Rigid Chiral Membranes

Statistical ensembles of flexible two-dimensional fluid membranes arise naturally in the description of many physical systems. Typically one encounters such systems in a regime of low tension but high stiffness against bending, which is just the opposite of the regime described by the Polyakov string. We study a class of couplings between membrane shape and in-plane order which break 3-space parity invariance. Remarkably there is only {\it one} such allowed coupling (up to boundary terms); this term will be present for any lipid bilayer composed of tilted chiral molecules. We calculate the renormalization-group behavior of this relevant coupling in a simplified model and show how thermal fluctuations effectively reduce it in the infrared.Comment: 11 pages, UPR-518T (This replaced version has fonts not used removed.

A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation

[EN] Curve squeal is an intense tonal noise occurring when a rail vehicle negotiates a sharp curve. The phenomenon can be considered to be chaotic, with a widely differing likelihood of occurrence on different days or even times of day. The term curve squeal may include several different phenomena with a wide range of dominant frequencies and potentially different excitation mechanisms. This review addresses the different squeal phenomena and the approaches used to model squeal noise; both time-domain and frequency-domain approaches are discussed and compared. Supporting measurements using test rigs and field tests are also summarised. A particular aspect that is addressed is the excitation mechanism. Two mechanisms have mainly been considered in previous publications. In many early papers the squeal was supposed to be generated by the so-called falling friction characteristic in which the friction coefficient reduces with increasing sliding velocity. More recently the mode coupling mechanism has been raised as an alternative. These two mechanisms are explained and compared and the evidence for each is discussed. Finally, a short review is given of mitigation measures and some suggestions are offered for why these are not always successful.Squicciarini, G.; Thompson, D.; Ding, B.; Baeza González, LM. (2018). A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation. Notes on Numerical Fluid Mechanics and Multidisciplinary Design. 139:3-41. https://doi.org/10.1007/978-3-319-73411-8_1S341139Anderson, D., Wheatley, N., Fogarty, B., Jiang, J., Howie, A., Potter, W.: Mitigation of curve squeal noise in Queensland, New South Wales and South Australia. In: Conference on Railway Engineering. pp. 625–636, Perth, Australia (2008)Hanson, D., Jiang, J., Dowdell, B., Dwight, R.: Curve squeal: causes, treatments and results. In INTER-NOISE and NOISE-CON Congress and Conference Proceedings, vol. 249, pp. 6316–6323. Melbourne, Australia (2014)Rudd, M.J.: Wheel/rail noise—part II: wheel squeal. J. Sound Vib. 46(3), 381–394 (1976)Remington, P.J.: Wheel/rail squeal and impact noise: what do we know? What don’t we know? Where do we go from here? J. Sound Vib. 116(2), 339–353 (1987)Remington, P.J.: Wheel/rail rolling noise: what do we know? What don’t we know? Where do we go from here? J. Sound Vib. 120(2), 203–226 (1988)Wickens, A.H.: Fundamentals of Rail Vehicle Dynamics, Guidance and Stability. Swets & Zeitlinger, Lisse (2003)Thompson, D.J.: Railway Noise and Vibration: Mechanisms, Modelling and Mitigation. Elsevier, Oxford (2009)Kalker, J.J.: Three Dimensional Elastic Bodies in Rolling Contact. Kluwer academic publishers, Dordrecht (1990)Vermeulen, P.J., Johnson, K.L.: Contact of nonspherical elastic bodies transmitting tangential forces. J. Appl. Mech. 31(2), 338–340 (1964)Shen, Z.Y., Hedrick, J.K., Elkins, J.A.: A comparison of alternative creep-force models for rail vehicle dynamic analysis. In: Proceedings of 8th IAVSD Symposium, Cambridge MA, Swets and Zeitlinger, Lisse, pp. 591–605 (1983)Huang, Z.Y.: Theoretical Modelling of Railway Curve Squeal. Ph.D. thesis, University of Southampton, UK (2007)Hoffmann, N., Fischer, M., Allgaier, R., Gaul, L.: A minimal model for studying properties of the mode-coupling type instability in friction induced oscillations. Mech. Res. Commun. 