Corporate Financing in Great Britain

Background: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 mu M, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 mu M. Conclusions/Significance: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer

On Pebble Automata for Data Languages with Decidable Emptiness Problem

In this paper we study a subclass of pebble automata (PA) for data languages for which the emptiness problem is decidable. Namely, we introduce the so-called top view weak PA. Roughly speaking, top view weak PA are weak PA where the equality test is performed only between the data values seen by the two most recently placed pebbles. The emptiness problem for this model is decidable. We also show that it is robust: alternating, nondeterministic and deterministic top view weak PA have the same recognition power. Moreover, this model is strong enough to accept all data languages expressible in Linear Temporal Logic with the future-time operators, augmented with one register freeze quantifier.Comment: An extended abstract of this work has been published in the proceedings of the 34th International Symposium on Mathematical Foundations of Computer Science (MFCS) 2009}, Springer, Lecture Notes in Computer Science 5734, pages 712-72

Assigning channels via the meet-in-the-middle approach

We study the complexity of the Channel Assignment problem. By applying the meet-in-the-middle approach we get an algorithm for the $\ell$-bounded Channel Assignment (when the edge weights are bounded by $\ell$) running in time $O^*((2\sqrt{\ell+1})^n)$. This is the first algorithm which breaks the $(O(\ell))^n$ barrier. We extend this algorithm to the counting variant, at the cost of slightly higher polynomial factor. A major open problem asks whether Channel Assignment admits a $O(c^n)$-time algorithm, for a constant $c$ independent of $\ell$. We consider a similar question for Generalized T-Coloring, a CSP problem that generalizes \CA. We show that Generalized T-Coloring does not admit a $2^{2^{o\left(\sqrt{n}\right)}} {\rm poly}(r)$-time algorithm, where $r$ is the size of the instance.Comment: SWAT 2014: 282-29

Lower Bounds for the Graph Homomorphism Problem

The graph homomorphism problem (HOM) asks whether the vertices of a given $n$-vertex graph $G$ can be mapped to the vertices of a given $h$-vertex graph $H$ such that each edge of $G$ is mapped to an edge of $H$. The problem generalizes the graph coloring problem and at the same time can be viewed as a special case of the $2$-CSP problem. In this paper, we prove several lower bound for HOM under the Exponential Time Hypothesis (ETH) assumption. The main result is a lower bound $2^{\Omega\left( \frac{n \log h}{\log \log h}\right)}$. This rules out the existence of a single-exponential algorithm and shows that the trivial upper bound $2^{{\mathcal O}(n\log{h})}$ is almost asymptotically tight. We also investigate what properties of graphs $G$ and $H$ make it difficult to solve HOM$(G,H)$. An easy observation is that an ${\mathcal O}(h^n)$ upper bound can be improved to ${\mathcal O}(h^{\operatorname{vc}(G)})$ where $\operatorname{vc}(G)$ is the minimum size of a vertex cover of $G$. The second lower bound $h^{\Omega(\operatorname{vc}(G))}$ shows that the upper bound is asymptotically tight. As to the properties of the "right-hand side" graph $H$, it is known that HOM$(G,H)$ can be solved in time $(f(\Delta(H)))^n$ and $(f(\operatorname{tw}(H)))^n$ where $\Delta(H)$ is the maximum degree of $H$ and $\operatorname{tw}(H)$ is the treewidth of $H$. This gives single-exponential algorithms for graphs of bounded maximum degree or bounded treewidth. Since the chromatic number $\chi(H)$ does not exceed $\operatorname{tw}(H)$ and $\Delta(H)+1$, it is natural to ask whether similar upper bounds with respect to $\chi(H)$ can be obtained. We provide a negative answer to this question by establishing a lower bound $(f(\chi(H)))^n$ for any function $f$. We also observe that similar lower bounds can be obtained for locally injective homomorphisms.Comment: 19 page

Algorithmic Analysis of Array-Accessing Programs

For programs whose data variables range over Boolean or finite domains, program verification is decidable, and this forms the basis of recent tools for software model checking. In this paper, we consider algorithmic verification of programs that use Boolean variables, and in addition, access a single array whose length is potentially unbounded, and whose elements range over pairs from Σ × D, where Σ is a finite alphabet and D is a potentially unbounded data domain. We show that the reachability problem, while undecidable in general, is (1) Pspace-complete for programs in which the array-accessing for-loops are not nested, (2) solvable in Ex-pspace for programs with arbitrarily nested loops if array elements range over a finite data domain, and (3) decidable for a restricted class of programs with doubly-nested loops. The third result establishes connections to automata and logics defining languages over data words

