Cofactor regeneration by a soluble pyridine nucleotide transhydrogenase for biological production of hydromorphone

We have applied the soluble pyridine nucleotide transhydrogenase of Pseudomonas fluorescens to a cell-free system for the regeneration of the nicotinamide cofactors NAD and NADP in the biological production of the important semisynthetic opiate drug hydromorphone. The original recombinant whole-cell system suffered from cofactor depletion resulting from the action of an NADP(+)-dependent morphine dehydrogenase and an NADH-dependent morphinone reductase. By applying a soluble pyridine nucleotide transhydrogenase, which can transfer reducing equivalents between NAD and NADP, we demonstrate with a cell-free system that efficient cofactor cycling in the presence of catalytic amounts of cofactors occurs, resulting in high yields of hydromorphone. The ratio of morphine dehydrogenase, morphinone reductase, and soluble pyridine nucleotide transhydrogenase is critical for diminishing the production of the unwanted by-product dihydromorphine and for optimum hydromorphone yields. Application of the soluble pyridine nucleotide transhydrogenase to the whole-cell system resulted in an improved biocatalyst with an extended lifetime. These results demonstrate the usefulness of the soluble pyridine nucleotide transhydrogenase and its wider application as a tool in metabolic engineering and biocatalysis

Vibrational branching ratios in photoionization of CO and N2

We report results of experimental and theoretical studies of the vibrational branching ratios for CO 4sigma(-1) photoionization from 20 to 185 eV. Comparison with results for the 2sigma(u)(-1) channel of the isoelectronic N-2 molecule shows the branching ratios for these two systems to be qualitatively different due to the underlying scattering dynamics: CO has a shape resonance at low energy but lacks a Cooper minimum at higher energies whereas the situation is reversed for N-2

Report in the Grand River Eagle

A report in the Grand River Eagle that a committee was organized in Grand Rapids to help the worthy and enterprising pastor, the Rev. A. C. Van Raalte, and his people in their settlement. Some members of the committee were appointed to visit Holland. E. B. Bostwick was chairman and A. D. Rathbone, secretary.https://digitalcommons.hope.edu/vrp_1840s/1138/thumbnail.jp

Exploring an extended role for pharmacy assistants on inpatient wards in UK hospitals: using mixed methods to develop the role of medicines assistants

Objectives: This project explored the deployment of pharmacy assistants to inpatient wards in a new role as ‘medicines assistants’ (MA). Methods: Ward-based MAs were introduced to six wards across two UK hospitals to support medicines administration. Each 30-bed ward delivered acute inpatient services with MAs supporting typical nursing medication administration rounds to 15 patients. Data were collected using activity diaries, observations, clinical audit and semistructured interviews with pharmacy assistants, pharmacy technicians, clinical pharmacists, nurses, ward managers and pharmacy managers. Thematic analysis, descriptive statistics and the Mann-Whitney U test were used to analyse qualitative and quantitative data, respectively. Results: MAs were able to act as a point of contact between the ward and the pharmacy department and were perceived to save nursing time. A statistically significant reduction in the length of time to complete morning medication administration to 15 patients was observed (mean 74.5 vs 60.8 min per round, p<0.05). On average, 17.4 hours of medicines-related activity per ward per week was carried out by MAs rather than by nursing staff. Participants identified broader training and clarity was needed in relation to the accountability and governance of patient-facing roles. Conclusion: Pharmacy assistants deployed as MAs can contribute to saving nursing time and bridge the gap between nursing and pharmacy professionals

Self-images in the present and future: Role of affect and the bipolar phenotype

Background Bipolar Spectrum Disorder (BPSD) is associated with changes in self-related processing and affect, yet the relationship between self-image and affect in the BPSD phenotype is unclear. Methods 47 young adults were assessed for hypomanic experiences (BPSD phenotype) using the Mood Disorders Questionnaire. Current and future self-images (e.g. I am… I will be…) were generated and rated for emotional valence, stability, and (for future self-images only) certainty. The relationship between self-image ratings and measures of affect (depression, anxiety and mania) were analysed in relation to the BPSD phenotype. Results The presence of the BPSD phenotype significantly moderated the relationship between (1) affect and stability ratings for negative self-images, and (2) affect and certainty ratings for positive future self-images. Higher positivity ratings for current self-images were associated with lower depression and anxiety scores. Limitations This was a non-clinical group of young adults sampled for hypomanic experiences, which limits the extension of the work to clinical levels of psychopathology. This study cannot address the causal relationships between affect, self-images, and BPSD. Future work should use clinical samples and experimental mood manipulation designs. Conclusions BPSD phenotype can shape the relationship between affect and current and future self-images. This finding will guide future clinical research to elucidate BPSD vulnerability mechanisms and, consequently, the development of early interventions

‘What is the self anyway?’ : towards a more parsimonious conceptualisation of the self : a review

The ‘self’ is of interest across multiple psychological, cognitive, and social sciences. Unhelpfully, a plethora of terms are used across different theoretical and empirical areas. This leads to inconsistency, confusion and lack of clarity and impedes cross-disciplinary communication and progress. To improve clarity, increase parsimony and support theoretical and empirical advances, it is important to establish clear terms that can be applied consistently across psychology. The aim of this paper is to present a comprehensive initial inventory of synthesised self-terms that can be used by, and across psychology. We review self-terms used across different areas in psychology and identify a set of terms that are most frequently and consistently used across these domains. We then present a synthesis of commonly used ‘self-terms’ that are specifically related to six psychological sub-disciplines; Cognitive, Social, Developmental, Neuroscience, Clinical and Personality psychology. A glossary of self-terms, together with frequently used synonymous self-terms are presented

Activation of P2X(7) receptors stimulates the expression of P2Y(2) receptor mRNA in astrocytes cultured from rat brain.

Under pathological conditions brain cells release ATP at concentrations reported to activate P2X7 ionotropic receptor subtypes expressed in both neuronal and glial cells. In the present study we report that the most potent P2X7 receptor agonist BzATP stimulates the expression of the metabotropic ATP receptor P2Y2 in cultured rat brain astrocytes. In other cell types several kinds of stimulation, including stress or injury, induce P2Y2 expression that, in turn, is involved in different cell reactions. Similarly, it has recently been found that in astrocytes and astrocytoma cells P2Y2 sites can trigger neuroprotective pathways through the activation of several mechanisms, including the induction of genes for antiapoptotic factors, neurotrophins, growth factors and neuropeptides. Here we present evidence that P2Y2 mRNA expression in cultured astrocytes peaks 6 h after BzATP exposure and returns to basal levels after 24 h. This effect was mimicked by high ATP concentrations (1 mM) and was abolished by P2X7-antagonists oATP and BBG. The BzATP-evoked P2Y2 receptor up-regulation in cultured astrocytes was coupled to an increased UTP-mediated intracellular calcium response. This effect was inhibited by oATP and BBG and by P2Y2siRNA, thus supporting evidence of increased P2Y2 activity. To further investigate the mechanisms by which P2X7 receptors mediated the P2Y2 mRNA up-regulation, the cells were pre-treated with the chelating agent EGTA, or with inhibitors of mitogen-activated kinase (MAPK) (PD98059) or protein kinase C, (GF109203X). Each inhibitor significantly reduced the extent to which BzATP induced P2Y2 mRNA. Both BzATP and ATP (1 mM) increased ERK1/2 activation. P2X7-induced ERK1/2 phosphorylation was unaffected by pre-treatment of astrocytes with EGTA whereas it was inhibited by GF109203X. Phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, rapidly increased ERK1/2 activation. We conclude that activation of P2X7 receptors in astrocytes enhances P2Y2 mRNA expression by a mechanism involving both calcium influx and PKC/MAPK signalling pathways

CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial

Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects. Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy. Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit. Trial registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016

Autobiographical memory and well-being in aging: the central role of semantic self-images

Higher levels of well-being are associated with longer life expectancies and better physical health. Previous studies suggest that processes involving the self and autobiographical memory are related to well-being, yet these relationships are poorly understood. The present study tested 32 older and 32 younger adults using scales measuring well-being and the affective valence of two types of autobiographical memory: episodic autobiographical memories and semantic self-images. Results showed that valence of semantic self-images, but not episodic autobiographical memories, was highly correlated with well-being,particularly in older adults. In contrast, well-being in older adults was unrelated to performance across a range of standardised memory tasks. These results highlight the role of semantic self-images in well-being, and have implications for the development of therapeutic interventions for well-being in aging