Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: the role of PCSK9 inhibitors

Familial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low-density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost-effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD

PAN@FIRE: Overview of the cross-language !ndian Text re-use detection competition

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-40087-2_6The development of models for automatic detection of text re-use and plagiarism across languages has received increasing attention in recent years. However, the lack of an evaluation framework composed of annotated datasets has caused these efforts to be isolated. In this paper we present the CL!TR 2011 corpus, the first manually created corpus for the analysis of cross-language text re-use between English and Hindi. The corpus was used during the Cross-Language !ndian Text Re-Use Detection Competition. Here we overview the approaches applied the contestants and evaluate their quality when detecting a re-used text together with its source.This research work is partially funded by the WIQ-EI (IRSES grant n. 269180)and ACCURAT (grant n. 248347) projects, and the Seventh Framework Programme (FP7/2007-2013) under grant agreement n. 246016 from the European Union. The first author was partially funded by the CONACyT-Mexico 192021 grant and currently works under the ERCIM “Alain Bensoussan” Fellowship Programme. The research of the second author is in the framework of the VLC/Campus Microcluster on Multimodal Interaction in Intelligent Systems and partially funded by the MICINN research project TEXT-ENTERPRISE 2.0 TIN2009-13391-C04-03 (plan I+D+i). The research from AU-KBC Centre is supported by the Cross Lingual Information Access (CLIA) Phase II Project.Barrón Cedeño, LA.; Rosso ., P.; Sobha, LD.; Clough ., P.; Stevenson ., M. (2013). PAN@FIRE: Overview of the cross-language !ndian Text re-use detection competition. En Multilingual Information Access in South Asian Languages. Springer Verlag (Germany). 7536:59-70. https://doi.org/10.1007/978-3-642-40087-2_6S59707536Addanki, K., Wu, D.: An Evaluation of MT Alignment Baseline Approaches upon Cross-Lingual Plagiarism Detection. In: FIRE [12]Aggarwal, N., Asooja, K., Buitelaar, P.: Cross Lingual Text Reuse Detection Using Machine Translation & Similarity Measures. In: FIRE [12]Alegria, I., Forcada, M., Sarasola, K. (eds.): Proceedings of the SEPLN 2009 Workshop on Information Retrieval and Information Extraction for Less Resourced Languages. University of the Basque Country, Donostia, Donostia (2009)Barrón-Cedeño, A., Rosso, P., Pinto, D., Juan, A.: On Cross-Lingual Plagiarism Analysis Using a Statistical Model. In: Stein, B., Stamatatos, E., Koppel, M. (eds.) ECAI 2008 Workshop on Uncovering Plagiarism, Authorship, and Social Software Misuse (PAN 2008), vol. 377, pp. 9–13. CEUR-WS.org, Patras (2008), http://ceur-ws.org/Vol-377Bendersky, M., Croft, W.: Finding Text Reuse on the Web. In: Baeza-Yates, R., Boldi, P., Ribeiro-Neto, B., Cambazoglu, B. (eds.) Proceedings of the Second ACM International Conference on Web Search and Web Data Mining, pp. 262–271. ACM, Barcelona (2009)Ceska, Z., Toman, M., Jezek, K.: Multilingual Plagiarism Detection. In: Proceedings of the 13th International Conference on Artificial Intelligence (ICAI 2008), pp. 83–92. Springer, Varna (2008)Clough, P.: Plagiarism in Natural and Programming Languages: an Overview of Current Tools and Technologies. Research Memoranda: CS-00-05, Department of Computer Science. University of Sheffield, UK (2000)Clough, P.: Old and new challenges in automatic plagiarism detection. National UK Plagiarism Advisory Service (2003), http://ir.shef.ac.uk/cloughie/papers/pasplagiarism.pdfClough, P., Gaizauskas, R.: Corpora and Text Re-Use. In: Lüdeling, A., Kytö, M., McEnery, T. (eds.) Handbook of Corpus Linguistics. Handbooks of Linguistics and Communication Science, pp. 1249–1271. Mouton de Gruyter (2009)Clough, P., Stevenson, M.: Developing a Corpus of Plagiarised Examples. Language Resources and Evaluation 45(1), 5–24 (2011)Comas, R., Sureda, J.: Academic Cyberplagiarism: Tracing the Causes to Reach Solutions. In: Comas, R., Sureda, J. (eds.) Academic Cyberplagiarism [online dossier], Digithum. Iss, vol. 10, pp. 1–6. UOC (2008), http://bit.ly/cyberplagiarism_csMajumder, P., Mitra, M., Bhattacharyya, P., Subramaniam, L., Contractor, D., Rosso, P. (eds.): FIRE 2010 and 2011. LNCS, vol. 7536. Springer, Heidelberg (2013)Gale, W., Church, K.: A Program for Aligning Sentences in Bilingual Corpora. Computational Linguistics 19, 75–102 (1993)Ghosh, A., Bhaskar, P., Pal, S., Bandyopadhyay, S.: Rule Based Plagiarism Detection using Information Retrieval. In: Petras, et al. [24]Gupta, P., Singhal, K.: Mapping Hindi-English Text Re-use Document Pairs. In: FIRE [12]Head, A.: How today’s college students use Wikipedia for course-related research. First Monday 15(3) (March 2010), http://www.uic.edu/htbin/cgiwrap/bin/ojs/index.php/fm/article/view/2830/2476IEEE: A Plagiarism FAQ (2008), http://bit.ly/ieee_plagiarism (published: 2008; accessed March 3, 2010)Kulathuramaiyer, N., Maurer, H.: Coping With the Copy-Paste-Syndrome. In: Proceedings of World Conference on E-Learning in Corporate, Government, Healthcare, and Higher Education 2007 (E-Learn 2007), pp. 1072–1079. AACE, Quebec City (2007)Lee, C., Wu, C., Yang, H.: A Platform Framework for Cross-lingual Text Relatedness Evaluation and Plagiarism Detection. In: Proceedings of the 3rd International Conference on Innovative Computing Information (ICICIC 2008). IEEE Computer Society (2008)Martínez, I.: Wikipedia Usage by Mexican Students. The Constant Usage of Copy and Paste. In: Wikimania 2009, Buenos Aires, Argentina (2009), http://wikimania2009.wikimedia.orgMaurer, H., Kappe, F., Zaka, B.: Plagiarism - a survey. Journal of Universal Computer Science 12(8), 1050–1084 (2006)Palkovskii, Y., Belov, A.: Exploring Cross Lingual Plagiarism Detection in Hindi-English with n-gram Fingerprinting and VSM based Similarity Detection. In: FIRE [12]Palkovskii, Y., Belov, A., Muzika, I.: Using WordNet-based Semantic Similarity Measurement in External Plagiarism Detection - Notebook for PAN at CLEF 2011. In: Petras, et al. [24]Petras, V., Forner, P., Clough, P. (eds.): Notebook Papers of CLEF 2011 LABs and Workshops, Amsterdam, The Netherlands (September 2011)Potthast, M., Stein, B., Eiselt, A., Barrón-Cedeño, A., Rosso, P.: Overview of the 1st international competition on plagiarism detection. In: Stein, B., Rosso, P., Stamatatos, E., Koppel, M., Agirre, E. (eds.) SEPLN 2009 Workshop on Uncovering Plagiarism, Authorship, and Social Software Misuse (PAN 2009), vol. 502, pp. 1–9. CEUR-WS.org, San Sebastian (2009), http://ceur-ws.org/Vol-502Potthast, M., Barrón-Cedeño, A., Stein, B., Rosso, P.: Cross-Language Plagiarism Detection. Language Resources and Evaluation (LRE), Special Issue on Plagiarism and Authorship Analysis 45(1), 1–18 (2011)Potthast, M., Eiselt, A., Barrón-Cedeño, A., Stein, B., Rosso, P.: Overview of the 3rd International Competition on Plagiarism Detection. In: Petras, et al. [24]Potthast, M., Stein, B., Barrón-Cedeño, A., Rosso, P.: An Evaluation Framework for Plagiarism Detection. In: Huang, C.R., Jurafsky, D. (eds.) Proceedings of the 23rd International Conference on Computational Linguistics (COLING 2010), pp. 997–1005. COLING 2010 Organizing Committee, Beijing (2010)Potthast, M., Barrón-Cedeño, A., Eiselt, A., Stein, B., Rosso, P.: Overview of the 2nd International Competition on Plagiarism Detection. In: Braschler, M., Harman, D. (eds.) Notebook Papers of CLEF 2010 LABs and Workshops, Padua, Italy (September 2010)Rambhoopal, K., Varma, V.: Cross-Lingual Text Reuse Detection Based On Keyphrase Extraction and Similarity Measures. In: FIRE [12]Weber, S.: Das Google-Copy-Paste-Syndrom. Wie Netzplagiate Ausbildung und Wissen gefahrden. Telepolis (2007

PRISM-PSY:Precise GPU-Accelerated Parameter Synthesis for Stochastic Systems

In this paper we present PRISM-PSY, a novel tool that performs precise GPU-accelerated parameter synthesis for continuous-time Markov chains and time-bounded temporal logic specifications. We redesign, in terms of matrix-vector operations, the recently formulated algorithms for precise parameter synthesis in order to enable effective dataparallel processing, which results in significant acceleration on many-core architectures. High hardware utilisation, essential for performance and scalability, is achieved by state space and parameter space parallelisation: the former leverages a compact sparse-matrix representation, and the latter is based on an iterative decomposition of the parameter space. Our experiments on several biological and engineering case studies demonstrate an overall speedup of up to 31-fold on a single GPU compared to the sequential implementation

Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab

Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE

Active site substitutions delineate distinct classes of eubacterial flap endonuclease

FENs (flap endonucleases) play essential roles in DNA replication, pivotally in the resolution of Okazaki fragments. In eubacteria, DNA PolI (polymerase I) contains a flap processing domain, the N-terminal 5′→3′ exonuclease. We present evidence of paralogous FEN-encoding genes present in many eubacteria. Two distinct classes of these independent FEN-encoding genes exist with four groups of eubacteria, being identified based on the number and type of FEN gene encoded. The respective proteins possess distinct motifs hallmarking their differentiation. Crucially, based on primary sequence and predicted secondary structural motifs, we reveal key differences at their active sites. These results are supported by biochemical characterization of two family members - ExoIX (exonuclease IX) from Escherichia coli and SaFEN (Staphylococcus aureus FEN). These proteins displayed marked differences in their ability to process a range of branched and linear DNA structures. On bifurcated substrates, SaFEN exhibited similar substrate specificity to previously characterized FENs. In quantitative exonuclease assays, SaFEN maintained a comparable activity with that reported for PolI. However, ExoIX showed no observable enzymatic activity. A threaded model is presented for SaFEN, demonstrating the probable interaction of this newly identified class of FEN with divalent metal ions and a branched DNA substrate. The results from the present study provide an intriguing model for the cellular role of these FEN sub-classes and illustrate the evolutionary importance of processing aberrant DNA, which has led to their maintenance alongside DNA PolI in many eubacteria

A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

BACKGROUND Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/ kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks

A model for transition of 5 '-nuclease domain of DNA polymerase I from inert to active modes