Crime in Maine 2014

Automata over infinite alphabets have recently come to be studied extensively as potentially useful tools for solving problems in verification and database theory. One popular model of automata studied is the Class Memory Automata (CMA), for which the emptiness problem is equivalent to Petri Net Reachability. We identify a restriction - which we call weakness - of CMA, and show that their emptiness problem is equivalent to Petri Net Coverability. Further, we show that in the deterministic case they are closed under all Boolean operations. We clarify the connections between weak CMA and existing automata over data languages. We also extend CMA to operate over multiple levels of nested data values, and show that while these have undecidable emptiness in general, adding the weakness constraint recovers decidability of emptiness, via reduction to coverability in well-structured transition systems. We also examine connections with existing automata over nested data.Comment: Preprint of LATA'15 pape

An automaton over data words that captures EMSO logic

We develop a general framework for the specification and implementation of systems whose executions are words, or partial orders, over an infinite alphabet. As a model of an implementation, we introduce class register automata, a one-way automata model over words with multiple data values. Our model combines register automata and class memory automata. It has natural interpretations. In particular, it captures communicating automata with an unbounded number of processes, whose semantics can be described as a set of (dynamic) message sequence charts. On the specification side, we provide a local existential monadic second-order logic that does not impose any restriction on the number of variables. We study the realizability problem and show that every formula from that logic can be effectively, and in elementary time, translated into an equivalent class register automaton

Dynamic Set Intersection

Consider the problem of maintaining a family $F$ of dynamic sets subject to insertions, deletions, and set-intersection reporting queries: given $S,S'\in F$, report every member of $S\cap S'$ in any order. We show that in the word RAM model, where $w$ is the word size, given a cap $d$ on the maximum size of any set, we can support set intersection queries in $O(\frac{d}{w/\log^2 w})$ expected time, and updates in $O(\log w)$ expected time. Using this algorithm we can list all $t$ triangles of a graph $G=(V,E)$ in $O(m+\frac{m\alpha}{w/\log^2 w} +t)$ expected time, where $m=|E|$ and $\alpha$ is the arboricity of $G$. This improves a 30-year old triangle enumeration algorithm of Chiba and Nishizeki running in $O(m \alpha)$ time. We provide an incremental data structure on $F$ that supports intersection {\em witness} queries, where we only need to find {\em one} $e\in S\cap S'$. Both queries and insertions take O\paren{\sqrt \frac{N}{w/\log^2 w}} expected time, where $N=\sum_{S\in F} |S|$. Finally, we provide time/space tradeoffs for the fully dynamic set intersection reporting problem. Using $M$ words of space, each update costs $O(\sqrt {M \log N})$ expected time, each reporting query costs $O(\frac{N\sqrt{\log N}}{\sqrt M}\sqrt{op+1})$ expected time where $op$ is the size of the output, and each witness query costs $O(\frac{N\sqrt{\log N}}{\sqrt M} + \log N)$ expected time.Comment: Accepted to WADS 201

On rr-Simple kk-Path

An $r$-simple $k$-path is a {path} in the graph of length $k$ that passes through each vertex at most $r$ times. The $r$-SIMPLE $k$-PATH problem, given a graph $G$ as input, asks whether there exists an $r$-simple $k$-path in $G$. We first show that this problem is NP-Complete. We then show that there is a graph $G$ that contains an $r$-simple $k$-path and no simple path of length greater than $4\log k/\log r$. So this, in a sense, motivates this problem especially when one's goal is to find a short path that visits many vertices in the graph while bounding the number of visits at each vertex. We then give a randomized algorithm that runs in time $$\mathrm{poly}(n)\cdot 2^{O( k\cdot \log r/r)}$$ that solves the $r$-SIMPLE $k$-PATH on a graph with $n$ vertices with one-sided error. We also show that a randomized algorithm with running time $\mathrm{poly}(n)\cdot 2^{(c/2)k/ r}$ with $c<1$ gives a randomized algorithm with running time \poly(n)\cdot 2^{cn} for the Hamiltonian path problem in a directed graph - an outstanding open problem. So in a sense our algorithm is optimal up to an $O(\log r)$ factor

Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib

Palbociclib is a CDK4/6 inhibitor approved for metastatic estrogen receptor-positive breast cancer. In addition to G1 cell cycle arrest, palbociclib treatment results in cell senescence, a phenotype that is not readily explained by CDK4/6 inhibition. In order to identify a molecular mechanism responsible for palbociclib-induced senescence, we performed thermal proteome profiling of MCF7 breast cancer cells. In addition to affecting known CDK4/6 targets, palbociclib induces a thermal stabilization of the 20S proteasome, despite not directly binding to it. We further show that palbociclib treatment increases proteasome activity independently of the ubiquitin pathway. This leads to cellular senescence, which can be counteracted by proteasome inhibitors. Palbociclib-induced proteasome activation and senescence is mediated by reduced proteasomal association of ECM29. Loss of ECM29 activates the proteasome, blocks cell proliferation, and induces a senescence-like phenotype. Finally, we find that ECM29 mRNA levels are predictive of relapse-free survival in breast cancer patients treated with endocrine therapy. In conclusion, thermal proteome profiling identifies the proteasome and ECM29 protein as mediators of palbociclib activity in breast cancer cells