The roles of the subunits in the function of the calcium channel

Dihydropyridine-sensitive voltage-dependent L-type calcium channels are critical to excitation-secretion and excitation-contraction coupling. The channel molecule is a complex of the main, pore-forming subunit alpha 1 and four additional subunits: alpha 2, delta, beta, and gamma (alpha 2 and delta are encoded by a single messenger RNA). The alpha 1 subunit messenger RNA alone directs expression of functional calcium channels in Xenopus oocytes, and coexpression of the alpha 2/delta and beta subunits enhances the amplitude of the current. The alpha 2, delta, and gamma subunits also have pronounced effects on its macroscopic characteristics, such as kinetics, voltage dependence of activation and inactivation, and enhancement by a dihydropyridine agonist. In some cases, specific modulatory functions can be assigned to individual subunits, whereas in other cases the different subunits appear to act in concert to modulate the properties of the channel

Social determinants of content selection in the age of (mis)information

Despite the enthusiastic rhetoric about the so called \emph{collective intelligence}, conspiracy theories -- e.g. global warming induced by chemtrails or the link between vaccines and autism -- find on the Web a natural medium for their dissemination. Users preferentially consume information according to their system of beliefs and the strife within users of opposite narratives may result in heated debates. In this work we provide a genuine example of information consumption from a sample of 1.2 million of Facebook Italian users. We show by means of a thorough quantitative analysis that information supporting different worldviews -- i.e. scientific and conspiracist news -- are consumed in a comparable way by their respective users. Moreover, we measure the effect of the exposure to 4709 evidently false information (satirical version of conspiracy theses) and to 4502 debunking memes (information aiming at contrasting unsubstantiated rumors) of the most polarized users of conspiracy claims. We find that either contrasting or teasing consumers of conspiracy narratives increases their probability to interact again with unsubstantiated rumors.Comment: misinformation, collective narratives, crowd dynamics, information spreadin

The cnidarian parasite Ceratonova shasta utilizes inherited and recruited venom-like compounds during infection

Background Cnidarians are the most ancient venomous organisms. They store a cocktail of venom proteins inside unique stinging organelles called nematocysts. When a cnidarian encounters chemical and physical cues from a potential threat or prey animal, the nematocyst is triggered and fires a harpoon-like tubule to penetrate and inject venom into the prey. Nematocysts are present in all Cnidaria, including the morphologically simple Myxozoa, which are a speciose group of microscopic, spore-forming, obligate parasites of fish and invertebrates. Rather than predation or defense, myxozoans use nematocysts for adhesion to hosts, but the involvement of venom in this process is poorly understood. Recent work shows some myxozoans have a reduced repertoire of venom-like compounds (VLCs) relative to free-living cnidarians, however the function of these proteins is not known. Methods We searched for VLCs in the nematocyst proteome and a time-series infection transcriptome of Ceratonova shasta, a myxozoan parasite of salmonid fish. We used four parallel approaches to detect VLCs: BLAST and HMMER searches to preexisting cnidarian venom datasets, the machine learning tool ToxClassifier, and structural modeling of nematocyst proteomes. Sequences that scored positive by at least three methods were considered VLCs. We then mapped their time-series expressions in the fish host and analyzed their phylogenetic relatedness to sequences from other venomous animals. Results We identified eight VLCs, all of which have closely related sequences in other myxozoan datasets, suggesting a conserved venom profile across Myxozoa, and an overall reduction in venom diversity relative to free-living cnidarians. Expression of the VLCs over the 3-week fish infection varied considerably: three sequences were most expressed at one day post-exposure in the fish’s gills; whereas expression of the other five VLCs peaked at 21 days post-exposure in the intestines, coinciding with the formation of mature parasite spores with nematocysts. Expression of VLC genes early in infection, prior to the development of nematocysts, suggests venoms in C. shasta have been repurposed to facilitate parasite invasion and proliferation within the host. Molecular phylogenetics suggested some VLCs were inherited from a cnidarian ancestor, whereas others were more closely related to sequences from venomous non-Cnidarian organisms and thus may have gained qualities of venom components via convergent evolution. The presence of VLCs and their differential expression during parasite infection enrich the concept of what functions a “venom” can have and represent targets for designing therapeutics against myxozoan infections

