A Minimal Model of Signaling Network Elucidates Cell-to-Cell Stochastic Variability in Apoptosis

Signaling networks are designed to sense an environmental stimulus and adapt to it. We propose and study a minimal model of signaling network that can sense and respond to external stimuli of varying strength in an adaptive manner. The structure of this minimal network is derived based on some simple assumptions on its differential response to external stimuli. We employ stochastic differential equations and probability distributions obtained from stochastic simulations to characterize differential signaling response in our minimal network model. We show that the proposed minimal signaling network displays two distinct types of response as the strength of the stimulus is decreased. The signaling network has a deterministic part that undergoes rapid activation by a strong stimulus in which case cell-to-cell fluctuations can be ignored. As the strength of the stimulus decreases, the stochastic part of the network begins dominating the signaling response where slow activation is observed with characteristic large cell-to-cell stochastic variability. Interestingly, this proposed stochastic signaling network can capture some of the essential signaling behaviors of a complex apoptotic cell death signaling network that has been studied through experiments and large-scale computer simulations. Thus we claim that the proposed signaling network is an appropriate minimal model of apoptosis signaling. Elucidating the fundamental design principles of complex cellular signaling pathways such as apoptosis signaling remains a challenging task. We demonstrate how our proposed minimal model can help elucidate the effect of a specific apoptotic inhibitor Bcl-2 on apoptotic signaling in a cell-type independent manner. We also discuss the implications of our study in elucidating the adaptive strategy of cell death signaling pathways.Comment: 9 pages, 6 figure

Simultaneous measurement of the muon neutrino charged-current cross section on oxygen and carbon without pions in the final state at T2K

