Identification of integrin drug targets for 17 solid tumor types.

Integrins are contributors to remodeling of the extracellular matrix and cell migration. Integrins participate in the assembly of the actin cytoskeleton, regulate growth factor signaling pathways, cell proliferation, and control cell motility. In solid tumors, integrins are involved in promoting metastasis to distant sites, and angiogenesis. Integrins are a key target in cancer therapy and imaging. Integrin antagonists have proven successful in halting invasion and migration of tumors. Overexpressed integrins are prime anti-cancer drug targets. To streamline the development of specific integrin cancer therapeutics, we curated data to predict which integrin heterodimers are pausible therapeutic targets against 17 different solid tumors. Computational analysis of The Cancer Genome Atlas (TCGA) gene expression data revealed a set of integrin targets that are differentially expressed in tumors. Filtered by FPKM (Fragments Per Kilobase of transcript per Million mapped reads) expression level, overexpressed subunits were paired into heterodimeric protein targets. By comparing the RNA-seq differential expression results with immunohistochemistry (IHC) data, overexpressed integrin subunits were validated. Biologics and small molecule drug compounds against these identified overexpressed subunits and heterodimeric receptors are potential therapeutics against these cancers. In addition, high-affinity and high-specificity ligands against these integrins can serve as efficient vehicles for delivery of cancer drugs, nanotherapeutics, or imaging probes against cancer

The Quantized O(1,2)/O(2)×Z2O(1,2)/O(2)\times Z_2 Sigma Model Has No Continuum Limit in Four Dimensions. I. Theoretical Framework

The nonlinear sigma model for which the field takes its values in the coset space $O(1,2)/O(2)\times Z_2$ is similar to quantum gravity in being perturbatively nonrenormalizable and having a noncompact curved configuration space. It is therefore a good model for testing nonperturbative methods that may be useful in quantum gravity, especially methods based on lattice field theory. In this paper we develop the theoretical framework necessary for recognizing and studying a consistent nonperturbative quantum field theory of the $O(1,2)/O(2)\times Z_2$ model. We describe the action, the geometry of the configuration space, the conserved Noether currents, and the current algebra, and we construct a version of the Ward-Slavnov identity that makes it easy to switch from a given field to a nonlinearly related one. Renormalization of the model is defined via the effective action and via current algebra. The two definitions are shown to be equivalent. In a companion paper we develop a lattice formulation of the theory that is particularly well suited to the sigma model, and we report the results of Monte Carlo simulations of this lattice model. These simulations indicate that as the lattice cutoff is removed the theory becomes that of a pair of massless free fields. Because the geometry and symmetries of these fields differ from those of the original model we conclude that a continuum limit of the $O(1,2)/O(2)\times Z_2$ model which preserves these properties does not exist.Comment: 25 pages, no figure

Variable weight neural networks and their applications on material surface and epilepsy seizure phase classifications

This paper presents a novel neural network having variable weights, which is able to improve its learning and generalization capabilities, to deal with classification problems. The variable weight neural network (VWNN) allows its weights to be changed in operation according to the characteristic of the network inputs so that it demonstrates the ability to adapt to different characteristics of input data resulting in better performance compared with ordinary neural networks with fixed weights. The effectiveness of the VWNN is tested with the consideration of two real-life applications. The first application is on the classification of materials using the data collected by a robot finger with tactile sensors sliding along the surface of a given material. The second application considers the classification of seizure phases of epilepsy (seizure-free, pre-seizure and seizure phases) using real clinical data. Comparisons are performed with some traditional classification methods including neural network, k-nearest neighbors and naive Bayes classification techniques. It is shown that the VWNN classifier outperforms the traditional methods in terms of classification accuracy and robustness property when input datais contaminated by noise

Evolution of interfaces and expansion in width

Interfaces in a model with a single, real nonconserved order parameter and purely dissipative evolution equation are considered. We show that a systematic perturbative approach, called the expansion in width and developed for curved domain walls, can be generalized to the interfaces. Procedure for calculating curvature corrections is described. We also derive formulas for local velocity and local surface tension of the interface. As an example, evolution of spherical interfaces is discussed, including an estimate of critical size of small droplets.Comment: Discussion of stability of the interface is added, and the numerical estimates of width and velocity of the interface in the liquid crystal example are corrected. 25 pages, Latex2

