Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 μM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 μM vs C eff = 0.04 ± 0.04 μM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors

Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis

AIMS: The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. METHODS AND RESULTS: Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. CONCLUSIONS: RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans

Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction

Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering

A Universal Model of Global Civil Unrest

Civil unrest is a powerful form of collective human dynamics, which has led to major transitions of societies in modern history. The study of collective human dynamics, including collective aggression, has been the focus of much discussion in the context of modeling and identification of universal patterns of behavior. In contrast, the possibility that civil unrest activities, across countries and over long time periods, are governed by universal mechanisms has not been explored. Here, we analyze records of civil unrest of 170 countries during the period 1919-2008. We demonstrate that the distributions of the number of unrest events per year are robustly reproduced by a nonlinear, spatially extended dynamical model, which reflects the spread of civil disorder between geographic regions connected through social and communication networks. The results also expose the similarity between global social instability and the dynamics of natural hazards and epidemics.Comment: 8 pages, 3 figure

In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2

Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development

Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1.

Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury.

Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction

Bayesian Methods for Exoplanet Science

Exoplanet research is carried out at the limits of the capabilities of current telescopes and instruments. The studied signals are weak, and often embedded in complex systematics from instrumental, telluric, and astrophysical sources. Combining repeated observations of periodic events, simultaneous observations with multiple telescopes, different observation techniques, and existing information from theory and prior research can help to disentangle the systematics from the planetary signals, and offers synergistic advantages over analysing observations separately. Bayesian inference provides a self-consistent statistical framework that addresses both the necessity for complex systematics models, and the need to combine prior information and heterogeneous observations. This chapter offers a brief introduction to Bayesian inference in the context of exoplanet research, with focus on time series analysis, and finishes with an overview of a set of freely available programming libraries.Comment: Invited revie

