couples with the global stellar oscillations. In this review we put emphasis on two, widely used, time-dependent convection formulations for estimating pulsation properties in one-dimensional stellar models. Applications to pulsating stars are presented with results for oscillation properties, such as the effects of convection dynamics on the oscillation frequencies, or the stability of pulsation modes, in classical pulsators and in stars supporting solar-type oscillations.Comment: Invited review article for Living Reviews in Solar Physics. 88 pages, 14 figure

Changes in health related quality of life 3 months after an acute coronary syndrome

BACKGROUND: The aim of the study was to identify the changes in Health Related Quality of Life (HRQL) 3 months after discharge from hospital, in patients who have had an acute coronary episode, and to determine the clinical and sociodemographic variables that explain those changes. METHODS: HRQL was assessed in 132 patients while they were admitted to the hospital and at 3 months after discharge, using the SF-36 health questionnaire. To identify the variables associated with the change, multiple linear regression models were constructed for two summary dimensions of the SF-36 (PCS and MCS) taking the change in the score of the dimension as dependent variable. RESULTS: There were no significant differences between the patients who completed the monitoring (n = 76) and those who were dropped out. After three months, a significant decrease was observed in the dimensions of physical functioning, general health, vitality, and Physical Summary Component (PCS). The variables revascularisation, age, and the interaction between previous history of coronary heart disease (CHD) and the presence of one or more risk factors explained 16.6% of the decrease in the PCS. The decrease in the PCS was 6.4 points less in the patients who had undergone revascularisation, 0.2 points less for each year of age, and 4.7 points less in the patients who had antecedents of the illness as well as one or more risk factors. CONCLUSION: The dimensions most affected at three months after an acute coronary episode were those related to the physical component. Undergoing revascularisation improved the PCS in patients, but in the younger patients and those without personal antecedents or risk factors, the PCS was affected more, perhaps due to greater expectations for recovery in these patients

MEvoLib v1.0: the first molecular evolution library for Python

BACKGROUND: Molecular evolution studies involve many different hard computational problems solved, in most cases, with heuristic algorithms that provide a nearly optimal solution. Hence, diverse software tools exist for the different stages involved in a molecular evolution workflow. RESULTS: We present MEvoLib, the first molecular evolution library for Python, providing a framework to work with different tools and methods involved in the common tasks of molecular evolution workflows. In contrast with already existing bioinformatics libraries, MEvoLib is focused on the stages involved in molecular evolution studies, enclosing the set of tools with a common purpose in a single high-level interface with fast access to their frequent parameterizations. The gene clustering from partial or complete sequences has been improved with a new method that integrates accessible external information (e.g. GenBank’s features data). Moreover, MEvoLib adjusts the fetching process from NCBI databases to optimize the download bandwidth usage. In addition, it has been implemented using parallelization techniques to cope with even large-case scenarios. CONCLUSIONS: MEvoLib is the first library for Python designed to facilitate molecular evolution researches both for expert and novel users. Its unique interface for each common task comprises several tools with their most used parameterizations. It has also included a method to take advantage of biological knowledge to improve the gene partition of sequence datasets. Additionally, its implementation incorporates parallelization techniques to enhance computational costs when handling very large input datasets

Lrp Acts as Both a Positive and Negative Regulator for Type 1 Fimbriae Production in Salmonella enterica Serovar Typhimurium

Leucine-responsive regulatory protein (Lrp) is known to be an indirect activator of type 1 fimbriae synthesis in Salmonella enterica serovar Typhimurium via direct regulation of FimZ, a direct positive regulator for type 1 fimbriae production. Using RT-PCR, we have shown previously that fimA transcription is dramatically impaired in both lrp-deletion (Δlrp) and constitutive-lrp expression (lrpC) mutant strains. In this work, we used chromosomal PfimA-lacZ fusions and yeast agglutination assays to confirm and extend our previous results. Direct binding of Lrp to PfimA was shown by an electrophoretic mobility shift assay (EMSA) and DNA footprinting assay. Site-directed mutagenesis revealed that the Lrp-binding motifs in PfimA play a role in both activation and repression of type 1 fimbriae production. Overproduction of Lrp also abrogates fimZ expression. EMSA data showed that Lrp and FimZ proteins independently bind to PfimA without competitive exclusion. In addition, both Lrp and FimZ binding to PfimA caused a hyper retardation (supershift) of the DNA-protein complex compared to the shift when each protein was present alone. Nutrition-dependent cellular Lrp levels closely correlated with the amount of type 1 fimbriae production. These observations suggest that Lrp plays important roles in type 1 fimbriation by acting as both a positive and negative regulator and its effect depends, at least in part, on the cellular concentration of Lrp in response to the nutritional environment

Unusual Dengue Virus 3 Epidemic in Nicaragua, 2009

The four dengue virus serotypes (DENV1–4) cause the most prevalent mosquito-borne viral disease affecting humans worldwide. In 2009, Nicaragua experienced the largest dengue epidemic in over a decade, marked by unusual clinical presentation, as observed in two prospective studies of pediatric dengue in Managua. From August 2009–January 2010, 212 dengue cases were confirmed among 396 study participants at the National Pediatric Reference Hospital. In our parallel community-based cohort study, 170 dengue cases were recorded in 2009–10, compared to 13–65 cases in 2004–9. In both studies, significantly more patients experienced “compensated shock” (poor capillary refill plus cold extremities, tachycardia, tachypnea, and/or weak pulse) in 2009–10 than in previous years (42.5% [90/212] vs. 24.7% [82/332] in the hospital study (p<0.001) and 17% [29/170] vs. 2.2% [4/181] in the cohort study (p<0.001). Signs of poor peripheral perfusion presented significantly earlier (1–2 days) in 2009–10 than in previous years according to Kaplan-Meier survival analysis. In the hospital study, 19.8% of subjects were transferred to intensive care, compared to 7.1% in previous years – similar to the cohort study. DENV-3 predominated in 2008–9, 2009–10, and 2010–11, and full-length sequencing revealed no major genetic changes from 2008–9 to 2010–11. In 2008–9 and 2010–11, typical dengue was observed; only in 2009–10 was unusual presentation noted. Multivariate analysis revealed only “2009–10” as a significant risk factor for Dengue Fever with Compensated Shock. Interestingly, circulation of pandemic influenza A-H1N1 2009 in Managua was shifted such that it overlapped with the dengue epidemic. We hypothesize that prior influenza A H1N1 2009 infection may have modulated subsequent DENV infection, and initial results of an ongoing study suggest increased risk of shock among children with anti-H1N1-2009 antibodies. This study demonstrates that parameters other than serotype, viral genomic sequence, immune status, and sequence of serotypes can play a role in modulating dengue disease outcome

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

<p>Abstract</p> <p>Background</p> <p>Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance <it>in vitro </it>occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7_DOX-2), epirubicin (MCF-7_EPI), paclitaxel (MCF-7_TAX-2), or docetaxel (MCF-7_TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters.</p> <p>Results</p> <p>In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance.</p> <p>Conclusion</p> <p>This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.</p

Effect of P to A Mutation of the N-Terminal Residue Adjacent to the Rgd Motif on Rhodostomin: Importance of Dynamics in Integrin Recognition

Rhodostomin (Rho) is an RGD protein that specifically inhibits integrins. We found that Rho mutants with the P48A mutation 4.4–11.5 times more actively inhibited integrin α5β1. Structural analysis showed that they have a similar 3D conformation for the RGD loop. Docking analysis also showed no difference between their interactions with integrin α5β1. However, the backbone dynamics of RGD residues were different. The values of the R2 relaxation parameter for Rho residues R49 and D51 were 39% and 54% higher than those of the P48A mutant, which caused differences in S2, Rex, and τe. The S2 values of the P48A mutant residues R49, G50, and D51 were 29%, 14%, and 28% lower than those of Rho. The Rex values of Rho residues R49 and D51 were 0.91 s−1 and 1.42 s−1; however, no Rex was found for those of the P48A mutant. The τe values of Rho residues R49 and D51 were 9.5 and 5.1 times lower than those of P48A mutant. Mutational study showed that integrin α5β1 prefers its ligands to contain (G/A)RGD but not PRGD sequences for binding. These results demonstrate that the N-terminal proline residue adjacent to the RGD motif affect its function and dynamics, which suggests that the dynamic properties of the RGD motif may be important in Rho's interaction with integrin α5β1

Deciphering the universe of RNA structures and trans RNA-RNA interactions of transcriptomes in vivo: from experimental protocols to computational analyses

The last few years have seen an explosion of experimental and computational methods for investigating RNA structures of entire transcriptomes in vivo. Very recent experimental protocols now also allow trans RNA–RNA interactions to be probed in a transcriptome-wide manner. All of the experimental strategies require comprehensive computational pipelines for analysing the raw data and converting it back into actual RNA structure features or trans RNA–RNA interactions. The overall performance of these methods thus strongly depends on the experimental and the computational protocols employed. In order to get the best out of both worlds, both aspects need to be optimised simultaneously. This review introduced the methods and proposes ideas how they could be further improved