Dark states of dressed Bose-Einstein condensates

We combine the ideas of dressed Bose-Einstein condensates, where an intracavity optical field allows one to design coupled, multicomponent condensates, and of dark states of quantum systems, to generate a full quantum entanglement between two matter waves and two optical waves. While the matter waves are macroscopically populated, the two optical modes share a single photon. As such, this system offers a way to influence the behaviour of a macroscopic quantum system via a microscopic ``knob''.Comment: 6 pages, no figur

Recent Developments in Understanding Two-dimensional Turbulence and the Nastrom-Gage Spectrum

Two-dimensional turbulence appears to be a more formidable problem than three-dimensional turbulence despite the numerical advantage of working with one less dimension. In the present paper we review recent numerical investigations of the phenomenology of two-dimensional turbulence as well as recent theoretical breakthroughs by various leading researchers. We also review efforts to reconcile the observed energy spectrum of the atmosphere (the spectrum) with the predictions of two-dimensional turbulence and quasi-geostrophic turbulence.Comment: Invited review; accepted by J. Low Temp. Phys.; Proceedings for Warwick Turbulence Symposium Workshop on Universal features in turbulence: from quantum to cosmological scales, 200

Direct and indirect control of the initiation of meiotic recombination by DNA damage checkpoint mechanisms in budding yeast

Meiotic recombination plays an essential role in the proper segregation of chromosomes at meiosis I in many sexually reproducing organisms. Meiotic recombination is initiated by the scheduled formation of genome-wide DNA double-strand breaks (DSBs). The timing of DSB formation is strictly controlled because unscheduled DSB formation is detrimental to genome integrity. Here, we investigated the role of DNA damage checkpoint mechanisms in the control of meiotic DSB formation using budding yeast. By using recombination defective mutants in which meiotic DSBs are not repaired, the effect of DNA damage checkpoint mutations on DSB formation was evaluated. The Tel1 (ATM) pathway mainly responds to unresected DSB ends, thus the sae2 mutant background in which DSB ends remain intact was employed. On the other hand, the Mec1 (ATR) pathway is primarily used when DSB ends are resected, thus the rad51 dmc1 double mutant background was employed in which highly resected DSBs accumulate. In order to separate the effect caused by unscheduled cell cycle progression, which is often associated with DNA damage checkpoint defects, we also employed the ndt80 mutation which permanently arrests the meiotic cell cycle at prophase I. In the absence of Tel1, DSB formation was reduced in larger chromosomes (IV, VII, II and XI) whereas no significant reduction was found in smaller chromosomes (III and VI). On the other hand, the absence of Rad17 (a critical component of the ATR pathway) lead to an increase in DSB formation (chromosomes VII and II were tested). We propose that, within prophase I, the Tel1 pathway facilitates DSB formation, especially in bigger chromosomes, while the Mec1 pathway negatively regulates DSB formation. We also identified prophase I exit, which is under the control of the DNA damage checkpoint machinery, to be a critical event associated with down-regulating meiotic DSB formation

Lifetime Studies at Metrology Light Source and ANKA

Abstract The Metrology Light Source (MLS), situated in Berlin (Germany) is an electron storage ring operating from 105 MeV to 630 MeV and is serving as the national primary radiation source standard from the near infrared to the extrem ultraviolet spectral region INTRODUCTION To provide users of synchrotron radiation with temporally stable experimental conditions, the lifetime τ of the stored beam with current I is a parameter of concern. This is valid for machines with a decaying beam such as ANKA and MLS, but as well for machines operated in top up mode such as BESSY II in Berlin. In 2012, the standard user operation at MLS yielded a lifetime of 3.5 hours at 150 mA beam current. Although reasonable due to the energy, this is a low value compared to 16 hours at ANKA and it would benefit the users of synchrotron radiation if it could be improved. THEORY There are two major loss mechanisms determining the lifetime of the electrons in an accelerator: The scattering of the electrons with residual gas atoms and the scattering of the electrons with other electrons within the bunch. The latter is known as the "Touschek effect", named after Bruno Touschek who first observed the effect at the small AdA electron-positron collider. The two contributions are called gas lifetime and Touschek lifetime respectively. The gas lifetime depends on the pressure P and a scattering cross section σ gas for particle losses, for which the interested reader is referred to The cross section itself is a function of the acceptance of the accelerator δ acc = Δp max /p 0 , while the pressure P depends in some respect on the beam current. The electrons in a bunch perform transverse betatron oscillations. Being an incoherent motion, this leads to * [email protected] Coulomb scattering. During the scattering process, transverse momentum gets transferred to longitudinal momentum. If the particles momentum deviation exceeds the momentum acceptance it will be lost. The resulting Touschek lifetime depends on the rate of scattering processes and therefore on the density within the bunch, i.e. on the bunch volume and the bunch current. Furthermore, it depends on the momentum acceptance with the power of three with σ x,y,s being the rms-bunch sizes and length and D(ξ) being a slowly varying function with respect to the acceptance δ acc . D also depends on the optical functions around the ring through ξ. The loss rates from Touschek effect and gas scattering add to the total loss rate 1/τ which can be measured. Multiplying the number of particles N (or the stored current I) to the Touschek lifetime τ T results in a constant: N · τ T = const. Therefore, when plotting I · τ for a Touschek dominated lifetime a constant can be expected with respect to current. Acceptance Touschek lifetime and gas lifetime depend on the acceptance of the accelerator. Two acceptances are important here, and whichever is the smallest is the limiting one: • RF-acceptance • Geometrical acceptance. The RF-acceptance δ acc,RF approximately depends on the applied cavity voltage V as [4] The geometrical acceptance depends on the minimal aperture of the vacuum chamber a(s) and the dimensions of the beam. For MLS a first order approximation considering only the horizontal plane is: with D x being the horizontal dispersion function. In the upper plot of Predictions In the lower part of EXPERIMENT In LIFETIME IMPROVEMENT The lifetime at MLS can be improved if the acceptance is only RF-limited even to larger voltages than 300 kV. To do so, the geometrical acceptance has to be improved. In order to find optics with an increased Touschek lifetime, brute force optics scans using a Fortran code were performed In Eq. 4, the horizontal dispersion function D x is in the denominator. By decreasing the dispersion function at the place with minimum aperture, the geometrical acceptance δ acc,geom can be improved. At MLS each quadrupole is powered independently. By tuning some quadrupoles of one family against the remaining ones of that family, the dispersion function was tuned to be zero at the septum. In The peak lifetime with respect to cavity voltage is now located at 500 kV, being the maximum applicable cavity voltage at the moment. In The total lifetime increase is as high as 80 %. By solely increasing the acceptance, and the change in optical functions, the lifetime would have been expected to increase by about 30 %. An explanation for the additional increase could be a strong halo around the beam due to intra-beam scattering. With this, the effect of leading the beam through the centre of the vacuum chamber at the septum could be explained as well. CONCLUSION AND OUTLOOK The theory of the Touschek effect describes the dependencies on energy and acceptance well. By understanding the different loss mechanisms and the methods to manipulate the different acceptances, it was possible to generate a new user optics with an by 80 % improved lifetime. To completely explain the total lifetime increase, further measurements are needed. To further increase the lifetime, alternate optics determined by optics scans will be tested ACKNOWLEDGMENT The authors like to thank Andreas Jankowiak (HZB) and Gerhard Ulm (PTB) for supporting this work. REFERENCES [1] R. Klein et al., Phys. Rev. ST-AB 11, 110701, 2008. [2] A.-S. Müller et al., "Energy Calibration Of The ANKA Storage Ring", Proceedings of EPAC 2004. [3] T. Goetsch, "Lifetime Studies at Metrology Light Source and Angströmquelle Karlsruhe" -Diploma Thesis, Karlsruhe Institut für Technologie, May 2013. [4] M. Sands, "The Physics Of Electron Storage Rings -An Introduction", National Technical Information Service, Springfield, Virginia, 1970. [5] J. le Duff, "Current And Current Density Limitations In Existing Electron Storage Rings", In: Nucl. Instr. and Meth. in Physics Research, 1985