29(4), 197–205 (2002)Hoffmann, N., Gaul, L.: Effects of damping on mode-coupling instability in friction induced oscillations. J. Appl. Math. Mech. 83(8), 524–534 (2003)Sinou, J.J., Jezequel, L.: Mode coupling instability in friction-induced vibrations and its dependency on system parameters including damping. Eur. J. Mech.-A/Solids 26(1), 106–122 (2007)Johnson, K.L.: Contact Mechanics. Cambridge University Press, Cambridge (1985)Kinkaid, N.M., O’Reilly, O.M., Papadopoulos, P.: Automotive disc brake squeal. J. Sound Vib. 267(1), 105–166 (2003)Ghazaly, N.M., El-Sharkawy, M., Ahmed, I.: A review of automotive brake squeal mechanisms. J. Mech. Des. Vibr. 1(1), 5–9 (2013)Ouyang, H., Nack, W., Yuan, Y., Chen, F.: Numerical analysis of automotive disc brake squeal: a review. Int. J. Veh. Noise Vib. 1(3–4), 207–231 (2005)Dorf, R.C., Bishop, R.H.: Modern Control Systems, 11th edn. Prentice Hall. (2008)De Beer, F.G., Janssens, M.H.A., Kooijman, P.P., van Vliet, W.J.: Curve squeal of railbound vehicles (part 1): frequency domain calculation model. In: Proceedings of Internoise, vol. 3, pp. 1560–1563. Nice, France (2000)Von Stappenbeck, H.: Das Kurvengeräusch der Straßenbahn. Möglichkeiten zu seiner Unterdrückung. Z. VDI 96(6), 171–175 (1954)Van Ruiten, C.J.M.: Mechanism of squeal noise generated by trams. J. Sound Vib. 120(2), 245–253 (1988)Nakai, M., Chiba, Y., Yokoi, M.: Railway wheel squeal: 1st report, on frequency of squeal. Bull. Jpn. Soc. Mech. Eng. 25, 1127–1134 (1982)Nakai, M., Chiba, Y., Yokoi, M.: Railway wheel squeal: 2nd report, mechanism of specific squeal frequency. Bull. Jpn. Soc. Mech. Eng. 27, 301–308 (1984)Nakai, M., Chiba, Y., Yokoi, M.: Railway wheel squeal: 3rd report, squeal of a disk simulating a wheel in internal resonances. Bull. Jpn. Soc. Mech. Eng. 28, 500–507 (1985)Schneider, E., Popp, K., Irretier, H.: Noise generation in railway wheels due to rail-wheel contact forces. J. Sound Vib. 120(2), 227–244 (1988)Kraft, K.: Der Einfluß der Fahrgeschwindigkeit auf den Haftwert zwischen Rad und Schiene. Arch. für Eisenbahntechnik 22, 58–78 (1967)Fingberg, U.: A model of wheel-rail squealing noise. J. Sound Vib. 143(3), 365–377 (1990)Périard, F.: Wheel-Rail Noise Generation: Curve Squealing by Trams. Ph.D. thesis, Technische Universiteit Delft (1998)Heckl, M.A., Abrahams, I.D.: Curve squeal of train wheels, part 1: mathematical model for its generation. J. Sound Vib. 229(3), 669–693 (2000)Heckl, M.A.: Curve squeal of train wheels, part 2: which wheel modes are prone to squeal? J. Sound Vib. 229(3), 695–707 (2000)Heckl, M.A.: Curve squeal of train wheels: unstable modes and limit cycles. Proc. R. Soc. Lond. A: Math. Phys. Eng. Sci. 458, 1949–1965 (2002)Liu, X., Meehan, P.A.: Wheel squeal noise: a simplified model to simulate the effect of rolling speed and angle of attack. J. Sound Vib. 338, 184–198 (2015)Meehan, P.A., Liu, X.: Analytical prediction and investigation of wheel squeal amplitude. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 69–80. Springer, Heidelberg (2018)Kooijman, P.P., Van Vliet, W.J., Janssens, M.H.A., De Beer, F.G.: Curve squeal of railbound vehicles (part 2): set-up for measurement of creepage dependent friction coefficient. In: Proceedings of Internoise, vol. 3, pp. 1564–1567. Nice, France (2000)De Beer, F.G., Janssens, M.H.A., Kooijman, P.P.: Squeal noise of rail-bound vehicles influenced by lateral contact position. J. Sound Vib. 267(3), 497–507 (2003)Thompson, D.J., Hemsworth, B., Vincent, N.: Experimental validation of the TWINS prediction program for rolling noise, part 1: description of the model and method. J. Sound Vib. 193(1), 123–135 (1996)Monk-Steel, A., Thompson, D.J.: Models for railway curve squeal noise. In: VIII International Conference on Recent Advances in Structural Dynamics, Southampton, UK (2003)Barman, J.F., Katzenelson, J.: A generalized Nyquist-type stability criterion for multivariable feedback systems. Int. J. Control 20(4), 593–622 (1974)Huang, Z.Y., Thompson, D.J., Jones, C.J.C.: Squeal prediction for a bogied vehicle in a curve. In Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM vol. 99, pp. 313–319. Springer, Heidelberg (2008)Hsu, S.S., Huang, Z., Iwnicki, S.D., Thompson, D.J., Jones, C.J., Xie, G., Allen, P.D.: Experimental and theoretical investigation of railway wheel squeal. Proc. Inst. Mech. Eng. Part F: J. Rail Rapid Transit 221(1), 59–73 (2007)Squicciarini, G., Usberti, S., Thompson, D.J., Corradi, R., Barbera, A.: Curve squeal in the presence of two wheel/rail contact points. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 603–610. Springer, Heidelberg (2015)Xie, G., Allen, P.D., Iwnicki, S.D., Alonso, A., Thompson, D.J., Jones, C.J., Huang, Z.Y.: Introduction of falling friction coefficients into curving calculations for studying curve squeal noise. Veh. Syst. Dyn. 44(sup1), 261–271 (2006)Giménez, J.G., Alonso, A., Gómez, E.: Introduction of a friction coefficient dependent on the slip in the FastSim algorithm. Veh. Syst. Dyn. 43(4), 233–244 (2005)Chiello, O., Ayasse, J.B., Vincent, N., Koch, J.R.: Curve squeal of urban rolling stock—part 3: theoretical model. J. Sound Vib. 293(3), 710–727 (2006)Collette, C.: Importance of the wheel vertical dynamics in the squeal noise mechanism on a scaled test bench. Shock Vibr. 19(2), 145–153 (2012)Brunel, J.F., Dufrénoy, P., Naït, M., Muñoz, J.L., Demilly, F.: Transient models for curve squeal noise. J. Sound Vib. 293(3), 758–765 (2006)Glocker, C., Cataldi-Spinola, E., Leine, R.I.: Curve squealing of trains: measurement, modelling and simulation. J. Sound Vib. 324(1), 365–386 (2009)Pieringer, A.: A numerical investigation of curve squeal in the case of constant wheel/rail friction. J. Sound Vib. 333(18), 4295–4313 (2014)Pieringer, A., Kropp, W.: A time-domain model for coupled vertical and tangential wheel/rail interaction—a contribution to the modelling of curve squeal. In: Maeda, T., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 118, pp. 221–229. Springer, Heidelberg (2012)Pieringer, A., Baeza, L., Kropp. W.: Modelling of railway curve squeal including effects of wheel rotation. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 417–424. Springer, Heidelberg (2015)Zenzerovic, I., Pieringer, A., Kropp. W.: Towards an engineering model for curve squeal. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 433–440. Springer, Heidelberg (2015)Zenzerovic, I., Kropp, W., Pieringer, A.: An engineering time-domain model for curve squeal: tangential point-contact model and Green’s functions approach. J. Sound Vib. 376, 149–165 (2016)Pieringer, A., Torstensson, P.T., Giner, J., Baeza, L.: Investigation of railway curve squeal using a combination of frequency- and time-domain models. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 81–93. Springer, Heidelberg (2018)Chen, G.X., Xiao, J.B., Liu, Q.Y., Zhou. Z.R.: Complex eigenvalue analysis of railway curve squeal. In: Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 99, pp. 433–439. Springer, Heidelberg (2008)Fourie, D.J., Gräbe, P.J., Heyns, P.S., Fröhling, R.D.: Analysis of wheel squeal due to unsteady longitudinal creepage using the complex eigenvalue method. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 55–67. Springer, Heidelberg (2018)Wang, C., Dwight, R., Li, W., Jiang, J.: Prediction on curve squeal in the case of constant wheel rail friction coefficient. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp XXX–XXX. Springer, Heidelberg (2018)Ding, B., Squicciarini, G., Thompson, D.J.: Effects of rail dynamics and friction characteristics on curve squeal. In: XIII International Conference on Motion and Vibration Control and XII International Conference on Recent Advances in Structural Dynamics (MoViC/RASD), Southampton (2016)Bleedorn, T.G., Johnstone. B.: Steerable steel wheel systems and wheel noise suppression. In: Conference Rec IAS 12th Annual Meeting, Los Angeles, California (1977)Koch, J.R., Vincent, N., Chollet, H., Chiello, O.: Curve squeal of urban rolling stock—part 2: parametric study on a 1/4 scale test rig. J. Sound Vib. 293(3), 701–709 (2006)Logston, C.F., Itami, G.S.: Locomotive friction-creep studies. ASME J. Eng. Ind. 102(3), 275–281 (1980)Ertz, M.: Creep force laws for wheel/rail contact with temperature-dependent coefficient of friction. In: 8th Mini Conference on Vehicle System Dynamics, Identification and Anomalies, Budapest (2002)Lang, W., Roth, R.: Optimale Kraftschlussausnutzung bei Hochleistungs-Schienenfahrzeugen. Eisenbahntechnische Rundsch. 42, 61–66 (1993)Polach, O.: Creep forces in simulations of traction vehicles running on adhesion limit. Wear 258(7), 992–1000 (2005)Zhang, W., Chen, J., Wu, X., Jin, X.: Wheel/rail adhesion and analysis by using full scale roller rig. Wear 253(1), 82–88 (2002)Harrison, H., McCanney, T., Cotter, J.: Recent developments in coefficient of friction measurements at the rail/wheel interface. Wear 253(1), 114–123 (2002)Gallardo-Hernandez, E.A., Lewis, R.: Twin disc assessment of wheel/rail adhesion. Wear 265(9), 1309–1316 (2008)Fletcher, D.I., Lewis, S.: Creep curve measurement to support wear and adhesion modelling, using a continuously variable creep twin disc machine. Wear 298–299, 57–65 (2013)Fletcher, D.I.: A new two-dimensional model of rolling–sliding contact creep curves for a range of lubrication types. Proc. Inst. Mech. Eng. Part J: J. Eng. Tribol. 227(6), 529–537 (2013)Matsumoto, A., Sato, Y., Ono, H., Wang, Y., Yamamoto, M., Tanimoto, M., Oka, Y.: Creep force characteristics between rail and wheel on scaled model. Wear 253(1), 199–203 (2002)Janssens, M.H.A., van Vliet, W.J., Kooijman, P.P., De Beer, F.G.: Curve squeal of railbound vehicles (part 3): measurement method and results. In: Proceedings of Internoise, vol. 3, pp. 1568–1571, Nice, France (2000)Monk-Steel, A.D., Thompson, D.J., De Beer, F.G., Janssens, M.H.A.: An investigation into the influence of longitudinal creepage on railway squeal noise due to lateral creepage. J. Sound Vib. 293(3), 766–776 (2006)Liu, X., Meehan, P.A.: Investigation of the effect of lateral adhesion and rolling speed on wheel squeal noise. Proc. Inst. Mech. Eng. Part F: J. Rail Rapid Transit 227(5), 469–480 (2013)Liu, X., Meehan, P.A.: Investigation of the effect of relative humidity on lateral force in rolling contact and curve squeal. Wear 310(1), 12–19 (2014)Liu, X., Meehan, P.A.: Investigation of squeal noise under positive friction characteristics condition provided by friction modifiers. J. Sound Vib. 371, 393–405 (2016)Jie, E., Kim, J.Y., Hwang, D.H., Lee, J.H., Kim, K.J., Kim, J.C.: An experimental study of squeal noise characteristics for railways using a scale model test rig. In: J. Pombo (ed.) Proceedings of the Third International Conference on Railway Technology: Research, Development and Maintenance, Cagliari, Sardinia, Italy (2016)Eadie, D.T., Santoro, M., Kalousek, J.: Railway noise and the effect of top of rail liquid friction modifiers: changes in sound and vibration spectral distributions in curves. Wear 258(7), 1148–1155 (2005)Bullen, R., Jiang, J.: Algorithms for detection of rail wheel squeal. In: 20th International Congress on Acoustics 2010, ICA 2010—Incorporating Proceedings of the 2010 Annual Conference of the Australian Acoustical Society. pp. 2212–2216 (2010)Stefanelli, R., Dual, J., Cataldi-Spinola, E.: Acoustic modelling of railway wheels and acoustic measurements to determine involved eigenmodes in the curve squealing phenomenon. Veh. Syst. Dyn. 44(sup1), 286–295 (2006)Vincent, N., Koch, J.R., Chollet, H., Guerder, J.Y.: Curve squeal of urban rolling stock—part 1: state of the art and field measurements. J. Sound Vib. 293(3), 691–700 (2006)Anderson, D., Wheatley, N.: Mitigation of wheel squeal and flanging noise on the Australian network. In: Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 99, pp. 399–405. Springer, Heidelberg (2008)Curley, D., Anderson, D.C., Jiang, J., Hanson, D.: Field trials of gauge face lubrication and top-of-rail friction modification for curve noise mitigation. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 449–456. Springer, Heidelberg (2015)Jiang, J., Hanson, D., Dowdell, B.: Wheel squeal—insights from wayside condition monitoring measurements and field trials. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 41–53. Springer, Heidelberg (2018)Jiang, J., Dwight, R., Anderson, D.: Field verification of curving noise mechanisms. In: Maeda, T., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 118, pp. 349–356. Springer, Heidelberg (2012)Jiang, J., Anderson, D.C., Dwight, R.: The mechanisms of curve squeal. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 587–594. Springer, Heidelberg (2015)Fourie, D.J., Gräbe, P.J., Heyns, P.S., Fröhling, R.D.: Experimental characterisation of railway wheel squeal occurring in large-radius curves. Proc. Inst. Mech. Eng. Part F: J. Rail Rapid Transit 230(6), 1561–1574 (2016)Corradi, R., Crosio, P., Manzoni, S., Squicciarini, G.: Experimental investigation on squeal noise in tramway sharp curves. In: Proceedings of the 8th International Conference on Structural Dynamics, EURODYN 2011, Leuven (2011)Merideno, I., Nieto, J., Gil-Negrete, N., Landaberea, A., Iartza, J.: Constrained layer damper modelling and performance evaluation for eliminating squeal noise in trams. Shock and Vibration (2014)Nelson J.T.: Wheel/rail noise control manual, TCRP Report 23 (1997)Krüger, F.: Schall- und Erschütterungsschutz im Schienenverkehr. Expert Verlag, Renningen (2001)Elbers, F., Verheijen, E.: Railway noise technical measures catalogue, UIC report UIC003-01-04fe (2013)Oertli, J.: Combatting curve squeal, phase II, final report, UIC (2005)Eadie, D.T., Santoro, M., Powell, W.: Local control of noise and vibration with KELTRACK™ friction modifier and protector® trackside application: an integrated solution. J. Sound Vib. 267(3), 761–772 (2003)Eadie, D.T., Santoro, M.: Top-of-rail friction control for curve noise mitigation and corrugation rate reduction. J. Sound Vib. 293(3), 747–757 (2006)Suda, Y., Iwasa, T., Komine, H., Tomeoka, M., Nakazawa, H., Matsumoto, K., Nakai, T., Tanimoto, M., Kishimoto, Y.: Development of onboard friction control. Wear 258(7), 1109–1114 (2005)Bühler, S., Thallemer, B.: How to avoid squeal noise on railways: state of the art and practical experience. In: Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 99, pp. 406–411. Springer, Heidelberg (2008)Jones, C.J.C., Thompson, D.J.: Rolling noise generated by railway wheels with visco-elastic layers. J. Sound Vib. 231(3), 779–790 (2000)Wetta, P., Demilly, F.: Reduction of wheel squeal noise generated on curves or during braking. In 11th International of Wheelset Congress, Paris (1995)Brunel, J.F., Dufrénoy, P., Demilly, F.: Modelling of squeal noise attenuation of ring damped wheels. Appl. Acoust. 65(5), 457–471 (2004)Marjani, S.R., Younesian, D.: Suppression of train wheel squeal noise by shunted piezoelectric elements. Int. J. Struct. Stab. Dyn. (2016)Heckl, M.A., Huang, X.Y.: Curve squeal of train wheels, part 3: active control. J. Sound Vib. 229(3), 709–735 (2000)Thompson, D.J., Jones, C.J.C., Waters, T.P., Farrington, D.: A tuned damping device for reducing noise from railway track. Appl. Acoust. 