Analyzing Users' Activity in On-line Social Networks over Time through a Multi-Agent Framework

[EN] The number of people and organizations using online social networks as a new way of communication is continually increasing. Messages that users write in networks and their interactions with other users leave a digital trace that is recorded. In order to understand what is going on in these virtual environments, it is necessary systems that collect, process, and analyze the information generated. The majority of existing tools analyze information related to an online event once it has finished or in a specific point of time (i.e., without considering an in-depth analysis of the evolution of users activity during the event). They focus on an analysis based on statistics about the quantity of information generated in an event. In this article, we present a multi-agent system that automates the process of gathering data from users activity in social networks and performs an in-depth analysis of the evolution of social behavior at different levels of granularity in online events based on network theory metrics. We evaluated its functionality analyzing users activity in events on Twitter.This work is partially supported by the PROME-TEOII/2013/019, TIN2014-55206-R, TIN2015-65515-C4-1-R, H2020-ICT-2015-688095.Del Val Noguera, E.; Martínez, C.; Botti, V. (2016). Analyzing Users' Activity in On-line Social Networks over Time through a Multi-Agent Framework. Soft Computing. 20(11):4331-4345. https://doi.org/10.1007/s00500-016-2301-0S433143452011Ahn Y-Y, Han S, Kwak H, Moon S, Jeong H (2007) Analysis of topological characteristics of huge online social networking services. In: Proceedings of the 16th WWW, pp 835–844Bastiaensens S, Vandebosch H, Poels K, Cleemput KV, DeSmet A, Bourdeaudhuij ID (2014) Cyberbullying on social network sites. an experimental study into behavioural intentions to help the victim or reinforce the bully. Comput Hum Behav 31:259–271Benevenuto F, Rodrigues T, Cha M, Almeida V (2009) Characterizing user behavior in online social networks. In: Proceedings of the 9th ACM SIGCOMM conference on Internet measurement conference. ACM, pp 49–62Borge-Holthoefer J, Rivero A, García I, Cauhé E, Ferrer A, Ferrer D, Francos D, Iñiguez D, Pérez MP, Ruiz G et al (2011) Structural and dynamical patterns on online social networks: the Spanish may 15th movement as a case study. PLoS One 6(8):e23883Borondo J, Morales AJ, Losada JC, Benito RM (2013) Characterizing and modeling an electoral campaign in the context of Twitter: 2011 Spanish presidential election as a case studyCatanese SA, De Meo P, Ferrara E, Fiumara G, Provetti A (2011) Crawling facebook for social network analysis purposes. In: Proceedings of the international conference on web intelligence, mining and semantics. ACM, p 52Cha M, Mislove A, Gummadi KP (2009) A measurement-driven analysis of information propagation in the flickr social network. In: Proceedings of the 18th international conference on World Wide Web. ACM, pp 721–730del Val E, Martínez C, Botti V (2015a) A multi-agent framework for the analysis of users behavior over time in on-line social networks. In: 10th International conference on soft computing models in industrial and environmental applications. Springer, Berlin, pp 191–201del Val E, Rebollo M, Botti V (2015b) Does the type of event influence how user interactions evolve on twitter? PLOS One 10(5):e0124049Eurostat (2016a) Internet use statistics—individuals. http://ec.europa.eu/eurostat/statistics-explained/index.php/Internet_use_statistics_-_individuals . Accessed 29 April 2016Eurostat (2016b) Social media—statistics on