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

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

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

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

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

Reachability computation for switching diffusions: Finite abstractions with certifiable and tuneable precision

We consider continuous time stochastic hybrid systems with no resets and continuous dynamics described by linear stochastic differential equations - models also known as switching diffusions. We show that for this class of models reachability (and dually, safety) properties can be studied on an abstraction defined in terms of a discrete time and finite space Markov chain (DTMC), with provable error bounds. The technical contribution of the paper is a characterization of the uniform convergence of the time discretization of such stochastic processes with respect to safety properties. This allows us to newly provide a complete and sound numerical procedure for reachability and safety computation over switching diffusions

The wonders of flap endonucleases: structure, function, mechanism and regulation.

Processing of Okazaki fragments to complete lagging strand DNA synthesis requires coordination among several proteins. RNA primers and DNA synthesised by DNA polymerase α are displaced by DNA polymerase δ to create bifurcated nucleic acid structures known as 5'-flaps. These 5'-flaps are removed by Flap Endonuclease 1 (FEN), a structure-specific nuclease whose divalent metal ion-dependent phosphodiesterase activity cleaves 5'-flaps with exquisite specificity. FENs are paradigms for the 5' nuclease superfamily, whose members perform a wide variety of roles in nucleic acid metabolism using a similar nuclease core domain that displays common biochemical properties and structural features. A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester. A proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5' nuclease superfamily. The homotrimeric proliferating cell nuclear antigen protein (PCNA) coordinates the actions of DNA polymerase, FEN and DNA ligase by facilitating the hand-off intermediates between each protein during Okazaki fragment maturation to maximise through-put and minimise consequences of intermediates being released into the wider cellular environment. FEN has numerous partner proteins that modulate and control its action during DNA replication and is also controlled by several post-translational modification events, all acting in concert to maintain precise and appropriate cleavage of Okazaki fragment intermediates during DNA replication

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes : Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

Background: The potential for global collaborations to better inform public health policy regarding major non-hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. (C) 2016 Elsevier Ireland Ltd.Peer reviewe

L’influence des relations familiales et sociales sur la consommation de médicaments psychotropes chez les personnes âgées

Les psychotropes occupent le deuxième rang dans la consommation de médicaments chez les personnes âgées. L'objectif de cette étude est de vérifier un modèle explicatif de la consommation de psychotropes dans cette population. Notre principale hypothèse est que la qualité des relations qu'entretient une personne âgée avec autrui, et particulièrement avec ses enfants, a une influence directe sur son bien-être psychologique, lequel a une influence directe sur la non-consommation de psychotropes. Une enquête a été réalisée auprès d'un échantillon de 500 personnes âgées de 65 à 84 ans, vivant à domicile. Au cours des trois mois précédant l'entrevue, 31,8 % des répondants ont consommé des psychotropes. Les données empiriques n'ayant pas permis de vérifier le modèle théorique retenu, des analyses multivariées ont conduit à l'élaboration d'un modèle explicatif de la consommation qui met en évidence que le bien-être psychologique et la santé sont les meilleurs prédicteurs de cette consommation. Un bien-être psychologique élevé diminue la consommation alors qu'un mauvais état de santé l'augmente. Les relations sociales influencent directement le bien-être psychologique alors que les relations familiales ont un effet de moindre importance. Le modèle explicatif proposé explique 13 % du phénomène de la consommation de psychotropes chez les personnes âgées.Psychotropic drugs are the second most commonly used medication by Quebec's elderly. The objective of this study is to test a theoretical model of psychotropic drug use in the elderly. The principal hypothesis is that the quality of relationships the elderly person has with others, particularly with his or her children, has a direct influence on his or her psychological well-being, which, in turn, directly affects the consumption of psychotropic agents. A survey was conducted on a sample of 500 elderly people, aged 65-84 years, living at home. 31.8% of the respondents used psychotropic drugs during the three-month period preceding the interview. Path analysis led to the elaboration of a modified model for the consumption of psychotropic drugs by the elderly which indicates that the best predictors of consumption are both the psychological well-being and the state of health of the individual. More elevated is the psychological well-being, less is the consumption of psychotropic drugs, whereas poor health condition increases it. The quality of an individual's social relationships has a direct influence on his or her psychological well-being, whereas family relationships are of lesser importance. Our model accounts for 13% of the predictors of psychotropic consumption by the elderly