Systematic Analysis of Double-Ionization Dynamics Based on Four-Body Dalitz Plots

We report on an experimental and theoretical systematic study of double ionization of helium by ion impact in terms of four-particle Dalitz plots. Several collision systems covering abroad range of perturbation parameters η (projectile charge to speed ratio) were investigated. With increasing η we observe a systematic trend from features, characteristic to correlated double-ionization mechanisms, to signatures of higher-order processes not requiring electron-electron correlations [the mechanism called two-step-two projectile-electron interaction (TS-2)]. The data for the largest η can qualitatively be amazingly well described by a simple model only including the TS-2 mechanism

Influence of large local and non-local bispectra on primordial black hole abundance

Primordial black holes represent a unique probe to constrain the early universe on small scales - providing the only constraints on the primordial power spectrum on the majority of scales. However, these constraints are strongly dependent on even small amounts of non-Gaussianity, which is unconstrained on scales significantly smaller than those visible in the CMB. This paper goes beyond previous considerations to consider the effects of a bispectrum of the equilateral, orthogonal and local shapes with arbitrary magnitude upon the abundance of primordial black holes. Non-Gaussian density maps of the early universe are generated from a given bispectrum and used to place constraints on the small scale power spectrum. When small, we show that the skewness provides an accurate estimate for how the constraint depends on non-Gaussianity, independently of the shape of the bispectrum. We show that the orthogonal template of non-Gaussianity has an order of magnitude weaker effect on the constraints than the local and equilateral templates.Comment: 11 pages, 4 figures, updated to match published version in JCAP02(2016)029, Journal of Cosmology and Astroparticle Physics, Volume 2016, February 201

Limit cycles, complex Floquet multipliers and intrinsic noise

We study the effects of intrinsic noise on chemical reaction systems, which in the deterministic limit approach a limit cycle in an oscillatory manner. Previous studies of systems with an oscillatory approach to a fixed point have shown that the noise can transform the oscillatory decay into sustained coherent oscillations with a large amplitude. We show that a similar effect occurs when the stable attractors are limit cycles. We compute the correlation functions and spectral properties of the fluctuations in suitably co-moving Frenet frames for several model systems including driven and coupled Brusselators, and the Willamowski-Roessler system. Analytical results are confirmed convincingly in numerical simulations. The effect is quite general, and occurs whenever the Floquet multipliers governing the stability of the limit cycle are complex, with the amplitude of the oscillations increasing as the instability boundary is approached.Comment: 15 pages, 8 figure

Infrared effects in inflationary correlation functions

In this article, I briefly review the status of infrared effects which occur when using inflationary models to calculate initial conditions for a subsequent hot, dense plasma phase. Three types of divergence have been identified in the literature: secular, "time-dependent" logarithms, which grow with time spent outside the horizon; "box-cutoff" logarithms, which encode a dependence on the infrared cutoff when calculating in a finite-sized box; and "quantum" logarithms, which depend on the ratio of a scale characterizing new physics to the scale of whatever process is under consideration, and whose interpretation is the same as conventional field theory. I review the calculations in which these divergences appear, and discuss the methods which have been developed to deal with them.Comment: Invited review for focus section of Classical & Quantum Gravity on nonlinear and nongaussian perturbation theory. Some improvements compared to version which will appear in CQG, especially in Sec. 2.3. 30 pages + references

Sequential and Direct Two-Photon Double Ionization of D₂ at Flash

Sequential and direct two-photon double ionization (DI) of D2 molecule is studied experimentally and theoretically at a photon energy of 38.8 eV. Experimental and theoretical kinetic energy releases of D++D+fragments, consisting of the contributions of sequential DI via the D2+(1sσg) state and direct DI via a virtual state, agree well with each other

Studying the accretion geometry of EXO 2030+375 at luminosities close to the propeller regime

The Be X-ray binary EXO2030+375 was in an extended low-luminosity state during most of 2016. We observed this state with NuSTAR and Swift, supported by INTEGRAL observations and optical spectroscopy with the Nordic Optical Telescope (NOT). We present a comprehensive spectral and timing analysis of these data here to study the accretion geometry and investigate a possible onset of the propeller effect. The H alpha data show that the circumstellar disk of the Be-star is still present. We measure equivalent widths similar to values found during more active phases in the past, indicating that the low-luminosity state is not simply triggered by a smaller Be disk. The NuSTAR data, taken at a 3-78 keV luminosity of similar to 6.8 x 10(35) erg s(-1) (for a distance of 7.1 kpc), are nicely described by standard accreting pulsar models such as an absorbed power law with a high-energy cutoff. We find that pulsations are still clearly visible at these luminosities, indicating that accretion is continuing despite the very low mass transfer rate. In phase-resolved spectroscopy we find a peculiar variation of the photon index from similar to 1.5 to similar to 2.5 over only about 3% of the rotational period. This variation is similar to that observed with XMM-Newton at much higher luminosities. It may be connected to the accretion column passing through our line of sight. With Swift/XRT we observe luminosities as low as 10(34) erg s(-1) where the data quality did not allow us to search for pulsations, but the spectrum is much softer and well described by either a blackbody or soft power-law continuum. This softer spectrum might be due to the accretion being stopped by the propeller effect and we only observe the neutron star surface cooling

Combination antiretroviral drugs in PLGA nanoparticle for HIV-1

<p>Abstract</p> <p>Background</p> <p>Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the <it>in vitro </it>release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).</p> <p>Methods</p> <p>Poly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing ritonavir (RTV), lopinavir (LPV), and efavirenz (EFV) were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay.</p> <p>Results</p> <p>Nanoparticle size averaged 262 ± 83.9 nm and zeta potential -11.4 ± 2.4. AR loading averaged 4% (w/v). Antiretroviral drug levels were determined in PBMCs after 100 μg of NP in 75 μL PBS was added to media. Intracellular peak AR levels from NPs (day 4) were RTV 2.5 ± 1.1; LPV 4.1 ± 2.0; and EFV 10.6 ± 2.7 μg and continued until day 28 (all AR ≥ 0.9 μg). Free drugs (25 μg of each drug in 25 μL ethanol) added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs). Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic.</p> <p>Conclusion</p> <p>These results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV). Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.</p

Functional Analysis of Retinitis Pigmentosa 2 (RP2) Protein Reveals Variable Pathogenic Potential of Disease-Associated Missense Variants

Genetic mutations are frequently associated with diverse phenotypic consequences, which limits the interpretation of the consequence of a variation in patients. Mutations in the retinitis pigmentosa 2 (RP2) gene are associated with X-linked RP, which is a phenotypically heterogenic form of retinal degeneration. The purpose of this study was to assess the functional consequence of disease-associated mutations in the RP2 gene using an in vivo assay. Morpholino-mediated depletion of rp2 in zebrafish resulted in perturbations in photoreceptor development and microphthalmia (small eye). Ultrastructural and immunofluorescence analyses revealed defective photoreceptor outer segment development and lack of expression of photoreceptor-specific proteins. The retinopathy phenotype could be rescued by expressing the wild-type human RP2 protein. Notably, the tested RP2 mutants exhibited variable degrees of rescue of rod versus cone photoreceptor development as well as microphthalmia. Our results suggest that RP2 plays a key role in photoreceptor development and maintenance in zebrafish and that the clinical heterogeneity associated with RP2 mutations may, in part, result from its potentially distinct functional relevance in rod versus cone photoreceptors

TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms

The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFκB-mediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFκB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival

The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel

<p>Abstract</p> <p>Background</p> <p>Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.</p> <p>Methods</p> <p>Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI₅₀ data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested <it>in vitro</it> for the ability to influence tumor susceptibility to arsenic trioxide.</p> <p>Results</p> <p>A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.</p> <p>Conclusions</p> <p>In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.</p