68(1), 43–57 (2007)Jiang, J., Ying, I., Hanson, D., Anderson, D.C.: An investigation of the influence of track dynamics on curve noise. In: Nielsen, J.C.O., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 126, pp. 441–448. Springer, Heidelberg (2015)Toward, M., Squicciarini, G., Thompson, D.J.: Reducing freight wagon noise at source. Int. Railway J. March, 47–49 (2015)Illingworth, R., Pollard, M.G.: The use of steering axle suspensions to reduce wheel and rail wear in curves. Proc. Inst. Mech. Eng. 196(1), 379–385 (1982)Garcia, J.F., Olaizola, X., Martin, L.M., Gimenez, J.G.: Theoretical comparison between different configurations of radial and conventional bogies. Veh. Syst. Dyn. 33(4), 233–259 (2000)Bruni, S., Goodall, R., Mei, T.X., Tsunashima, H.: Control and monitoring for railway vehicle dynamics. Veh. Syst. Dyn. 45(7–8), 743–779 (2007)Hiensch, M., Larsson, P.O., Nilsson, O., Levy, D., Kapoor, A., Franklin, F., Nielsen, J., Ringsberg, J., Josefson, L.: Two-material rail development: field test results regarding rolling contact fatigue and squeal noise behaviour. Wear 258(7), 964–972 (2005)Kopp, E.: Fünf Jahre Erfahrungen mit asymmetrisch geschliffenen Schienenprofilen. Eisenbahn Techn. Rundsch. 40, 665 (1991

Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future

Meta Modeling for Business Process Improvement

Conducting business process improvement (BPI) initiatives is a topic of high priority for today’s companies. However, performing BPI projects has become challenging. This is due to rapidly changing customer requirements and an increase of inter-organizational business processes, which need to be considered from an end-to-end perspective. In addition, traditional BPI approaches are more and more perceived as overly complex and too resource-consuming in practice. Against this background, the paper proposes a BPI roadmap, which is an approach for systematically performing BPI projects and serves practitioners’ needs for manageable BPI methods. Based on this BPI roadmap, a domain-specific conceptual modeling method (DSMM) has been developed. The DSMM supports the efficient documentation and communication of the results that emerge during the application of the roadmap. Thus, conceptual modeling acts as a means for purposefully codifying the outcomes of a BPI project. Furthermore, a corresponding software prototype has been implemented using a meta modeling platform to assess the technical feasibility of the approach. Finally, the usability of the prototype has been empirically evaluated

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

Railway-induced ground vibrations – a review of vehicle effects

This paper is a review of the effect of vehicle characteristics on ground- and track borne-vibrations from railways. It combines traditional theory with modern thinking and uses a range of numerical analysis and experimental results to provide a broad analysis of the subject area. First, the effect of different train types on vibration propagation is investigated. Then, despite not being the focus of this work, numerical approaches to vibration propagation modelling within the track and soil are briefly touched upon. Next an in-depth discussion is presented related to the evolution of numerical models, with analysis of the suitability of various modelling approaches for analysing vehicle effects. The differences between quasi-static and dynamic characteristics are also discussed with insights into defects such as wheel/rail irregularities. Additionally, as an appendix, a modest database of train types are presented along with detailed information related to their physical attributes. It is hoped that this information may provide assistance to future researchers attempting to simulate railway vehicle vibrations. It is concluded that train type and the contact conditions at the wheel/rail interface can be influential in the generation of vibration. Therefore, where possible, when using numerical approach, the vehicle should be modelled in detail. Additionally, it was found that there are a wide variety of modelling approaches capable of simulating train types effects. If non-linear behaviour needs to be included in the model, then time domain simulations are preferable, however if the system can be assumed linear then frequency domain simulations are suitable due to their reduced computational demand