Authors: K. Abe,56 N. Akhlaq,45 R. Akutsu,57 A. Ali,32 C. Alt,11 C. Andreopoulos,54,34 L. Anthony,21 M. Antonova,19 S. Aoki,31 A. Ariga,2 T. Arihara,59 Y. Asada,69 Y. Ashida,32 E. T. Atkin,21 Y. Awataguchi,59 S. Ban,32 M. Barbi,46 G. J. Barker,66 G. Barr,42 D. Barrow,42 M. Batkiewicz-Kwasniak,15 A. Beloshapkin,26 F. Bench,34 V. Berardi,22 L. Berns,58 S. Bhadra,70 S. Bienstock,53 S. Bolognesi,6 T. Bonus,68 B. Bourguille,18 S. B. Boyd,66 A. Bravar,13 D. Bravo Berguño,1 C. Bronner,56 S. Bron,13 A. Bubak,51 M. Buizza Avanzini ,10 T. Campbell,7 S. Cao,16 S. L. Cartwright,50 M. G. Catanesi,22 A. Cervera,19 D. Cherdack,17 N. Chikuma,55 G. Christodoulou,12 M. Cicerchia,24,† J. Coleman,34 G. Collazuol,24 L. Cook,42,28 D. Coplowe,42 A. Cudd,7 A. Dabrowska,15 G. De Rosa,23 T. Dealtry,33 S. R. Dennis,34 C. Densham,54 F. Di Lodovico,30 N. Dokania,39 S. Dolan,12 T. A. Doyle,33 O. Drapier,10 J. Dumarchez,53 P. Dunne,21 A. Eguchi,55 L. Eklund,14 S. Emery-Schrenk,6 A. Ereditato,2 A. J. Finch,33 G. Fiorillo,23 C. Francois,2 M. Friend,16,‡ Y. Fujii,16,‡ R. Fujita,55 D. Fukuda,40 R. Fukuda,60 Y. Fukuda,37 K. Fusshoeller,11 C. Giganti,53 M. Gonin,10 A. Gorin,26 M. Guigue,53 D. R. Hadley,66 J. T. Haigh,66 P. Hamacher-Baumann,49 M. Hartz,62,28 T. Hasegawa,16,‡ S. Hassani,6 N. C. Hastings,16 Y. Hayato,56,28 A. Hiramoto,32 M. Hogan,8 J. Holeczek,51 N. T. Hong Van,20,27 T. Honjo,41 F. Iacob,24 A. K. Ichikawa,32 M. Ikeda,56 T. Ishida,16,‡ M. Ishitsuka,60 K. Iwamoto,55 A. Izmaylov,26 N. Izumi,60 M. Jakkapu,16 B. Jamieson,67 S. J. Jenkins,50 C. Jesús-Valls,18 M. Jiang,32 P. Jonsson,21 C. K. Jung,39,§ X. Junjie,57 P. B. Jurj,21 M. Kabirnezhad,42 A. C. Kaboth,48,54 T. Kajita,57,§ H. Kakuno,59 J. Kameda,56 D. Karlen,63,62 S. P. Kasetti,35 Y. Kataoka,56 Y. Katayama,69 T. Katori,30 Y. Kato,56 E. Kearns,3,28,§ M. Khabibullin,26 A. Khotjantsev,26 T. Kikawa,32 H. Kikutani,55 H. Kim,41 S. King,30 J. Kisiel,51 A. Knight,66 T. Kobata,41 T. Kobayashi,16,‡ L. Koch,42 T. Koga,55 A. Konaka,62 L. L. Kormos,33 Y. Koshio,40,§ A. Kostin,26 K. Kowalik,38 H. Kubo,32 Y. Kudenko,26,∥ N. Kukita,41 S. Kuribayashi,32 R. Kurjata,65 T. Kutter,35 M. Kuze,58 L. Labarga,1 J. Lagoda,38 M. Lamoureux,24 D. Last,43 M. Lawe,33 M. Licciardi,10 R. P. Litchfield,14 S. L. Liu,39 X. Li,39 A. Longhin,24 L. Ludovici,25 X. Lu,42 T. Lux,18 L. N. Machado,23 L. Magaletti,22 K. Mahn,36 M. Malek,50 S. Manly,47 L. Maret,13 A. D. Marino,7 L. Marti-Magro,56,28 T. Maruyama,16,‡ T. Matsubara,16 K. Matsushita,55 V. Matveev,26 C. Mauger,43 K. Mavrokoridis,34 E. Mazzucato,6 N. McCauley,34 J. McElwee,50 K. S. McFarland,47 C. McGrew,39 A. Mefodiev,26 C. Metelko,34 M. Mezzetto,24 A. Minamino,69 O. Mineev,26 S. Mine,5 M. Miura,56,§ L. Molina Bueno,11 S. Moriyama,56,§ Th. A. Mueller,10 L. Munteanu,6 S. Murphy,11 Y. Nagai,7 T. Nakadaira,16,‡ M. Nakahata,56,28 Y. Nakajima,56 A. Nakamura,40 K. Nakamura,28,16,‡ S. Nakayama,56,28 T. Nakaya,32,28 K. Nakayoshi,16,‡ C. E. R. Naseby,21 T. V. Ngoc,20,¶ K. Niewczas,68 K. Nishikawa,16,* Y. Nishimura,29 E. Noah,13 T. S. Nonnenmacher,21 F. Nova,54 P. Novella,19 J. Nowak,33 J. C. Nugent,14 H. M. O’Keeffe,33 L. O’Sullivan,50 T. Odagawa,32 T. Ogawa,16 R. Okada,40 K. Okumura,57,28 T. Okusawa,41 S. M. Oser,4,62 R. A. Owen,45 Y. Oyama,16,‡ V. Palladino,23 V. Paolone,44 M. Pari,24 W. C. Parker,48 S. Parsa,13 J. Pasternak,21 M. Pavin,62 D. Payne,34 G. C. Penn,34 L. Pickering,36 C. Pidcott,50 G. Pintaudi,69 C. Pistillo,2 B. Popov,53,** K. Porwit,51 M. Posiadala-Zezula,64 A. Pritchard,34 B. Quilain,10 T. Radermacher,49 E. Radicioni,22 B. Radics,11 P. N. Ratoff,33 C. Riccio,39 E. Rondio,38 S. Roth,49 A. Rubbia,11 A. C. Ruggeri,23 C. Ruggles,14 A. Rychter,65 K. Sakashita,16,‡ F. Sánchez,13 G. Santucci,70 C. M. Schloesser,11 K. Scholberg,9,§ M. Scott,21 Y. Seiya,41,†† T. Sekiguchi,16,‡ H. Sekiya,56,28,§ D. Sgalaberna,11 A. Shaikhiev,26 A. Shaykina,26 M. Shiozawa,56,28 W. Shorrock,21 A. Shvartsman,26 M. Smy,5 J. T. Sobczyk,68 H. Sobel,5,28 F. J. P. Soler,14 Y. Sonoda,56 S. Suvorov,26,6 A. Suzuki,31 S. Y. Suzuki,16,‡ Y. Suzuki,28 A. A. Sztuc,21 M. Tada,16,‡ M. Tajima,32 A. Takeda,56 Y. Takeuchi,31,28 H. K. Tanaka,56,§ H. A. Tanaka,52,61 S. Tanaka,41 Y. Tanihara,69 N. Teshima,41 L. F. Thompson,50 W. Toki,8 C. Touramanis,34 T. Towstego,61 K. M. Tsui,34 T. Tsukamoto,16,‡ M. Tzanov,35 Y. Uchida,21 M. Vagins,28,5 S. Valder,66 Z. Vallari,39 D. Vargas,18 G. Vasseur,6 W. G. S. Vinning,66 T. Vladisavljevic,54 V. V. Volkov,26 T. Wachala,15 J. Walker,67 J. G. Walsh,33 Y. Wang,39 D. Wark,54,42 M. O. Wascko,21 A. Weber,54,42 R. Wendell,32,§ M. J. Wilking,39 C. Wilkinson,2 J. R. Wilson,30 K. Wood,39 C. Wret,47 K. Yamamoto,41,†† C. Yanagisawa,39,‡‡ G. Yang,39 T. Yano,56 K. Yasutome,32 N. Yershov,26 M. Yokoyama,55,§ T. Yoshida,58 M. Yu,70 A. Zalewska,15 J. Zalipska,38 K. Zaremba,65 G. Zarnecki,38 M. Ziembicki,65 E. D. Zimmerman,7 M. Zito,53 S. Zsoldos,30 and A. Zykova26 (T2K Collaboration)This paper reports the first simultaneous measurement of the double differential muon neutrino chargedcurrent cross section on oxygen and carbon without pions in the final state as a function of the outgoing muon kinematics, made at the ND280 off-axis near detector of the T2K experiment. The ratio of the oxygen and carbon cross sections is also provided to help validate various models’ ability to extrapolate between carbon and oxygen nuclear targets, as is required in T2K oscillation analyses. The data are taken using a neutrino beam with an energy spectrum peaked at 0.6 GeV. The extracted measurement is compared with the prediction from different Monte Carlo neutrino-nucleus interaction event generators, showing particular model separation for very forward-going muons. Overall, of the models tested, the result is best described using local Fermi gas descriptions of the nuclear ground state with RPA suppression

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS:Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting

PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p 10(-4) associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.Peer reviewe

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma

Background: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. Methods: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. Results: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. Conclusions and interpretations: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment

Assessment of the Antiviral Properties of Recombinant Porcine SP-D against Various Influenza A Viruses In Vitro

The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs) in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted

Measurement of neutrino and antineutrino neutral-current quasielasticlike interactions on oxygen by detecting nuclear deexcitation γ rays

Neutrino- and antineutrino-oxygen neutral-current quasielastic-like interactions are measured at Super-Kamiokande using nuclear de-excitation $\gamma$-rays to identify signal-like interactions in data from a $14.94 \ (16.35)\times 10^{20}$protons-on-target exposure of the T2K neutrino (antineutrino) beam. The measured flux-averaged cross sections on oxygen nuclei are$\langle \sigma_{\nu {\rm -NCQE}} \rangle = 1.70 \pm 0.17 ({\rm stat.}) ^{+ {\rm 0.51}}_{- {\rm 0.38}} ({\rm syst.}) \times 10^{-38} \ {\rm cm^2/oxygen}$with a flux-averaged energy of 0.82 GeV and$\langle \sigma_{\bar{\nu} {\rm -NCQE}} \rangle = 0.98 \pm 0.16 ({\rm stat.}) ^{+ {\rm 0.26}}_{- {\rm 0.19}} ({\rm syst.}) \times 10^{-38} \ {\rm cm^2/oxygen}$ with a flux-averaged energy of 0.68 GeV, for neutrinos and antineutrinos, respectively. These results are the most precise to date, and the antineutrino result is the first cross section measurement of this channel. They are compared with various theoretical predictions. The impact on evaluation of backgrounds to searches for supernova relic neutrinos at present and future water Cherenkov detectors is also discussed

Search for electron antineutrino appearance in a long-baseline muon antineutrino beam

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions