Revisiting timed logics with automata modalities

© 2019 ACM. It is well known that (timed) ω-regular properties such as 'p holds at every even position' and 'p occurs at least three times within the next 10 time units' cannot be expressed in Metric Interval Temporal Logic (MITL) and Event Clock Logic (ECL). A standard remedy to this deficiency is to extend these with modalities defined in terms of automata. In this paper, we show that the logics EMITL0, ∞ (adding non-deterministic finite automata modalities into the fragment of MITL with only lower- and upper-bound constraints) and EECL (adding automata modalities into ECL) are already as expressive as EMITL (full MITL with automata modalities). In particular, the satisfiability and model-checking problems for EMITL0, ∞ and EECL are PSPACE-complete, whereas the same problems for EMITL are EXPSPACE-complete. We also provide a simple translation from EMITL0, ∞ to diagonal-free timed automata, which enables practical satisfiability and model checking based on off-the-shelf tools

On verifying timed hyperproperties

We study the satisfiability and model-checking problems for timed hyperproperties specified with HyperMTL, a timed extension of HyperLTL. Depending on whether interleaving of events in different traces is allowed, two possible semantics can be defined for timed hyperproperties: asynchronous and synchronous. While the satisfiability problem can be decided similarly to HyperLTL regardless of the choice of semantics, we show that the model-checking problem, unless the specification is alternation-free, is undecidable even when very restricted timing constraints are allowed. On the positive side, we show that model checking HyperMTL with quantifier alternations is possible under certain conditions in the synchronous semantics, or when there is a fixed bound on the length of the time domain.EP/K026399/1 and EP/P020011/

Timed hyperproperties

We study the satisfiability and model-checking problems for timed hyperproperties specified with HyperMITL, a timed extension of HyperLTL. While the satisfiability problem can be solved similarly as for HyperLTL, we show that the model-checking problem for HyperMITL, unless the specification is alternation-free, is undecidable even when very restricted timing constraints are allowed. On the positive side, we show that model checking HyperMITL with quantifier alternations is possible under certain semantic restrictions. As an intermediate tool, we give an ‘asynchronous’ interpretation of Wilke's monadic logic of relative distance (L ) and show that it characterises timed languages recognised by timed automata with silent transitions. d

Assessment of Cellular Estrogenic Activity Based on Estrogen Receptor-Mediated Reduction of Soluble-Form Catechol-O-Methyltransferase (COMT) Expression in an ELISA-Based System

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The effect of ex-vivo rotenone intoxication on dopamine re-uptake of LRRK2-R1441G mutant mouse

Poster presentationpublished_or_final_versio

PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion

Background: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. Methods: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Results: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Conclusion: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.published_or_final_versio

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity

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Identification of lead anti-human cytomegalovirus compounds targeting MAP4K4 via machine learning analysis of kinase inhibitor screening data

Chemogenomic approaches involving highly annotated compound sets and cell based high throughput screening are emerging as a means to identify novel drug targets. We have previously screened a collection of highly characterized kinase inhibitors (Khan et al., Journal of General Virology, 2016) to identify compounds that increase or decrease expression of a human cytomegalovirus (HCMV) protein in infected cells. To identify potential novel anti-HCMV drug targets we used a machine learning approach to relate our phenotypic data from the aforementioned screen to kinase inhibition profiling of compounds used in this screen. Several of the potential targets had no previously reported role in HCMV replication. We focused on one potential anti-HCMV target, MAPK4K, and identified lead compounds inhibiting MAP4K4 that have anti-HCMV activity with little cellular cytotoxicity. We found that treatment of HCMV infected cells with inhibitors of MAP4K4, or an siRNA that inhibited MAP4K4 production, reduced HCMV replication and impaired detection of IE2-60, a viral protein necessary for efficient HCMV replication. Our findings demonstrate the potential of this machine learning approach to identify novel anti-viral drug targets, which can inform the discovery of novel anti-viral lead compounds

Dignity amidst liminality: Healing within suffering among Chinese terminal cancer patients

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Positron-electron autocorrelation function study of E-center in silicon

A study was conducted on the positron-electron autocorrelation function of defect center in silicon. The positron annihilation lifetime spectroscopy (PALS) spectra taken on the as-grown and defected samples of silicon were studied. It was found that the positron binding energy to the defect could be estimated from the ratio of the positron-electron autocorrelates for bulk crystal and defect trapped positron states.published_or_final_versio