Bacteria contain DNA polymerase I (PolI), a single polypeptide chain consisting of similar to 930 residues, possessing DNA-dependent DNA polymerase, 3'-5' proofreading and 5'-3' exonuclease (also known as flap endonuclease) activities. PolI is particularly important in the processing of Okazaki fragments generated during lagging strand replication and must ultimately produce a double-stranded substrate with a nick suitable for DNA ligase to seal. PolI's activities must be highly coordinated both temporally and spatially otherwise uncontrolled 5'-nuclease activity could attack a nick and produce extended gaps leading to potentially lethal double-strand breaks. To investigate the mechanism of how PolI efficiently produces these nicks, we present theoretical studies on the dynamics of two possible scenarios or models. In one the flap DNA substrate can transit from the polymerase active site to the 5'-nuclease active site, with the relative position of the two active sites being kept fixed; while the other is that the 5'-nuclease domain can transit from the inactive mode, with the 5'-nuclease active site distant from the cleavage site on the DNA substrate, to the active mode, where the active site and substrate cleavage site are juxtaposed. The theoretical results based on the former scenario are inconsistent with the available experimental data that indicated that the majority of 5'-nucleolytic processing events are carried out by the same PolI molecule that has just extended the upstream primer terminus. By contrast, the theoretical results on the latter model, which is constructed based on available structural studies, are consistent with the experimental data. We thus conclude that the latter model rather than the former one is reasonable to describe the cooperation of the PolI's polymerase and 5'-3' exonuclease activities. Moreover, predicted results for the latter model are presented

Direct observation of DNA threading in flap endonuclease complexes

Maintenance of genome integrity requires that branched nucleic acid molecules are accurately processed to produce double-helical DNA. Flap endonucleases are essential enzymes that trim such branched molecules generated by Okazaki fragment synthesis during replication. Here, we report crystal structures of bacteriophage T5 flap endonuclease in complexes with intact DNA substrates, and products, at resolutions of 1.9–2.2 Å. They reveal single-stranded DNA threading through a hole in the enzyme enclosed by an inverted Vshaped helical arch straddling the active site. Residues lining the hole induce an unusual barb-like conformation in the DNA substrate juxtaposing the scissile phosphate and essential catalytic metal ions. A series of complexes and biochemical analyses show how the substrate’s single-stranded branch approaches, threads through, and finally emerges on the far side of the enzyme. Our studies suggest that substrate recognition involves an unusual “flycasting, thread, bend and barb” mechanis

Anti-inflammatory effect of bee pollen ethanol extract from Cistus sp. of Spanish on carrageenan-induced rat hind paw edema

<p>Abstract</p> <p>Background</p> <p>Bee pollen, a honeybee product, is the feed for honeybees prepared themselves by pollens collecting from plants and has been consumed as a perfect food in Europe, because it is nutritionally well balanced. In this study, we aimed to investigate the anti-inflammatory effect of bee pollen from <it>Cistus </it>sp. of Spanish origin by a method of carrageenan-induced paw edema in rats, and to investigate the mechanism of anti-inflammatory action and also to elucidate components involved in bee pollen extracted with ethanol.</p> <p>Methods</p> <p>The bee pollen bulk, its water extract and its ethanol extract were administered orally to rats. One hour later, paw edema was produced by injecting of 1% solution of carrageenan, and paw volume was measured before and after carrageenan injection up to 5 h. The ethanol extract and water extract were measured COX-1 and COX-2 inhibitory activities using COX inhibitor screening assay kit, and were compared for the inhibition of NO production in LPS-stimulated RAW 264.7 cells. The constituents of bee pollen were purified from the ethanol extract subjected to silica gel or LH-20 column chromatography. Each column chromatography fractions were further purified by repeated ODS or silica gel column chromatography.</p> <p>Results</p> <p>The bee pollen bulk mildly suppressed the carrageenan-induced paw edema and the water extract showed almost no inhibitory activity, but the ethanol extract showed relatively strong inhibition of paw edema. The ethanol extract inhibited the NO production and COX-2 but not COX-1 activity, but the water extract did not affect the NO production or COX activities. Flavonoids were isolated and purified from the ethanol extract of bee pollen, and identified at least five flavonoids and their glycosides.</p> <p>Conclusions</p> <p>It is suggested that the ethanol extract of bee pollen show a potent anti-inflammatory activity and its effect acts <it>via </it>the inhibition of NO production, besides the inhibitory activity of COX-2. Some flavonoids included in bee pollen may partly participate in some of the anti-inflammatory action. The bee pollen would be beneficial not only as a dietary supplement but also as a functional food.</p