C-Alkyl inositol phosphates for use in receptor-ligand engineering

The phosphatidylinositol phosphates (PIPns) and inositol phosphates (IPns) are intricately involved in cell signalling. They bind to a vast array of proteins, which results in a host of physiological responses. Therefore it is difficult to determine the precise downstream effects of an individual protein-phosphoinositide interaction. Perturbations of these networks occur in pathological conditions such as cancer and diabetes increasing the need to understand these systems. Receptor-Ligand Engineering (RLE) may provide the tools to map these interactions. Chemical modification of the small PIPn or IPn ligand and complementary mutation of binding site amino acids is used to create a unique protein-ligand binding pair. Once the modified protein is engineered into the cell line, the dose dependent effects of its stimulation with the complementary ligand can be studied in isolation from signal pathway cross-talk. Phosphatidylinositol 4,5-diphosphate [PtdIns(4,5)P2 / PIP2] and phosphatidylinositol 3,4,5- triphosphate [PtdIns(3,4,5)P3 / PIP3] analogues with C-alkyl groups replacing the axial inositol C-H protons would be suitable ligands for RLE. To date, no such analogues are known in the literature. The key challenges in preparation of such compounds are selective protection and deprotection of the myo-inositol hydroxyls, introduction of new inositol C-substituents with retention of myostereochemistry, and phosphorylation of an unnatural tertiary centre. 4-C-Alkyl IP3 and 4-C-alkyl IP4 analogues were chosen as targets to explore the chemical limitations of analogue synthesis. Orthoesters simultaneously tied up the 1-, 3- and 5-O differentiating between the remaining three hydroxyls in a rigid structure. Oxidation of the isolated 4-OH to the inos-4-ose and selective reintroduction of the myo-geometry by addition of dimethyl sulfoxonium methylide generated the key exo-methylene oxide intermediate. Lithium alkyl cyano cuprates were employed to open the exo-methylene oxide introducing primary, β-secondary, and β- tertiary alkyl and aryl protrusions. 4-C-Alkyl triols were prepared by regiocontrolled DIBAL-H reduction of the orthobenzoate to a benzyl ether, directed by the 4-C-alkyl protrusion. The corresponding 4-C-alkyl tetrols were obtained by acidic hydrolysis of the orthobenzoate and cleavage of the resultant benzoate ester. All polyols were then phosphorylated and globally deprotected to generate the final series of 4-C-alkyl IP3 and IP4 analogues. Some initial investigations were also performed to extend this methodology to prepare 4- and 5-C-alkyl derivatives from a common precursor

Tribo-electrification and Powder Adhesion Studies in the Development of Polymeric Hydrophilic Drug Matrices

The generation of tribo-electric charge during pharmaceutical powder processing can cause a range of complications, including segregation of components leading to content uniformity and particle surface adhesion. This phenomenon becomes problematical when excipients are introduced to a powder mixture alongside the highly charging active pharmaceutical ingredient(s) (APIs). The aim of this study was to investigate the tribo-electric charging and adhesion properties of a model drug, theophylline. Moreover, binary powder mixtures of theophylline with methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC), having different polymer to drug ratios, were formed in order to study the impact of polymer concentration, particle size, substitution ratio and molecular size on the tribo-electric charging and surface adhesion properties of the drug. Furthermore, the relationship between tribo-electric charging and surface adhesion was also studied. The diversity in physicochemical properties of MC/HPMC has shown a significant impact on the tribo-electric charging and adhesion behaviour of theophylline. It was found that the magnitude of electrostatic charge and the level of surface adhesion of the API were significantly reduced with an increase in MC and HPMC concentration, substitution ratios and molecular size. In addition, the tribo-electric charge showed a linear relationship with particle surface adhesion, but the involvement of other forces cannot be neglected

Monetary policy and cross-border interbank market fragmentation: lessons from the crisis

We present a two-country model with an enhanced banking sector featuring risky lending and cross-border interbank market frictions. We find that (i) the strength of the financial accelerator, when applied to banks operating under uncertainty in an interbank market, will critically depend on the economic and financial structure of the economy; (ii) adverse shocks to the real economy can be the source of banking crisis, causing an increase in interbank funding costs, aggravating the initial shock; and (iii) asset purchases and central bank long-term refinancing operations can be effective substitutes for, or supplements to, conventional monetary policy.Revised Versio

New insights into the role of ID proteins in breast cancer metastasis: a MET affair

The establishment of lethal metastases depends on the capacity of a small number of cancer cells to regenerate a tumor after entering a target organ. Stankic and colleagues have identified a role for the inhibitor of differentiation protein, ID1, as a critical regulator of breast cancer stem-like properties and metastatic colonization. Under the control of tumor growth factor-beta signaling, ID1 induces mesenchymal-epithelial transition at the metastatic site by antagonizing the activity of the basic helix-loop-helix transcription factor Twist1. This study sheds light on mechanisms that initiate metastatic outgrowth, and strengthens the concept that epithelial-mesenchymal plasticity is crucial at different stages of metastasis

Preparing Masters level mental health nurses to work within a wellness paradigm: findings from the eMenthe project

Mental health promotion remains an important component of mental health nursing practice. Supporting wellness at both individual and societal levels has been identified as one of the key tenets of mental health promotion. However, the prevailing biomedical paradigm of mental health education and practice has meant that many nurses have not been equipped to incorporate a wellness perspective into their mental health practice. This paper reports on an exploratory study which details the knowledge, skills and attitudes required by Masters level mental health nurses to practice within a wellness paradigm from the perspective of three groups of key stakeholders; service users and family members (n= 23), experienced mental health nurses (n=49) and Masters level mental health nursing students (n=37). Findings, which were reported from individual and focus group interviews across five European countries, suggest a need to re-orientate mental health nursing education to include a focus on wellness and resilience to equip mental health nurses with the skills to work within a strengths-based rather than a deficits-based model of mental health practice. Key challenges to working within a wellness paradigm were identified in the prevailing dominance of the biomedical model of cause and treatment of mental health problems which focuses on symptoms rather than the holistic functioning of the individual, and positions the person as passive in the nurse-service user relationship

Credit crunches from occasionally binding bank borrowing constraints

We present a model in which banks and other financial intermediaries face both occasionally binding borrowing constraints, and costs of equity issuance. Near the steady state, these intermediaries can raise equity finance at no cost through retained earnings. However, even moderately large shocks cause their borrowing constraints to bind, leading to contractions in credit offered to firms, and requiring the intermediaries to raise further funds by paying the cost to issue equity. This leads to the occasional sharp increases in interest spreads and the counter-cyclical, positively skewed equity issuance that are characteristic of the credit crunches observed in the data

Resilience: Easy to use but hard to define

First conceptualized in the 1970s, resilience has become a popular term in the ecological literature, used in the title, abstract, or keywords of approximately 1% of papers identified by ISI Web of Science in the field of environmental sciences and ecology in 2011. However, many papers make only passing reference to the term and do not explain what resilience means in the context of their study system, despite there being a number of possible definitions. In an attempt to determine how resilience is being used in ecological studies, we surveyed 234 papers published between 2004 and 2011 that were identified under the topic “resilience” by ISI Web of Science. Of these, 38% used the word resilience fewer than three times (often in the abstract or keyword list), 66% did not define the term, and 71% did not provide a citation to the resilience literature. Studies that defined resilience most often discussed it as pertaining to an entire ecosystem under continuous rather than discrete disturbance. Given the complex nature of this concept, we believe that care should be taken to properly describe what is meant by the term resilience in ecological studies