GAP-independent functions of DLC1 in metastasis.

Metastases are responsible for most cancer-related deaths. One of the hallmarks of metastatic cells is increased motility and migration through extracellular matrixes. These processes rely on specific small GTPases, in particular those of the Rho family. Deleted in liver cancer-1 (DLC1) is a tumor suppressor that bears a RhoGAP activity. This protein is lost in most cancers, allowing malignant cells to proliferate and disseminate in a Rho-dependent manner. However, DLC1 is also a scaffold protein involved in alternative pathways leading to tumor and metastasis suppressor activities. Recently, substantial information has been gathered on these mechanisms and this review is aiming at describing the potential and known alternative GAP-independent mechanisms allowing DLC1 to impair migration, invasion, and metastasis formation

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells.

It is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that nonresponders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Here, we initially focused on the bleomycin genotoxin because of the limited information about the genes implicated in the sensitivity or resistance to this compound. Using a whole-genome CRISPR/Cas9 gene knockout approach, we identified ASH2L, a core component of the H3K4 methyl transferase complex, as a protein required for bleomycin sensitivity in L1236 Hodgkin lymphoma. Knocking down ASH2L in these cells and in the NT2D1 testicular cancer cell line rendered them resistant to bleomycin, etoposide, and cisplatin but did not affect their sensitivity toward ATM or ATR inhibitors. ASH2L knockdown decreased cell proliferation and facilitated DNA repair via homologous recombination and nonhomologous end-joining mechanisms. Data from the Tumor Cancer Genome Atlas indicate that patients with testicular cancer carrying alterations in the ASH2L gene are more likely to relapse than patients with unaltered ASH2L genes. The cell models we have used are derived from cancers currently treated either partially (Hodgkin's lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. In situations where tumors are expressing low levels of ASH2L, which may allow them to resist genotoxic treatment, the use of ATR or ATM inhibitors may be more efficacious as our data indicate that ASH2L knockdown does not affect sensitivity to these inhibitors

Thermodynamic evidence of fractionalized excitations in {\alpha}-RuCl3

Fractionalized excitations are of considerable interest in recent condensed-matter physics. Fractionalization of the spin degrees of freedom into localized and itinerant Majorana fermions are predicted for the Kitaev spin liquid, an exactly solvable model with bond-dependent interactions on a two-dimensional honeycomb lattice. As function of temperature, theory predicts a characteristic two-peak structure of the heat capacity as fingerprint of these excitations. Here we report on detailed heat-capacity experiments as function of temperature and magnetic field in high-quality single crystals of {\alpha}-RuCl3 and undertook considerable efforts to determine the exact phonon background. We measured single-crystalline RhCl3 as non-magnetic reference and performed ab-initio calculations of the phonon density of states for both compounds. These ab-initio calculations document that the intrinsic phonon contribution to the heat capacity cannot be obtained by a simple rescaling of the nonmagnetic reference using differences in the atomic masses. Sizable renormalization is required even for non-magnetic RhCl3 with its minute difference from the title compound. In {\alpha}-RuCl3 in zero magnetic field, excess heat capacity exists at temperatures well above the onset of magnetic order. In external magnetic fields far beyond quantum criticality, when long-range magnetic order is fully suppressed, the excess heat capacity exhibits the characteristic two-peak structure. In zero field, the lower peak just appears at temperatures around the onset of magnetic order and seems to be connected with canonical spin degrees of freedom. At higher fields, beyond the critical field, this peak is shifted to 10 K. The high-temperature peak located around 50 K is hardly influenced by external magnetic fields, carries the predicted amount of entropy, R/2 ln2, and may resemble remnants of Kitaev physics

Precise laser spectroscopy of the antiprotonic helium atom and CPT test on antiproton mass and charge

We have measured twelve transition frequencies of the antiprotonic helium atom (pbar-He+) with precisions of 0.1--0.2 ppm using a laser spectroscopic method. The agreement between the experiment and theories was so good that we can put a limit on the proton-antiproton mass (or charge) difference. The new limit is expected to be much smaller than the already published value, 60 ppb.Comment: proceeding of the conference, "PANIC02

Fast and Scalable Score-Based Kernel Calibration Tests

We introduce the Kernel Calibration Conditional Stein Discrepancy test (KCCSD test), a nonparametric, kernel-based test for assessing the calibration of probabilistic models with well-defined scores. In contrast to previous methods, our test avoids the need for possibly expensive expectation approximations while providing control over its type-I error. We achieve these improvements by using a new family of kernels for score-based probabilities that can be estimated without probability density samples, and by using a conditional goodness-of-fit criterion for the KCCSD test's U-statistic. We demonstrate the properties of our test on various synthetic settings

Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor.

TAT-RasGAP317-326, a peptide corresponding to the 317-326 sequence of p120 RasGAP coupled with a cell-permeable TAT-derived peptide, sensitizes the death response of various tumor cells to several anticancer treatments. We now report that this peptide is also able to increase cell adherence, prevent cell migration and inhibit matrix invasion. This is accompanied by a marked modification of the actin cytoskeleton and focal adhesion redistribution. Interestingly, integrins and the small Rho GTP-binding protein, which are well-characterized proteins modulating actin fibers, adhesion and migration, do not appear to be required for the pro-adhesive properties of TAT-RasGAP317-326. In contrast, deleted in liver cancer-1, a tumor suppressor protein, the expression of which is often deregulated in cancer cells, was found to be required for TAT-RasGAP317-326 to promote cell adherence and inhibit migration. These results show that TAT-RasGAP317-326, besides its ability to favor tumor cell death, hampers cell migration and invasion

Perspectives of Nuclear Physics in Europe: NuPECC Long Range Plan 2010

The goal of this European Science Foundation Forward Look into the future of Nuclear Physics is to bring together the entire Nuclear Physics community in Europe to formulate a coherent plan of the best way to develop the field in the coming decade and beyond.<p></p> The primary aim of Nuclear Physics is to understand the origin, evolution, structure and phases of strongly interacting matter, which constitutes nearly 100% of the visible matter in the universe. This is an immensely important and challenging task that requires the concerted effort of scientists working in both theory and experiment, funding agencies, politicians and the public.<p></p> Nuclear Physics projects are often “big science”, which implies large investments and long lead times. They need careful forward planning and strong support from policy makers. This Forward Look provides an excellent tool to achieve this. It represents the outcome of detailed scrutiny by Europe’s leading experts and will help focus the views of the scientific community on the most promising directions in the field and create the basis for funding agencies to provide adequate support.<p></p> The current NuPECC Long Range Plan 2010 “Perspectives of Nuclear Physics in Europe” resulted from consultation with close to 6 000 scientists and engineers over a period of approximately one year. Its detailed recommendations are presented on the following pages. For the interested public, a short summary brochure has been produced to accompany the Forward Look.<p></p&gt

First observation of two hyperfine transitions in antiprotonic He-3

We report on the first experimental results for microwave spectroscopy of the hyperfine structure of antiprotonic He-3. Due to the helium nuclear spin, antiprotonic He-3 has a more complex hyperfine structure than antiprotonic He-4 which has already been studied before. Thus a comparison between theoretical calculations and the experimental results will provide a more stringent test of the three-body quantum electrodynamics (QED) theory. Two out of four super-super-hyperfine (SSHF) transition lines of the (n,L)=(36,34) state were observed. The measured frequencies of the individual transitions are 11.12559(14) GHz and 11.15839(18) GHz, less than 1 MHz higher than the current theoretical values, but still within their estimated errors. Although the experimental uncertainty for the difference of these frequencies is still very large as compared to that of theory, its measured value agrees with theoretical calculations. This difference is crucial to be determined because it is proportional to the magnetic moment of the antiproton.Comment: 8 pages, 6 figures, just published (online so far) in Physics Letters

GHRS and ORFEUS-II Observations of the Highly Ionized Interstellar Medium Toward ESO141-055

We present Goddard High Resolution Spectrograph and ORFEUS-II measurements of Si IV, CIV, N V, and O VI absorption in the interstellar medium of the Galactic disk and halo toward the nucleus of the Seyfert galaxy ESO141-055. The high ionization absorption is strong, with line strengths consistent with the spectral signature expected for hot (log T = 5-6) collisionally ionized gas in either a ``Galactic fountain'' or an inhomogeneous medium containing a mixture of conductive interfaces and turbulent mixing layers. The total O VI column density of log N ~ 15 suggests that the scale height of O VI is large (>3 kpc) in this direction. Comparison of the high ion column densities with measurements for other sight lines indicates that the highly ionized gas distribution is patchy. The amount of O VI perpendicular to the Galactic plane varies by at least a factor of ~4 among the complete halo sight lines thus far studied. In addition to the high ion absorption, lines of low ionization species are also present in the spectra. With the possible exception of Ar I, which may have a lower than expected abundance resulting from partial photoionization of gas along the sight line, the absorption strengths are typical of those expected for the warm, neutral interstellar medium. The sight line intercepts a cold molecular cloud with log N(H2) ~ 19. The cloud has an identifiable counterpart in IRAS 100-micron emission maps of this region of the sky. We detect a Ly-alpha absorber associated with ESO141-055 at z = 0.03492. This study presents an enticing glimpse into the interstellar and intergalactic absorption patterns that will be observed at high spectral resolution by the Far Ultraviolet Spectroscopic Explorer.Comment: 24 pages + 8 figures, uses aaspp4.sty. Accepted for publication in Ap

Systematic study of the decay rates of antiprotonic helium states

A systematic study of the decay rates of antiprotonic helium (\pbhef and \pbhet) at CERN AD (Antiproton Decelerator) has been made by a laser spectroscopic method. The decay rates of some of its short-lived states, namely those for which the Auger rates $\gamma_{\mathrm{A}}$ are much larger than their radiative decay rates ($\gamma_{\mathrm{rad}} \sim 1$ $\mu$s$^{-1}$), were determined from the time distributions of the antiproton annihilation signals induced by laser beams, and the widths of the atomic resonance lines. The magnitude of the decay rates, especially their relation with the transition multipolarity, is discussed and compared with theoretical calculations.Comment: 6 pages, 5 figures, and 1 tabl