Refinement with Time - Refining the Run-Time of Algorithms in Isabelle/HOL

Separation Logic with Time Credits is a well established method to formally verify the correctness and run-time of algorithms, which has been applied to various medium-sized use-cases. Refinement is a technique in program verification that makes software projects of larger scale manageable. Combining these two techniques for the first time, we present a methodology for verifying the functional correctness and the run-time analysis of algorithms in a modular way. We use it to verify Kruskal\u27s minimum spanning tree algorithm and the Edmonds - Karp algorithm for network flow. An adaptation of the Isabelle Refinement Framework [Lammich and Tuerk, 2012] enables us to specify the functional result and the run-time behaviour of abstract algorithms which can be refined to more concrete algorithms. From these, executable imperative code can be synthesized by an extension of the Sepref tool [Lammich, 2015], preserving correctness and the run-time bounds of the abstract algorithm

Cooling of Molecular Ion Beams

An overview of the use of stored ion beams and phase space cooling (electron cooling) is given for the field of molecular physics. Emphasis is given to interactions between molecular ions and electrons studied in the electron cooler: dissociative recombination and, for internally excited molecular ions, electron-induced ro-vibrational cooling. Diagnostic methods for the transverse ion beam properties and for the internal exciation of the molecular ions are discussed, and results for phase space cooling and internal (vibrational) cooling are presented for hydrogen molecular ions

Coulomb-explosion imaging of CH2+: target-polarization effects and bond-angle distribution

The effect of target polarization fields on the bond-angle distribution following the foil-induced Coulomb explosion of CH2+ has been measured. Incorporating a detailed model description of the polarization effects and other target effects into a Monte Carlo simulation of the experiment, a good description of the various observables is obtained. In particular, the bond-angle distribution is found to agree with existing ab initio calculations.This work has been supported in part by the German-Israel Foundation for Scientific Research (GIF) under Contract No. I-707-55.7/2001, the Spanish Ministerio de Ciencia y Tecnología (Project Nos. BFM2003-04457-C02-01/02 and HA2001-0052), the DAAD in the framework of the Acciones Integrados Program 2002/03, and the European Community within the Research Training Network “Electron Transfer Reactions.” One of the authors (S.H.A.) thanks the Fundación Cajamurcia for a Postdoctoral Grant

Integration of Formal Proof into Unified Assurance Cases with Isabelle/SACM

Assurance cases are often required to certify critical systems. The use of formal methods in assurance can improve automation, increase confidence, and overcome errant reasoning. However, assurance cases can never be fully formalised, as the use of formal methods is contingent on models that are validated by informal processes. Consequently, assurance techniques should support both formal and informal artifacts, with explicated inferential links between them. In this paper, we contribute a formal machine-checked interactive language, called Isabelle/SACM, supporting the computer-assisted construction of assurance cases compliant with the OMG Structured Assurance Case Meta-Model. The use of Isabelle/SACM guarantees well-formedness, consistency, and traceability of assurance cases, and allows a tight integration of formal and informal evidence of various provenance. In particular, Isabelle brings a diverse range of automated verification techniques that can provide evidence. To validate our approach, we present a substantial case study based on the Tokeneer secure entry system benchmark. We embed its functional specification into Isabelle, verify its security requirements, and form a modular security case in Isabelle/SACM that combines the heterogeneous artifacts. We thus show that Isabelle is a suitable platform for critical systems assurance

Assignment of resonances in dissociative recombination of HD+ ions: high-resolution measurements compared with accurate computations