the use by enterprises. http://ec.europa.eu/eurostat/statistics-explained/index.php/Social_media_-_statistics_on_the_use_by_enterprises#Further_Eurostat_information . Accessed 29 April 2016García Fornes AM, Rodrigo Solaz M, Terrasa Barrena AM, Inglada J, Javier V, Jorge Cano J, Mulet Mengual L, Palomares Chust A, Búrdalo Rapa LA, Giret Boggino AS et al (2015) Magentix 2 user’s manualGolbeck J, Robles C, Turner K (2011) Predicting personality with social media. In: CHI’11, pp 253–262Guimerà R, Llorente A, Moro E, Sales-Pardo M (2012) Predicting human preferences using the block structure of complex social networks. PloS One 7(9):e44620Huberman BA, Romero DM, Wu F (2008) Social networks that matter: Twitter under the microscope. arXiv preprint arXiv:0812.1045Jamali M, Abolhassani H (2006) Different aspects of social network analysis. In: 2006 IEEE/WIC/ACM international conference on web intelligence (WI 2006 main conference proceedings)(WI’06). IEEE, pp 66–72Jiang Y, Jiang J (2014) Understanding social networks from a multiagent perspective. Parallel Distrib Syst IEEE Trans 25(10):2743–2759Kossinets G, Watts D (2006) Empirical analysis of an evolving social network. Science 311(5757):88–90Kumar R, Novak J, Tomkins A (2010) Structure and evolution of online social networks. In: Yu PS, Han J, Faloutsos C (eds) Link mining: models, algorithms, and applications. Springer, New York, pp 337–357Lazer D (2009) Life in the network: the coming age of computational social science. Science 323(5915):721–723Leskovec J, Adamic LA, Huberman BA (2007) The dynamics of viral marketing. ACM Trans Web 1(1):5Licoppe C, Smoreda Z (2005) Are social networks technologically embedded? How networks are changing today with changes in communication technology. Soc Netw 27(4):317–335Lotan G, Graeff E, Ananny M, Gaffney D, Pearce I, Boyd D (2011) The revolutions were tweeted: information flows during the 2011 tunisian and egyptian revolutions. Int J Commun 5:1375–1405Peña-López I, Congosto M, Aragón P (2013) Spanish indignados and the evolution of 15M: towards networked para-institutions. Big data: challenges and opportunities, pp 25–26Perliger A, Pedahzur A (2011) Social network analysis in the study of terrorism and political violence. PS Polit Sci Polit 44:45–50Romero DM, Galuba W, Asur S, Huberman BA (2011a) Influence and passivity in social media. In: Proceedings of the 20th WWW, pp 113–114Romero DM, Meeder B, Kleinberg J (2011b) Differences in the mechanics of information diffusion across topics: idioms, political hashtags, and complex contagion on Twitter. In: Proceedings of the 20th WWW, pp 695–704Stockman FN, Doreian P, (1997) Evolution of social networks: processes and principles. In: Doreian P, Stokman FN (eds) Evolution of social networks. Routledge, London, pp 233–250Traud AL, Mucha PJ, Porter MA (2012) Social structure of facebook networks. Phys A Stat Mech Its Appl 391(16):4165–4180Ugander J, Karrer B, Backstrom L, Marlow C (2011) The anatomy of the Facebook social graph. arXiv preprint arXiv:1111.4503Valero S, del Val E, Alemany J, Botti V (2015) Using magentix2 in smart-home environments. In: 10th International conference on soft computing models in industrial and environmental applications. Springer, Berlin, pp 27–37Wasserman S, Faust K (1994) Social network analysis: methods and applications. Cambridge University Press, CambridgeWersm (2015) How much data is generated every minute on social media? http://wersm.com/how-much-data-is-generated-every-minute-on-social-media/ . Accessed 29 April 201

Does \u2018bigger\u2019mean \u2018better\u2019? Pitfalls and shortcuts associated with big data for social research

