On FO2 quantifier alternation over words

We show that each level of the quantifier alternation hierarchy within FO^2[<] -- the 2-variable fragment of the first order logic of order on words -- is a variety of languages. We then use the notion of condensed rankers, a refinement of the rankers defined by Weis and Immerman, to produce a decidable hierarchy of varieties which is interwoven with the quantifier alternation hierarchy -- and conjecturally equal to it. It follows that the latter hierarchy is decidable within one unit: given a formula alpha in FO^2[<], one can effectively compute an integer m such that alpha is equivalent to a formula with at most m+1 alternating blocks of quantifiers, but not to a formula with only m-1 blocks. This is a much more precise result than what is known about the quantifier alternation hierarchy within FO[<], where no decidability result is known beyond the very first levels

The role of copper in disulfiram-induced toxicity and radiosensitisation of cancer cells.

Abstract Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anti-cancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the anti-tumor efficacy of external beam -irradiation and 131I-metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. Methods: The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE(2c) neuroblastoma and UVW/NAT glioma cells. Synergistic interaction between disulfiram and radiotherapy was evaluated by combination index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice. Results: Escalating disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 M was copper-dependent, whereas cytotoxicity at concentrations greater than 10 M was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram’s radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of 131I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. Conclusions: The results demonstrate that (i) the cytotoxicity of disulfiram was copper-dependent; (ii) molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity; (iii) copper was required for the radiosensitizing activity of disulfiram and (iv) copper-complexed disulfiram enhanced the efficacy not only of external beam radiation but also of targeted radionuclide therapy in the form of 131I-MIBG. Therefore disulfiram may have anti-cancer potential in combination with radiotherapy

Seismic history from in situ 36Cl cosmogenic nuclide data on limestone fault scarps using Bayesian reversible jump Markov chain Monte Carlo

International audienceConstraining the past seismic activity and the slip-rates of faults over several millennials is crucial for seismic hazard assessment. Chlorine 36 (36 Cl) in situ produced cosmogenic nuclide is increasingly used to retrieve past earthquakes histories on seismically exhumed limestone normal fault-scarps. Following Schlagenhauf et al., (2010) modelling approach, we present a new methodology to retrieve the exhumation history based on a Bayesian transdimensional inversion of the 36 Cl data. This procedure uses the reversible jump Markov chains Monte-Carlo algorithm (RJ-MCMC, Green 1995) which enables 1-exploring the parameter space (number of events, age and slip of the events), 2-finding the most probable scenarios, and 3- precisely quantifying the associated uncertainties. Through a series of synthetic tests, the algorithm revealed a great capacity to constrain event slips and ages in a short computational time (several days) with a precision that can reach 0.1 ky and 0.5 m for the age and slip ofexhumation event, respectively. In addition, our study show that the amount of 36 Cl accumulated when the sampled fault-plane was still buried under the colluvial wedge, prior its exhumation, might represents up to 35 % of the total 36 Cl. This contribution can be accurately 25 determined with a depth profile that strongly increases the precision of the exhumation scenario

Inhibition of Poly(ADP-Ribose) polymerase enhances the toxicity of 131I-Metaiodobenzylguanidine/Topotecan combination therapy to cells and xenografts that express the noradrenaline transporter

Targeted radiotherapy using [131I]meta-iodobenzylguanidine ([131I]MIBG) has produced remissions in some neuroblastoma patients. We previously reported that combining [131I]MIBG with the topoisomerase I (Topo-I) inhibitor topotecan induced long-term DNA damage and supra-additive toxicity to NAT-expressing cells and xenografts. This combination treatment is undergoing clinical evaluation. This present study investigated the potential of PARP-1 inhibition, in vitro and in vivo, to further enhance [131I]MIBG/topotecan efficacy

Evidence for thermal fatigue on Mars from rockfall patterns on impact crater slopes

Individual block falls are one of the currently active surface processes on Mars. Similarly to Earth, clasts detach from upslope outcrops roll or bounce downslope, leaving a track on the substratum (Fig. 1). The trails show that the rockfalls are recent, as aeolian processes would infill topographic lows over time. Using rover-track erasure rates, these tracks are likely <100 ka. On Earth, slope instability is usually caused by phase changes of H2O [1]. However, solar-induced thermal stress could also play a key-role in rock breakdown leading to rockfalls [2]. Although liquid water is not stable at the surface of Mars today, sub-surface water ice is known to be present from mid- to high-latitudes [3]. Water ice and CO2 seasonal frost on shadowed pole-facing slopes may exist at latitudes down to 30° [4] or less [5]. On the other hand, insolation-related thermal stress has been used to explain fracture orientation patterns in martian boulders observed by the Mars Exploration Rovers [6] and other studies suggest that it could cause rock breakdown on airless bodies [7]. Therefore, both phase transitions and solar-induced thermal stress are plausible mechanisms for rock breakdown and preconditioning slopes for rockfalls on modern Mars. In this study we analyze distribution of rockfalls on impact crater walls to assess whether one of these mechanisms could be involved in local rock breakdown

Evidence for thermal-stress-induced rockfalls on Mars impact crater slopes

Here we study rocks falling from exposed outcrops of bedrock, which have left tracks on the slope over which they have bounced and/or rolled, in fresh impact craters (1–10 km in diameter) on Mars. The presence of these tracks shows that these rocks have fallen relatively recently because aeolian processes are known to infill topographic lows over time. Mapping of rockfall tracks indicate trends in frequency with orientation, which in turn depend on the latitudinal position of the crater. Craters in the equatorial belt (between 15°N and 15°S) exhibit higher frequencies of rockfall on their N-S oriented slopes compared to their E-W ones. Craters >15° N/S have notably higher frequencies on their equator-facing slopes as opposed to the other orientations. We computed solar radiation on the surface of crater slopes to compare insolation patterns and rockfall spatial distribution, and find statistically significant correlations between maximum diurnal insolation and rockfall frequency. Our results indicate that solar-induced thermal stress plays a more important role under relatively recent climate conditions in rock breakdown and preconditioning slopes for rockfalls than phase transitions of H2O or CO2, at mid and equatorial latitudes. Thermal stress should thus be considered as an important factor in promoting mass-wasting process on impact crater walls and other steep slopes on Mars

The Word Problem for Omega-Terms over the Trotter-Weil Hierarchy

For two given $\omega$-terms $\alpha$ and $\beta$, the word problem for $\omega$-terms over a variety $\boldsymbol{\mathrm{V}}$ asks whether $\alpha=\beta$ in all monoids in $\boldsymbol{\mathrm{V}}$. We show that the word problem for $\omega$-terms over each level of the Trotter-Weil Hierarchy is decidable. More precisely, for every fixed variety in the Trotter-Weil Hierarchy, our approach yields an algorithm in nondeterministic logarithmic space (NL). In addition, we provide deterministic polynomial time algorithms which are more efficient than straightforward translations of the NL-algorithms. As an application of our results, we show that separability by the so-called corners of the Trotter-Weil Hierarchy is witnessed by $\omega$-terms (this property is also known as $\omega$-reducibility). In particular, the separation problem for the corners of the Trotter-Weil Hierarchy is decidable

Reasoning with the HERMIT: tool support for equational reasoning on GHC core programs

A benefit of pure functional programming is that it encourages equational reasoning. However, the Haskell language has lacked direct tool support for such reasoning. Consequently, reasoning about Haskell programs is either performed manually, or in another language that does provide tool support (e.g. Agda or Coq). HERMIT is a Haskell-specific toolkit designed to support equational reasoning and user-guided program transformation, and to do so as part of the GHC compilation pipeline. This paper describes HERMIT’s recently developed support for equational reasoning, and presents two case studies of HERMIT usage: checking that type-class laws hold for specific instance declarations, and mechanising textbook equational reasoning

Genetical genomics: spotlight on QTL hotspots

No abstract available