The collision-energy resolved rate coefficient for dissociative recombination of HD+ ions in the vibrational ground state is measured using the photocathode electron target at the heavy-ion storage ring TSR. Rydberg resonances associated with ro-vibrational excitation of the HD+ core are scanned as a function of the electron collision energy with an instrumental broadening below 1 meV in the low-energy limit. The measurement is compared to calculations using multichannel quantum defect theory, accounting for rotational structure and interactions and considering the six lowest rotational energy levels as initial ionic states. Using thermal equilibrium level populations at 300 K to approximate the experimental conditions, close correspondence between calculated and measured structures is found up to the first vibrational excitation threshold of the cations near 0.24 eV. Detailed assignments, including naturally broadened and overlapping Rydberg resonances, are performed for all structures up to 0.024 eV. Resonances from purely rotational excitation of the ion core are found to have similar strengths as those involving vibrational excitation. A dominant low-energy resonance is assigned to contributions from excited rotational states only. The results indicate strong modifications in the energy dependence of the dissociative recombination rate coefficient through the rotational excitation of the parent ions, and underline the need for studies with rotationally cold species to obtain results reflecting low-temperature ionized media.Comment: 15 pages, 10 figures. Paper to appear in Phys. Rev. A (version as accepted

Unravelling Site-Specific Photo-Reactions of Ethanol on Rutile TiO2(110)

Finding the active sites of catalysts and photo-catalysts is crucial for an improved fundamental understanding and the development of efficient catalytic systems. Here we have studied the photo-activated dehydrogenation of ethanol on reduced and oxidized rutile TiO2(110) in ultrahigh vacuum conditions. Utilizing scanning tunnelling microscopy, various spectroscopic techniques and theoretical calculations we found that the photo-reaction proceeds most efficiently when the reactants are adsorbed on regular Ti surface sites, whereas species that are strongly adsorbed at surface defects such as O vacancies and step edges show little reaction under reducing conditions. We propose that regular Ti surface sites are the most active sites in photo-reactions on TiO2

Increased TIMP-3 expression alters the cellular secretome through dual inhibition of the metalloprotease ADAM10 and ligand-binding of the LRP-1 receptor

The tissue inhibitor of metalloproteinases-3 (TIMP-3) is a major regulator of extracellular matrix turnover and protein shedding by inhibiting different classes of metalloproteinases, including disintegrin metalloproteinases (ADAMs). Tissue bioavailability of TIMP-3 is regulated by the endocytic receptor low-density-lipoprotein receptor-related protein-1 (LRP-1). TIMP-3 plays protective roles in disease. Thus, different approaches have been developed aiming to increase TIMP-3 bioavailability, yet overall effects of increased TIMP-3 in vivo have not been investigated. Herein, by using unbiased mass-spectrometry we demonstrate that TIMP-3-overexpression in HEK293 cells has a dual effect on shedding of transmembrane proteins and turnover of soluble proteins. Several membrane proteins showing reduced shedding are known as ADAM10 substrates, suggesting that exogenous TIMP-3 preferentially inhibits ADAM10 in HEK293 cells. Additionally identified shed membrane proteins may be novel ADAM10 substrate candidates. TIMP-3-overexpression also increased extracellular levels of several soluble proteins, including TIMP-1, MIF and SPARC. Levels of these proteins similarly increased upon LRP-1 inactivation, suggesting that TIMP-3 increases soluble protein levels by competing for their binding to LRP-1 and their subsequent internalization. In conclusion, our study reveals that increased levels of TIMP-3 induce substantial modifications in the cellular secretome and that TIMP-3-based therapies may potentially provoke undesired, dysregulated functions of ADAM10 and LRP-1

Program Verification in the Presence of I/O

Software veri?cation tools that build machine-checked proofs of functional correctness usually focus on the algorithmic content of the code. Their proofs are not grounded in a formal semantic model of the environment that the program runs in, or the program’s interaction with that environment. As a result, several layers of translation and wrapper code must be trusted. In contrast, the CakeML project focuses on endto-end veri?cation to replace this trusted code with veri?ed code in a cost-e?ective manner. In this paper, we present infrastructure for developing and verifying impure functional programs with I/O and imperative ?le handling. Specifically, we extend CakeML with a low-level model of ?le I/O, and verify a high-level ?le I/O library in terms of the model. We use this library to develop and verify several Unix-style command-line utilities: cat, sort, grep, di? and patch. The work?ow we present is built around the HOL4 theorem prover, and therefore all our results have machine-checked proofs

Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

The multifunctional signaling protein p75 neurotrophin receptor (p75NTR) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75NTR is required for p75NTR-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75NTR or treatment of animals bearing p75NTR-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75NTR was observed in p75NTR-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75NTR as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma

Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates