Generation and characterization of antigenic variants induced by exposure of tumor cells to UV radiation in vitro

Antigenic changes present in nonantigenic tumor cells exposed to UV radiation (UV) in vitro were investigated by addressing the following questions: (1) Are antigenic variants (AV) produced that are rejected in normal but not immunosuppressed mice? (2) Does generation of AV depend upon intrinsic properties of the cells exposed or result from the action of UV? (3) Is antigenic modification induced by UV due to increased histocompatibility antigen expression? (4) Do AV crossreact immunologically with parental tumor or with other AV? and (5) Is the UV-associated common antigen expressed on UV-induced tumors present on UV-irradiated tumor cells? AV were generated at different frequencies following in vitro UV irradiation of a spontaneous murine fibrosarcoma (51% of cell lines tested), a murine melanoma (56%), and two melanoma clones (100% and 11%). This indicated that the percentage of AV produced is an intrinsic property of the cell line exposed. The increased antigenicity did not correlate with an increased expression of class I histocompatibility antigens. Immunological experiments demonstrated that the AV and parental cells shared a determinant that was susceptible to immune recognition, but incapable of inducing immunity. In contrast, the AV were noncrossreactive, suggesting that variant-specific antigens were also expressed. Finally, the AV were recognized by UV-induced suppressor cells, indicating that the UV-associated common antigen expressed by UV-induced tumors was also present. This investigation provides new information on the susceptibility of tumors to antigenic modification by UV and on the relationship between tumor antigens and neoplastic transformation. Furthermore, it suggests an immunological approach for cancer therapy. ^

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.141.

Yellow laser light generation by frequency doubling of the output from a master oscillator fiber power amplifier system

We present a power-scalable approach for yellow laser-light generation based on standard Ytterbium (Yb) doped fibers. To force the cavity to lase at 1154 nm, far above the gain-maximum, measures must be taken to fulfill lasing condition and to suppress competing amplified spontaneous emission (ASE) in the high-gain region. To prove the principle we built a fiber-laser cavity and a fiber-amplifier both at 1154 nm. In between cavity and amplifier we suppressed the ASE by 70 dB using a fiber Bragg grating (FBG) based filter. Finally we demonstrated efficient single pass frequency doubling to 577 nm with a periodically poled lithium niobate crystal (PPLN). With our linearly polarized 1154 nm master oscillator power fiber amplifier (MOFA) system we achieved slope efficiencies of more than 15 % inside the cavity and 24 % with the fiber-amplifier. The frequency doubling followed the predicted optimal efficiency achievable with a PPLN crystal. So far we generated 1.5 W at 1154nm and 90 mW at 577 nm. Our MOFA approach for generation of 1154 nm laser radiation is power-scalable by using multi-stage amplifiers and large mode-area fibers and is therefore very promising for building a high power yellow laser-light source of several tens of Watt.

Isotopic-geochemical features of spontaneous gases from mud volcanoes in Eastern Georgia

Isotopic-geochemical study revealed presence of mantle He (3He/4He up to 223x10**-8) in gases from mud volcanoes of Eastern Georgia. This fact confirms that the Middle Kura basin fill encloses an intrusive body previously distinguished from geophysical data. Wide variations of carbon isotopic composition d13C in CH4 and CO2 and chemical composition of gas and water at temporally constant 3He/4He ratio indicate their relation with crustal processes. Unusual direct correlations of 3He/4He ratio with concentrations of He and CH4 and 40Ar/36Ar ratio can be explained by generation of gas in the Cenozoic sequence of the Middle Kura basin.

Spontaneous mutations recovered as mosaics in the mouse specific-locus test

The specific-locus test (SLT) detects new mutants among mice heterozygous for seven recessive visible markers. Spontaneous mutations can be manifested not only as singleton whole-body mutants in controls (for which we report new data), but as mosaics—either visible (manifesting mottled coat color) in the scored generation (G2) or masked, among the wild-type parental generation (G1). Masked G1 mosaics reveal themselves by producing clusters of whole-body mutants in G2. We provide evidence that most, if not all, mosaics detected in the SLT (both radiation and control progenies) result from a single-strand spontaneous mutation subsequent to the last premeiotic mitosis and before the first postmeiotic one of a parental genome—the “perigametic interval.” Such events in the genomes of the G1 and G0 result, respectively, in visible and masked 50:50 mosaics. Per cell cycle, the spontaneous mutation rate in the perigametic interval is much higher than that in pregamete mitotic divisions. A clearly different locus spectrum further supports the hypothesis of different origin, and casts further doubt on the validity of the doubling-dose risk-estimation method. Because mosaics cannot have arisen in mitotic germ cells, and are not induced by radiation exposure in the perigametic interval, they should not be included in calculations of radiation-induced germ-line mutation rates. For per-generation calculations, inclusion of mosaics yields a spontaneous frequency 1.7 times that calculated from singletons alone for mutations contributed by males; including both sexes, the multiple is 2.2.

A new mechanism of sound generation in songbirds

Our current understanding of the sound-generating mechanism in the songbird vocal organ, the syrinx, is based on indirect evidence and theoretical treatments. The classical avian model of sound production postulates that the medial tympaniform membranes (MTM) are the principal sound generators. We tested the role of the MTM in sound generation and studied the songbird syrinx more directly by filming it endoscopically. After we surgically incapacitated the MTM as a vibratory source, zebra finches and cardinals were not only able to vocalize, but sang nearly normal song. This result shows clearly that the MTM are not the principal sound source. The endoscopic images of the intact songbird syrinx during spontaneous and brain stimulation-induced vocalizations illustrate the dynamics of syringeal reconfiguration before phonation and suggest a different model for sound production. Phonation is initiated by rostrad movement and stretching of the syrinx. At the same time, the syrinx is closed through movement of two soft tissue masses, the medial and lateral labia, into the bronchial lumen. Sound production always is accompanied by vibratory motions of both labia, indicating that these vibrations may be the sound source. However, because of the low temporal resolution of the imaging system, the frequency and phase of labial vibrations could not be assessed in relation to that of the generated sound. Nevertheless, in contrast to the previous model, these observations show that both labia contribute to aperture control and strongly suggest that they play an important role as principal sound generators.

Transcriptional and posttranslational plasticity and the generation of inflammatory pain

Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain reflects direct activation of specific receptors on nociceptor terminals by inflammatory mediators. Pain hypersensitivity is the consequence of early posttranslational changes, both in the peripheral terminals of the nociceptor and in dorsal horn neurons, as well as later transcription-dependent changes in effector genes, again in primary sensory and dorsal horn neurons. This inflammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathways phosphorylate membrane proteins, changing their function, and activate transcription factors, altering gene expression. Two distinct aspects of sensory neuron function are changed as a result of these processes, basal sensitivity, or the capacity of peripheral stimuli to evoke pain, and stimulus-evoked hypersensitivity, the capacity of certain inputs to generate prolonged alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes both potentiate the system and alter neuronal phenotype. Potentiation occurs as a result of the up-regulation in the dorsal root ganglion of centrally acting neuromodulators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those that induce stimulus-induced hypersensitivity. Alterations in phenotype includes the acquisition by A fibers of neurochemical features typical of C fibers, enabling these fibers to induce stimulus-evoked hypersensitivity, something only C fiber inputs normally can do. Elucidation of the molecular mechanisms responsible provides new opportunities for therapeutic approaches to managing inflammatory pain.

Entanglement induced by spontaneous emission in spatially extended two-atom systems

The role of the collective antisymmetric state in entanglement creation by spontaneous emission in a system of two non-overlapping two-level atoms has been investigated. Populations of the collective atomic states and the Wootters entanglement measure (concurrence) for two sets of initial atomic conditions are calculated and illustrated graphically. Calculations include the dipole-dipole interaction and a spatial separation between the atoms that the antisymmetric state of the system is included throughout even for small interatomic separations. It is shown that spontaneous emission can lead to a transient entanglement between the atoms even if the atoms were prepared initially in an unentangled state. It is found that the ability of spontaneous emission to create transient entanglement relies on the absence of population in the collective symmetric state of the system. For the initial state of only one atom excited, entanglement builds up rapidly in time and reaches a maximum for parameter values corresponding roughly to zero population in the symmetric state. On the other hand, for the initial condition of both atoms excited, the atoms remain unentangled until the symmetric state is depopulated. A simple physical interpretation of these results is given in terms of the diagonal states of the density matrix of the system. We also study entanglement creation in a system of two non-identical atoms of different transition frequencies. It is found that the entanglement between the atoms can be enhanced compared to that for identical atoms, and can decay with two different time scales resulting from the coherent transfer of the population from the symmetric to the antisymmetric state. In addition, it was found that a decaying initial entanglement between the atoms can display a revival behaviour.

Pattern generation by dissipative parametric instability

Nonlinear instabilities are responsible for spontaneous pattern formation in a vast number of natural and engineered systems, ranging from biology to galaxy buildup. We propose a new instability mechanism leading to pattern formation in spatially extended nonlinear systems, which is based on a periodic antiphase modulation of spectrally dependent losses arranged in a zigzag way: an effective filtering is imposed at symmetrically located wave numbers k and -k in alternating order. The properties of the dissipative parametric instability differ from the features of both key classical concepts of modulation instabilities, i.e., the Benjamin-Feir instability and the Faraday instabiltyity. We demonstrate how the dissipative parametric instability can lead to the formation of stable patterns in one- and two-dimensional systems. The proposed instability mechanism is generic and can naturally occur or can be implemented in various physical systems.

Gamma-shaped long-cavity normal-dispersion mode-locked Er-fiber laser for sub-nanosecond high-energy pulsed generation

We propose the design of a novel ?-shaped fiber laser resonator and apply it to build a long-cavity normaldispersion mode-locked Er-fiber laser which features enhanced functionalities for management and optimization of pulsed lasing regimes. We report the generation of sub-nanosecond pulses with the energy of ~0.5 µJ at a kilohertz-scale repetition rate in an all-fiber system based on the new laser design. A combination of special design solutions in the laser, such as polarization instability compensation in the ultra-long arm of the resonator, intra-cavity spectral selection of radiation with a broadband fiber Bragg grating, and polarization selection by means of a tilted refractive index grating, ensures low amplified spontaneous emission (ASE) noise and high stability of the laser system output parameters.

Gamma-shaped long-cavity normal-dispersion mode-locked Er-fiber laser for sub-nanosecond high-energy pulsed generation

We propose the design of a novel ?-shaped fiber laser resonator and apply it to build a long-cavity normaldispersion mode-locked Er-fiber laser which features enhanced functionalities for management and optimization of pulsed lasing regimes. We report the generation of sub-nanosecond pulses with the energy of ~0.5 µJ at a kilohertz-scale repetition rate in an all-fiber system based on the new laser design. A combination of special design solutions in the laser, such as polarization instability compensation in the ultra-long arm of the resonator, intra-cavity spectral selection of radiation with a broadband fiber Bragg grating, and polarization selection by means of a tilted refractive index grating, ensures low amplified spontaneous emission (ASE) noise and high stability of the laser system output parameters.

Soliton's eigenvalue based analysis on the generation mechanism of rogue wave phenomenon in optical fibers exhibiting weak third order dispersion

One of the extraordinary aspects of nonlinear wave evolution which has been observed as the spontaneous occurrence of astonishing and statistically extraordinary amplitude wave is called rogue wave. We show that the eigenvalues of the associated equation of nonlinear Schrödinger equation are almost constant in the vicinity of rogue wave and we validate that optical rogue waves are formed by the collision between quasi-solitons in anomalous dispersion fiber exhibiting weak third order dispersion.