Unification modulo Lists with Reverse as Solving Simple Sets of Word Equations

Decision procedures for various list theories have been investigated in the literature with applications to automated verification. Here we show that the unifiability problem for some list theories with a reverse operator is NP-complete. We also give a unifiability algorithm for the case where the theories are extended with a length operator on lists

Monoclinic paracetamol vs. paracetamol-4,4'-bipyridine co-crystal; what is the difference? a charge density study

Paracetamol (PCM) has two well-documented polymorphic forms at room temperature; monoclinic Form I is more stable than the other orthorhombic Form II. Form II exhibits improved tabletting properties compared to Form I due to low shearing forces; however, difficulties in its manufacture have limited its use in industrial manufacture. Previous studies have found that the introduction of a co-former to form co-crystals would allow the PCM molecule to exist in a conformation similar to that of the orthorhombic form while being more stable at room temperature. Experimental charge density analysis of the paracetamol-4,4′-bipyridine (PCM-44BP) co-crystal system, and its constituent molecules, has been carried out to examine the forces that drive the formation and stabilisation of the co-crystal, while allowing PCM to maintain a packing motif similar to that found in Form II. It is hoped studies on this well-known compound will help apply the knowledge gained to other drug molecules that are less successful. The PCM molecules in the co-crystal were found to exhibit similar packing motifs to that found in Form I, however, intercalation of the 44BP molecule between the PCM layers resulted in a shallower angle between molecular planes, which could result in the required lateral shear. Topological analysis identified more weak interactions in the co-crystal compared to the individual molecules, thus allowing for greater stability as evidenced by the lattice energies. Weak interactions in the PCM-44BP co-crystal were found to range in strength from 4.08–84.33 kJ mol−1, and this variety allowed the PCM-44BP planes to be held together, while a weak π–π interaction (15.14 kJ mol−1) allowed lateral shear to occur, thus mimicking the planes found in Form II PCM and offering the possibility of improved tabletting properties. A comparison of integrated atomic charges between partitions of the PCM molecules in the single and co-crystal found that the hydroxyl and amide groups were involved in greater hydrogen bonding in the co-crystal, resulting in a charge redistribution across the molecule evidenced by a larger molecular dipole moment (µ = 12.34D). These findings, in addition to the co-crystal having the largest lattice energy, form a potential basis with which to predict that the co-crystal exhibits improved solubility and stability profiles. It is anticipated that these findings will contribute to improvements in the formulation and other physical properties of PCM and other pharmaceutical compounds

Unification modulo Lists with Reverse as Solving Simple Sets of Word Equations

Decision procedures for various list theories have been investigated in the literature with applications to automated verification. Here we show that the unifiability problem for some list theories with a reverse operator is NP-complete. We also give a unifiability algorithm for the case where the theories are extended with a length operator on lists

An analysis of the experimental and theoretical charge density distributions of the piroxicam-saccharin co-crystal and its constituents

Experimental and theoretical charge density analyses of piroxicam (1), saccharin (2) and their 1:1 co-crystal complex (3) have been carried out. Electron density distribution (EDD) was determined through the use of high-resolution single crystal X-ray diffraction and the data were modelled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. A method for optimising the core density refinement of sulfur atoms is discussed, with emphasis on the reduction of residual electron density that is typically associated with this atom. The asymmetric unit of complex (3) contains single molecules of saccharin and the zwitterionic form of piroxicam. These are held together by weak interactions (hydrogen bonds, π-π and van der Waals interactions), ranging in strength from 4 to 160 kJmol-1, working together to stabilise the complex;. analysis of the molecular electrostatic potential (MEP) of the complexes showed electron redistribution within the cocrystal, facilitating the formation of these generally weak interactions. Interestingly, in the zwitterionic form of piroxicam, the charge distribution reveals that the positive and negative charges are not associated with the formal charges normally associated with this description, but are distributed over adjacent molecular fragments. The use of anisotropic displacement parameters (ADPs) for hydrogen atoms in the multipole model was also investigated but no improvement in the quality of the topological analysis was found.The University of Sydney Bridging Support Scheme. The Danish National Research Foundation (Center for Materials Crystallography, DNRF-93

A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of Piroxicam.

Experimental charge density distribution studies of two polymorphic forms of piroxicam, β- piroxicam (1) and piroxicam monohydrate (2), were carried out via high-resolution single crystal X-ray diffraction experiments and multipole refinement. The asymmetric unit of (2) consists of two discrete piroxicam molecules, (2a) and (2b), and two water molecules. Geometry differs between (1) and (2) due to the zwitterionic nature of (2) which results in the rotation of pyridine ring around the C(10)–N(2) bond by approximately 180°. Consequently, the pyridine and amide are no longer co-planar and (2) forms two exclusive, strong hydrogen bonds, H(3) …O(4) and H(2) …O(3), with bond energy of 66.14 kJ mol-1 and 112.82 kJ mol- 1 for (2a), 58.35 kJ mol-1 and 159.51 kJ mol-1 for (2b) respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified on calculation of atomic charges in the zwitterion shows the formally positive charge of the pyridyl nitrogen is redistributed over the whole of the pyridine ring instead of concentrated at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazinecarboxamide moiety. Multipole derived lattice energy for (1) is -304 kJ mol-1 and that for (2) is -571 kJ mol-1, which is in agreement with the experimentally determined observations of higher solubility and dissolution rates of (1) compared to (2)

Partisan Profiles in Presidential Policies: an Extension of Presidential Preferences for Inflation versus Unemployment

In a recent article, Zaleski does not find any clear difference between the political preferences of Republican and Democratic administrations with respect to the choice between unemployment and inflation. This paper provides empirical support for the opposite conclusion in a generalization of Zaleski's approach allowing for instrument costs

Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck−/− “loss-of-function” counterparts, HckF/F “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from HckF/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage

A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer

The MYC proto-oncogene (MYC) is one of the most frequently overexpressed genes in breast cancer that drives cancer stem cell-like traits, resulting in aggressive disease progression and poor prognosis. In this study, we identified zinc finger transcription factor 148 (ZNF148, also called Zfp148 and ZBP-89) as a direct target of MYC. ZNF148 suppressed cell proliferation and migration and was transcriptionally repressed by MYC in breast cancer. Depletion of ZNF148 by short hairpin RNA (shRNA) and CRISPR/Cas9 increased triple-negative breast cancer (TNBC) cell proliferation and migration. Global transcriptome and chromatin occupancy analyses of ZNF148 revealed a central role in inhibiting cancer cell de-differentiation and migration. Mechanistically, we identified the Inhibitor of DNA binding 1 and 3 (ID1, ID3), drivers of cancer stemness and plasticity, as previously uncharacterized targets of transcriptional repression by ZNF148. Silencing of ZNF148 increased the stemness and tumorigenicity in TNBC cells. These findings uncover a previously unknown tumor suppressor role for ZNF148, and a transcriptional regulatory circuitry encompassing MYC, ZNF148, and ID1/3 in driving cancer stem cell traits in aggressive breast cancer

Structural and compositional variations of basic Cu(II) chlorides in the herbertsmithite and gillardite structure field.

© 2017 The Mineralogical Society. This document is the author’s final accepted version of the journal article. You are advised to consult the published version if you wish to cite from it

Exploring the binding of barbital to a synthetic macrocyclic receptor. A charge density study

Experimental charge density distribution studies, complemented by quantum mechanical theoretical calculations, of a host–guest system composed of a macrocycle (1) and barbital (2) in a 1:1 ratio (3) have been carried out via high-resolution single-crystal X-ray diffraction. The data were modeled using the conventional multipole model of electron density according to the Hansen–Coppens formalism. The asymmetric unit of macrocycle 1 contained an intraannular ethanol molecule and an extraannular acetonitrile molecule, and the asymmetric unit of 3 also contained an intraannular ethanol molecule. Visual comparison of the conformations of the macrocyclic ring shows the rotation by 180° of an amide bond attributed to competitive hydrogen bonding. It was found that the intraannular and extraannular molecules inside were orientated to maximize the number of hydrogen bonds present, with the presence of barbital in 3 resulting in the greatest stabilization. Hydrogen bonds ranging in strength from 4 to 70 kJ mol–1 were the main stabilizing force. Further analysis of the electrostatic potential among 1, 2, and 3 showed significant charge redistribution when cocrystallization occurred, which was further confirmed by a comparison of atomic charges. The findings presented herein introduce the possibility of high-resolution X-ray crystallography playing a more prominent role in the drug design process