Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite

Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin

Reversible silencing of lumbar spinal interneurons unmasks a task-specific network for securing hindlimb alternation

Neural circuitry in the lumbar spinal cord governs two principal features of locomotion, rhythm and pattern, which reflect intra- and interlimb movement. These features are functionally organized into a hierarchy that precisely controls stepping in a stereotypic, speed-dependent fashion. Here, we show that a specific component of the locomotor pattern can be independently manipulated. Silencing spinal L2 interneurons that project to L5 selectively disrupts hindlimb alternation allowing a continuum of walking to hopping to emerge from the otherwise intact network. This perturbation, which is independent of speed and occurs spontaneously with each step, does not disrupt multi-joint movements or forelimb alternation, nor does it translate to a non-weight-bearing locomotor activity. Both the underlying rhythm and the usual relationship between speed and spatiotemporal characteristics of stepping persist. These data illustrate that hindlimb alternation can be manipulated independently from other core features of stepping, revealing a striking freedom in an otherwise precisely controlled system

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-

Physical activity attitudes, intentions and behaviour among 18-25 year olds: a mixed method study

Peer reviewedPublisher PD

Cirsium species show disparity in patterns of genetic variation at their range-edge, despite similar patterns of reproduction and isolation

Genetic variation was assessed across the UK geographical range of Cirsium acaule and Cirsium heterophyllum. A decline in genetic diversity and increase in population divergence approaching the range edge of these species was predicted based on parallel declines in population density and seed production reported seperately. Patterns were compared with UK populations of the widespread Cirsium arvense.Populations were sampled along a latitudinal transect in the UK and genetic variation assessed using microsatellite markers. Cirsium acaule shows strong isolation by distance, a significant decline in diversity and an increase in divergence among range-edge populations. Geographical structure is also evident in C. arvense, whereas no such patterns are seen in C.heterophyllum. There is a major disparity between patterns of genetic variation in C. acaule and C. heterophyllum despite very similar patterns in seed production and population isolation in these species. This suggests it may be misleading to make assumptions about the geographical structure of genetic variation within species based solely on the present-day reproduction and distribution of populations

Clinical course, costs and predictive factors for response to treatment in carpal tunnel syndrome: The PALMS study protocol

Background Carpal tunnel syndrome (CTS) is the most common neuropathy of the upper limb and a significant contributor to hand functional impairment and disability. Effective treatment options include conservative and surgical interventions, however it is not possible at present to predict the outcome of treatment. The primary aim of this study is to identify which baseline clinical factors predict a good outcome from conservative treatment (by injection) or surgery in patients diagnosed with carpal tunnel syndrome. Secondary aims are to describe the clinical course and progression of CTS, and to describe and predict the UK cost of CTS to the individual, National Health Service (NHS) and society over a two year period. Methods/Design In this prospective observational cohort study patients presenting with clinical signs and symptoms typical of CTS and in whom the diagnosis is confirmed by nerve conduction studies are invited to participate. Data on putative predictive factors are collected at baseline and follow-up through patient questionnaires and include standardised measures of symptom severity, hand function, psychological and physical health, comorbidity and quality of life. Resource use and cost over the 2 year period such as prescribed medications, NHS and private healthcare contacts are also collected through patient self-report at 6, 12, 18 and 24 months. The primary outcome used to classify treatment success or failures will be a 5-point global assessment of change. Secondary outcomes include changes in clinical symptoms, functioning, psychological health, quality of life and resource use. A multivariable model of factors which predict outcome and cost will be developed. Discussion This prospective cohort study will provide important data on the clinical course and UK costs of CTS over a two-year period and begin to identify predictive factors for treatment success from conservative and surgical interventions