\u2018Big data is here to stay.\u2019 This key statement has a double value: is an assumption as well as the reason why a theoretical reflection is needed. Furthermore, Big data is something that is gaining visibility and success in social sciences even, overcoming the division between humanities and computer sciences. In this contribution some considerations on the presence and the certain persistence of Big data as a socio-technical assemblage will be outlined. Therefore, the intriguing opportunities for social research linked to such interaction between practices and technological development will be developed. However, despite a promissory rhetoric, fostered by several scholars since the birth of Big data as a labelled concept, some risks are just around the corner. The claims for the methodological power of bigger and bigger datasets, as well as increasing speed in analysis and data collection, are creating a real hype in social research. Peculiar attention is needed in order to avoid some pitfalls. These risks will be analysed for what concerns the validity of the research results \u2018obtained through Big data. After a pars distruens, this contribution will conclude with a pars construens; assuming the previous critiques, a mixed methods research design approach will be described as a general proposal with the objective of stimulating a debate on the integration of Big data in complex research projecting

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10(11) vp/mL, n = 21; 3 × 10(11) vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy

Radical nephroureterectomy for pathologic T4 upper tract urothelial cancer: can oncologic outcomes be improved with multimodality therapy?

Purpose To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes. Materials and Methods Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU. Results The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06). Conclusions Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC

A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging

A hallmark of aging is loss of differentiated cell identity. Age

The GENESIS (Randomized, Multicenter Study of the Pimecrolimus-Eluting and Pimecrolimus/Paclitaxel-Eluting Coronary Stent System in Patients with De Novo Lesions of the Native Coronary Arteries) Trial

ObjectivesThe aim of this study was to compare, in a randomized multicenter trial, paclitaxel-eluting stents (CoStar, Conor Medsystems, Menlo Park, California) versus pimecrolimus-eluting stents (Corio, Conor Medsystems) versus stents with dual elution of both drugs (SymBio, Conor Medsystems) in native coronary arteries.BackgroundThe CoStar cobalt-chromium reservoir-based stent platform, eluting paclitaxel in a controlled way via a bioresorbable polymer, reduces restenosis versus its respective bare-metal stent. The reservoir system allows the use of other drugs targeted to different mechanisms involved in the process of vascular restenosis and simultaneous loading of multiple, synergistic drugs.MethodsPatients with single de novo lesions were asymmetrically randomized to 1 of the 3 types of stent (1:2:2). Six-month coronary angiography was planned in all. The primary analysis was a noninferiority test for the primary end point of 6-month angiographic in-stent late lumen loss of Corio versus CoStar and SymBio versus CoStar. Secondary end points included binary angiographic restenosis and major adverse clinical events (cardiac death, myocardial infarction, target vessel revascularization).ResultsThe trial was prematurely suspended after 246 patients were enrolled (planned enrollment: 375 patients): 49 patients received CoStar, 97 received SymBio, and 100 received Corio. In-stent late loss was significantly reduced with CoStar versus either SymBio or Corio (0.58 ± 0.58 mm vs. 0.96 ± 0.73 mm and 0.58 ± 0.58 mm vs. 1.40 ± 0.67 mm, p < 0.001 for both comparisons). Binary in-stent restenosis rates were, 7.1%, 20%, and 40.9%, respectively (p < 0.001 for both comparisons); 6-month major adverse cardiac event rates were, 2.0%, 14.4%, and 39.0%, respectively (p < 0.001 for both comparisons).ConclusionsStents eluting pimecrolimus or the dual combination of pimecrolimus and paclitaxel failed to show angiographic noninferiority when compared with paclitaxel-eluting stents. (A Randomized, Multi-Center Study of the Pimecrolimus-Eluting and Pimecrolimus/Paclitaxel-Eluting Coronary Stent Systems; NCT00322569

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

© Springer-Verlag GmbH Germany, part of Springer Nature 2018Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients and methods: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Results: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). Conclusion: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.Peer reviewedFinal Accepted Versio