Recommending Learning Videos for MOOCs and Flipped Classrooms

[EN] New teaching approaches are emerging in higher education, such as flipped classrooms. In addition, academic institutions are offering new types of training like Massive Online Open Courses. Both of these new ways of education require high-quality learning objects for their success, with learning videos being the most common to provide theoretical concepts. This paper describes a hybrid learning recommender system based on content-based techniques, which is able to recommend useful videos to learners and teachers from a learning video repository. This hybrid technique has been successfully applied to a real scenario such as the central video repository of the Universitat Politècnica de València.This work was partially supported by MINECO/FEDER RTI2018-095390-B-C31 and TIN2017-89156-R projects of the Spanish government, and PROMETEO/2018/002 project of Generalitat Valenciana. J. Jordán and V. Botti are funded by UPV PAID-06-18 project. J. Jordán is also funded by grant APOSTD/2018/010 of Generalitat Valenciana - Fondo Social Europeo.Jordán, J.; Valero Cubas, S.; Turró, C.; Botti Navarro, VJ. (2020). Recommending Learning Videos for MOOCs and Flipped Classrooms. Springer. 146-157. https://doi.org/10.1007/978-3-030-49778-1_12S146157Blei, D.M., Ng, A.Y., Jordan, M.I.: Latent Dirichlet allocation. J. Mach. Learn. Res. 3, 993–1022 (2003)Bobadilla, J., Serradilla, F., Hernando, A.: Collaborative filtering adapted to recommender systems of e-learning. Knowl.-Based Syst. 22(4), 261–265 (2009)Burke, R.: Hybrid recommender systems: survey and experiments. User Model. User-Adap. Inter. 12(4), 331–370 (2002)Chen, W., Niu, Z., Zhao, X., Li, Y.: A hybrid recommendation algorithm adapted in e-learning environments. World Wide Web 17(2), 271–284 (2012). https://doi.org/10.1007/s11280-012-0187-zvan Dijck, J., Poell, T.: Higher education in a networked world: European responses to U.S. MOOCs. Int. J. Commun.: IJoC 9, 2674–2692 (2015)Dwivedi, P., Bharadwaj, K.K.: e-learning recommender system for a group of learners based on the unified learner profile approach. Expert Syst. 32(2), 264–276 (2015)Herlocker, J., Konstan, J., Terveen, L., Riedl, J.: Evaluating collaborative filtering recommender systems. ACM Trans. Inf. Syst. 22(1), 5–53 (2004)Institute and Committee of Electrical and Electronics Engineers: Learning Technology Standards: IEEE Standard for Learning Object Metadata. IEEE Standard 1484.12.1 (2002)Klašnja-Milićević, A., Ivanović, M., Nanopoulos, A.: Recommender systems in e-learning environments: a survey of the state-of-the-art and possible extensions. Artif. Intell. Rev. 44(4), 571–604 (2015). https://doi.org/10.1007/s10462-015-9440-zMaassen, P., Nerland, M., Yates, L. (eds.): Reconfiguring Knowledge in Higher Education. Higher Education Dynamics, vol. 50. Springer, Heidelberg (2018). https://doi.org/10.1007/978-3-319-72832-2MLLP research group, Universitat Politècnica de València: Tlp: The translectures-upv platform. http://www.mllp.upv.es/tlpO’Flaherty, J., Phillips, C.: The use of flipped classrooms in higher education: a scoping review. Internet High. Educ. 25, 85–95 (2015)Richardson, M., Dominowska, E., Ragno, R.: Predicting clicks: estimating the click-through rate for new ads. In: Proceedings of the 16th international conference on World Wide Web, pp. 521–530 (2007)Rodríguez, P., Heras, S., Palanca, J., Duque, N., Julián, V.: Argumentation-based hybrid recommender system for recommending learning objects. In: Rovatsos, M., Vouros, G., Julian, V. (eds.) EUMAS/AT -2015. LNCS (LNAI), vol. 9571, pp. 234–248. Springer, Cham (2016). https://doi.org/10.1007/978-3-319-33509-4_19Roehl, A., Reddy, S.L., Shannon, G.J.: The flipped classroom: an opportunity to engage millennial students through active learning strategies. J. Fam. Consum. Sci. 105, 44–49 (2013)Salton, G., Buckley, C.: Term-weighting approaches in automatic text retrieval. Inf. Process. Manag. 24(5), 513–523 (1988)Stoica, A.S., Heras, S., Palanca, J., Julian, V., Mihaescu, M.C.: A semi-supervised method to classify educational videos. In: Pérez García, H., Sánchez González, L., Castejón Limas, M., Quintián Pardo, H., Corchado Rodríguez, E. (eds.) HAIS 2019. LNCS (LNAI), vol. 11734, pp. 218–228. Springer, Cham (2019). https://doi.org/10.1007/978-3-030-29859-3_19Tarus, J.K., Niu, Z., Yousif, A.: A hybrid knowledge-based recommender system for e-learning based on ontology and sequential pattern mining. Future Gener. Comput. Syst. 72, 37–48 (2017)Tucker, B.: The flipped classroom. Online instruction at home frees class time for learning. Educ. Next Winter 2012, 82–83 (2012)Turcu, G., Heras, S., Palanca, J., Julian, V., Mihaescu, M.C.: Towards a custom designed mechanism for indexing and retrieving video transcripts. In: Pérez García, H., Sánchez González, L., Castejón Limas, M., Quintián Pardo, H., Corchado Rodríguez, E. (eds.) HAIS 2019. LNCS (LNAI), vol. 11734, pp. 299–309. Springer, Cham (2019). https://doi.org/10.1007/978-3-030-29859-3_26Turró, C., Morales, J.C., Busquets-Mataix, J.: A study on assessment results in a large scale flipped teaching experience. In: 4th International Conference on Higher Education Advances (HEAD 2018), pp. 1039–1048 (2018)Turró, C., Despujol, I., Busquets, J.: Networked teaching, the story of a success on creating e-learning content at Universitat Politècnica de València. EUNIS J. High. Educ. (2014)Zajda, J., Rust, V. (eds.): Globalisation and Higher Education Reforms. GCEPR, vol. 15. Springer, Cham (2016). https://doi.org/10.1007/978-3-319-28191-