Aminoglycoside antibiotics and autism: a speculative hypothesis

BACKGROUND: Recently, it has been suspected that there is a relationship between therapy with some antibiotics and the onset of autism; but even more curious, some children benefited transiently from a subsequent treatment with a different antibiotic. Here, we speculate how aminoglycoside antibiotics might be associated with autism. PRESENTATION: We hypothesize that aminoglycoside antibiotics could a) trigger the autism syndrome in susceptible infants by causing the stop codon readthrough, i.e., a misreading of the genetic code of a hypothetical critical gene, and/or b) improve autism symptoms by correcting the premature stop codon mutation in a hypothetical polymorphic gene linked to autism. TESTING: Investigate, retrospectively, whether a link exists between aminoglycoside use (which is not extensive in children) and the onset of autism symptoms (hypothesis "a"), or between amino glycoside use and improvement of these symptoms (hypothesis "b"). Whereas a prospective study to test hypothesis "a" is not ethically justifiable, a study could be designed to test hypothesis "b". IMPLICATIONS: It should be stressed that at this stage no direct evidence supports our speculative hypothesis and that its main purpose is to initiate development of new ideas that, eventually, would improve our understanding of the pathobiology of autism

Adrenal Dysfunction in Hemodynamically Unstable Patients in the Emergency Department

Objective: Adrenal failure, a treatable condition, can have catastrophic consequences if unrecognized in critically ill ED patients. The authors' objective was to prospectively study adrenal function in a case series of hemodynamically unstable (high-risk) patients from a large, urban ED over a 12-month period. Methods: In a prospective manner, critically ill adult patients presenting to the ED were enrolled when presenting with a mean arterial blood pressure ≤60 mm Hg requiring vasopressor therapy for more than one hour after receiving fluid resuscitation (central venous pressure of 12-15 mm Hg or a minimum of 40 mL/kg of crystalloid). Patients were excluded if presenting with hemorrhage, trauma, or AIDS, or if steroids were used within the previous six months. An adrenocorticotropic hormone (ACTH) stimulation test was performed and serum cortisol was measured. Treatment for adrenal insufficiency was not instituted. Results: A total of 57 consecutive patients were studied. Of these, eight (14%) had baseline serum cortisol concentrations of <20 Μg/dL (<552 nmol/L), which was considered adrenal insufficiency (AI). Three additional patients (5%) had subnormal 60-minute post-ACTH-stimulation cortisol responses (<30 Μg/dL) and a delta cortisol ≤9 Μg/dL, which is the difference between the baseline and 60-minute levels. This is functional hypoadrenalism (FH). There were no laboratory abnormalities that distinguished patients with AI or FH from those with preserved adrenal function (PAF). Rates of survival to discharge did not differ between the AI group (7 of 8) and PAF patients (21 of 46; p = 0.052). Conclusions: Adrenal dysfunction is common in high-risk ED patients. Overall, it has a frequency of 19% among a homogeneous population of hemodynamically unstable vasopressor-dependent patients. The effect of physiologic glucocorticoid replacement in this setting remains to be determined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71956/1/j.1553-2712.1999.tb00417.x.pd

Prevalence of Acanthosis Nigricans in an urban population in Sri Lanka and its utility to detect metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Insulin resistance (IR) plays a major role in the pathogenesis of metabolic syndrome. Acanthosis nigricans (AN) is an easily detectable skin condition that is strongly associated with IR. The aims of this study were, firstly, to investigate the prevalence of AN among adults in an urban Sri Lankan community and secondly, to describe its utility to detect metabolic syndrome.</p> <p>Findings</p> <p>In a community based investigation, 35-64 year adults who were selected using stratified random sampling, underwent interview, clinical examination, liver ultrasound scanning, and biochemical and serological tests. Metabolic syndrome was diagnosed on revised ATP III criteria for Asian populations. AN was identified by the presence of dark, thick, velvety skin in the neck.</p> <p>2957 subjects were included in this analysis. The prevalence of AN, metabolic syndrome and type 2 diabetes mellitus were 17.4%, 34.8% and 19.6%, respectively. There was a strong association between AN and metabolic syndrome. The sensitivity, specificity, positive predictive value and negative predictive value of AN to detect metabolic syndrome were 28.2%, 89.0%, 45.9% and 79.0% for males, and 29.2%, 88.4%, 65.6% and 62.3% for females, respectively.</p> <p>Conclusions</p> <p>AN was common in our study population, and although it did not have a high enough sensitivity to be utilized as a screening test for metabolic syndrome, the presence of AN strongly predicts metabolic syndrome.</p