Generalized Totalizer Encoding for Pseudo-Boolean Constraints

Pseudo-Boolean constraints, also known as 0-1 Integer Linear Constraints, are used to model many real-world problems. A common approach to solve these constraints is to encode them into a SAT formula. The runtime of the SAT solver on such formula is sensitive to the manner in which the given pseudo-Boolean constraints are encoded. In this paper, we propose generalized Totalizer encoding (GTE), which is an arc-consistency preserving extension of the Totalizer encoding to pseudo-Boolean constraints. Unlike some other encodings, the number of auxiliary variables required for GTE does not depend on the magnitudes of the coefficients. Instead, it depends on the number of distinct combinations of these coefficients. We show the superiority of GTE with respect to other encodings when large pseudo-Boolean constraints have low number of distinct coefficients. Our experimental results also show that GTE remains competitive even when the pseudo-Boolean constraints do not have this characteristic.Comment: 10 pages, 2 figures, 2 tables. To be published in 21st International Conference on Principles and Practice of Constraint Programming 201

A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future

Efficient Certified Resolution Proof Checking

We present a novel propositional proof tracing format that eliminates complex processing, thus enabling efficient (formal) proof checking. The benefits of this format are demonstrated by implementing a proof checker in C, which outperforms a state-of-the-art checker by two orders of magnitude. We then formalize the theory underlying propositional proof checking in Coq, and extract a correct-by-construction proof checker for our format from the formalization. An empirical evaluation using 280 unsatisfiable instances from the 2015 and 2016 SAT competitions shows that this certified checker usually performs comparably to a state-of-the-art non-certified proof checker. Using this format, we formally verify the recent 200 TB proof of the Boolean Pythagorean Triples conjecture

Comprehensive vascular imaging using optical coherence tomography-based angiography and photoacoustic tomography

Studies have proven the relationship between cutaneous vasculature abnormalities and dermatological disorders, but to image vasculature noninvasively in vivo, advanced optical imaging techniques are required. In this study, we imaged a palm of a healthy volunteer and three subjects with cutaneous abnormalities with photoacoustic tomography (PAT) and optical coherence tomography with angiography extension (OCTA). Capillaries in the papillary dermis that are too small to be discerned with PAT are visualized with OCTA. From our results, we speculate that the PA signal from the palm is mostly from hemoglobin in capillaries rather than melanin, knowing that melanin concentration in volar skin is significantly smaller than that in other areas of the skin. We present for the first time OCTA images of capillaries along with the PAT images of the deeper vessels, demonstrating the complementary effective imaging depth range and the visualization capabilities of PAT and OCTA for imaging human skin in vivo. The proposed imaging system in this study could significantly improve treatment monitoring of dermatological diseases associated with cutaneous vasculature abnormalities

On Tackling the Limits of Resolution in SAT Solving

The practical success of Boolean Satisfiability (SAT) solvers stems from the CDCL (Conflict-Driven Clause Learning) approach to SAT solving. However, from a propositional proof complexity perspective, CDCL is no more powerful than the resolution proof system, for which many hard examples exist. This paper proposes a new problem transformation, which enables reducing the decision problem for formulas in conjunctive normal form (CNF) to the problem of solving maximum satisfiability over Horn formulas. Given the new transformation, the paper proves a polynomial bound on the number of MaxSAT resolution steps for pigeonhole formulas. This result is in clear contrast with earlier results on the length of proofs of MaxSAT resolution for pigeonhole formulas. The paper also establishes the same polynomial bound in the case of modern core-guided MaxSAT solvers. Experimental results, obtained on CNF formulas known to be hard for CDCL SAT solvers, show that these can be efficiently solved with modern MaxSAT solvers

IN VITRO AND IN VIVO DISPOSITION OF 2,2-DIMETHYL-N-(2,4,6- TRIMETHOXYPHENYL)DODECANAMIDE (CI-976) Identification of a Novel Five-Carbon Cleavage Metabolite in Rats

ABSTRACT: The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration. The major metabolite observed both in vitro and in vivo was identified as the 6-carbon, chain-shortened 5,5-dimethyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid (M-4). M-4 was determined to be formed from the -carboxylic acid 11,11-dimethyl-12-oxo ACAT 2 , (E.C. 2.3.1.1.26) is a key enzyme involved in cholesterol absorption from the gastrointestinal tract and cholesterol deposition in the body (1). The therapeutic potential of ACAT inhibitors as lipid lowering and antiatherosclerotic agents has been postulated for the treatment of hypercholesterolemia (2). The fatty acid anilide, CI-976 ( In vivo pharmacokinetic studies in male rats found CI-976 to have moderate absorption and bioavailability (29%), with an intravenous elimination half-life of 8 hr (6). After intravenous or oral administration to male rats, CI-976 was extensively metabolized to a single major urinary metabolite identified as M-4 ( To understand further the metabolism of CI-976, studies to determine the disposition and metabolism in rats were performed. The metabolism of CI-976 was examined both in hepatocyte suspensions and after oral administration to both male and female rats. In these studies, the metabolic pathways leading to the formation of M-4 were explored using metabolic intermediates as substrates, and by examining the effects of various inhibitors and inducers on the metabolism of CI-976 in hepatocyte incubations. Metabolites found in postreaction hepatocyte incubations and rat urine were characterized by HPLC, LC/MS, and GC/MS. Similar types of experiments were conducted with a new metabolite observed both in vitro and in vivo, which arises from an unusual mechanism (i.e. removal of 5-carbon units from the CI-976 fatty acid side chain). Materials and Methods CI-976 and [ 14 C]CI-976 (20.72 Ci/mg ring-labeled, 99.5% chemical and radiochemical purity); methyl-5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphe

Natural Image Coding in V1: How Much Use is Orientation Selectivity?

Orientation selectivity is the most striking feature of simple cell coding in V1 which has been shown to emerge from the reduction of higher-order correlations in natural images in a large variety of statistical image models. The most parsimonious one among these models is linear Independent Component Analysis (ICA), whereas second-order decorrelation transformations such as Principal Component Analysis (PCA) do not yield oriented filters. Because of this finding it has been suggested that the emergence of orientation selectivity may be explained by higher-order redundancy reduction. In order to assess the tenability of this hypothesis, it is an important empirical question how much more redundancies can be removed with ICA in comparison to PCA, or other second-order decorrelation methods. This question has not yet been settled, as over the last ten years contradicting results have been reported ranging from less than five to more than hundred percent extra gain for ICA. Here, we aim at resolving this conflict by presenting a very careful and comprehensive analysis using three evaluation criteria related to redundancy reduction: In addition to the multi-information and the average log-loss we compute, for the first time, complete rate-distortion curves for ICA in comparison with PCA. Without exception, we find that the advantage of the ICA filters is surprisingly small. Furthermore, we show that a simple spherically symmetric distribution with only two parameters can fit the data even better than the probabilistic model underlying ICA. Since spherically symmetric models are agnostic with respect to the specific filter shapes, we conlude that orientation selectivity is unlikely to play a critical role for redundancy reduction

A SAT Approach to Clique-Width

Clique-width is a graph invariant that has been widely studied in combinatorics and computer science. However, computing the clique-width of a graph is an intricate problem, the exact clique-width is not known even for very small graphs. We present a new method for computing the clique-width of graphs based on an encoding to propositional satisfiability (SAT) which is then evaluated by a SAT solver. Our encoding is based on a reformulation of clique-width in terms of partitions that utilizes an efficient encoding of cardinality constraints. Our SAT-based method is the first to discover the exact clique-width of various small graphs, including famous graphs from the literature as well as random graphs of various density. With our method we determined the smallest graphs that require a small pre-described clique-width.Comment: proofs in section 3 updated, results remain unchange

CLPM: A Cross-Linked Peptide Mapping Algorithm for Mass Spectrometric Analysis

BACKGROUND: Protein-protein, protein-DNA and protein-RNA interactions are of central importance in biological systems. Quadrapole Time-of-flight (Q-TOF) mass spectrometry is a sensitive, promising tool for studying these interactions. Combining this technique with chemical crosslinking, it is possible to identify the sites of interactions within these complexes. Due to the complexities of the mass spectrometric data of crosslinked proteins, new software is required to analyze the resulting products of these studies. RESULT: We designed a Cross-Linked Peptide Mapping (CLPM) algorithm which takes advantage of all of the information available in the experiment including the amino acid sequence from each protein, the identity of the crosslinker, the identity of the digesting enzyme, the level of missed cleavage, and possible chemical modifications. The algorithm does in silico digestion and crosslinking, calculates all possible mass values and matches the theoretical data to the actual experimental data provided by the mass spectrometry analysis to identify the crosslinked peptides. CONCLUSION: Identifying peptides by their masses can be an efficient starting point for direct sequence confirmation. The CLPM algorithm provides a powerful tool in identifying these potential interaction sites in combination with chemical crosslinking and mass spectrometry. Through this cost-effective approach, subsequent efforts can quickly focus attention on investigating these specific interaction sites