The Republic Of Acastus v. The State Of Rubia: The Case Concerning The Elysian Fields

The Republic of Acastus and the State of Rubria have agreed to submit the present controversy for final resolution by the International Court of Justice ( ICJ ) by Special Agreement pursuant to Article 40, Paragraph 1 of the Statute of this Cour

Quality Metrics for Stem Cell-Derived Cardiac Myocytes

Summary Advances in stem cell manufacturing methods have made it possible to produce stem cell-derived cardiac myocytes at industrial scales for in vitro muscle physiology research purposes. Although FDA-mandated quality assurance metrics address safety issues in the manufacture of stem cell-based products, no standardized guidelines currently exist for the evaluation of stem cell-derived myocyte functionality. As a result, it is unclear whether the various stem cell-derived myocyte cell lines on the market perform similarly, or whether any of them accurately recapitulate the characteristics of native cardiac myocytes. We propose a multiparametric quality assessment rubric in which genetic, structural, electrophysiological, and contractile measurements are coupled with comparison against values for these measurements that are representative of the ventricular myocyte phenotype. We demonstrated this procedure using commercially available, mass-produced murine embryonic stem cell- and induced pluripotent stem cell-derived myocytes compared with a neonatal mouse ventricular myocyte target phenotype in coupled in vitro assays

Using a systematic review to uncover theory and outcomes for a complex intervention in health and social care: : Life Story Work for people with dementia as a worked example

Objectives: To use a systematic review to uncover theories of change and outcomes for Life Story Work (LSW) in dementia care to inform a feasibility study. We describe the methods and discuss their use in identifying appropriate outcomes for evaluative research, and their potential for improving evaluation of ‘theory poor’ interventions. Life Story Work (LSW) involves gathering information about a person, their history and interests and producing a tangible output, usually a book. It is used increasingly in dementia care; however, theory about if, how and why it affects which outcomes is poorly developed, making the choice of evaluation methods and appropriate outcomes difficult. Methods A systematic review, carried out using Centre for Reviews and Dissemination guidelines, searched for evidence on underlying theory, good practice, and effectiveness of LSW to inform a feasibility study. For the theory element, a ‘landscaping review’ analysed the extracted text, using qualitative techniques and mind maps to uncover both explicit and implicit links (causal routes) between LSW and outcomes. We triangulated review findings with qualitative research (focus groups) with people with dementia, caregivers, and professionals that explored the outcomes that they would like to see from LSW. Results Of the 56 publications reviewed, only 16 were useful for the theory analysis. Six overarching outcomes were identified: the self-worth and empowerment of people with dementia; individual psychological outcomes; improved relationships between care staff and the individual with dementia; better care; more effective engagement of family members/carers within the care setting; and helping carers to cope. Twelve final theories linking these outcomes to LSW via a causal pathway were elicited. There was substantial overlap in the outcomes identified by the review and by carers, people with dementia and professionals. Together, the results informed our choice of outcome measures for a pilot evaluation. Conclusions This approach may enable researchers to identify and develop the theory necessary before evaluation of a complex intervention in other under- or un- theorised areas. It has the potential both to shorten development stages (and thereby costs) in intervention research and improve the intervention itself

Understanding the [NiFe] Hydrogenase Active Site Environment through Ultrafast Infrared and 2D-IR Spectroscopy of the Subsite Analogue K[CpFe(CO)(CN)2] in Polar and Protic Solvents

The [CpFe(CO)(CN)2]− unit is an excellent structural model for the Fe(CO)(CN)2 moiety of the active site found in [NiFe] hydrogenases. Ultrafast infrared (IR) pump–probe and 2D-IR spectroscopy have been used to study K[CpFe(CO)(CN)2] (M1) in a range of protic and polar solvents and as a dry film. Measurements of anharmonicity, intermode vibrational coupling strength, vibrational relaxation time, and solvation dynamics of the CO and CN stretching modes of M1 in H2O, D2O, methanol, dimethyl sulfoxide, and acetonitrile reveal that H-bonding to the CN ligands plays an important role in defining the spectroscopic characteristics and relaxation dynamics of the Fe(CO)(CN)2 unit. Comparisons of the spectroscopic and dynamic data obtained for M1 in solution and in a dry film with those obtained for the enzyme led to the conclusion that the protein backbone forms an important part of the bimetallic active site environment via secondary coordination sphere interactions

K 1-6: an asymmetric planetary nebula with a binary central star

We present new imaging data and archival multiwavelength observations of the little studied emission nebula K 1-6 and its central star. Narrow-band images in H-alpha (+ [NII]) and [OIII] taken with the Faulkes Telescope North reveal a stratified, asymmetric, elliptical nebula surrounding a central star which has the colours of a late G- or early K-type subgiant or giant. GALEX ultraviolet images reveal a very hot subdwarf or white dwarf coincident in position with this star. The cooler, optically dominant star is strongly variable with a period of 21.312 +/- 0.008 days, and is possibly a high amplitude member of the RS CVn class, although an FK Com classification is also possible. Archival ROSAT data provide good evidence that the cool star has an active corona. We conclude that K 1-6 is most likely an old bona fide planetary nebula at a distance of ~1.0 kpc, interacting with the interstellar medium, and containing a binary or ternary central star. The observations and data analyses reported in this paper were conducted in conjunction with Year 11 high school students as part of an Australian Research Council Linkage Grant science education project, denoted Space To Grow, conducted jointly by professional astronomers, educational researchers, teachers, and high-school students.Comment: 13 pages, 5 figures, accepted by the Publications of the Astronomical Society of Australia (PASA

Life Story Work in Dementia Care : Summary of findings

In 2012 the Social Policy Research Unit at the University of York launched the first study of its kind to investigate life story work from first principles. We asked: What is life story work? What is considered to be good practice in life story work in dementia care? How do service providers and family carers use life story work? Can life story work be evaluated in real world care settings? What are the costs of doing life story work as part of everyday care

Exploring good practice in life story work with people with dementia : the findings of a qualitative study looking at the multiple views of stakeholders

Introduction: Despite growing international interest in life story work as a tool for person-centred dementia care, there is little agreement on what constitutes good practice and little evidence from the perspectives of people with dementia or their family carers. Design and methods: This paper reports the findings from the qualitative element of a larger study looking at the feasibility of evaluating life story work. Ten focus groups were held with 73 participants: four groups of people with dementia (25 participants), three with family carers (21 participants), and three with staff, professionals and volunteers with experience of life story work (27 participants). Findings: It became apparent through our focus groups that, when people talk about ‘life story work’, different people mean different things. This related to both process and outcomes. In particular, a person with dementia may have very different views from others about what life story work is for and how their life story products should be used. There was general agreement that a good practice approach would be tailored to the individual needs and preferences of the person with dementia. However, in practice many settings used templates and the process was led by staff or completed by family carers. Conclusion: We produced nine key features of good practice which could be used to guide the life story work process. Key elements include: the recognition that not everyone will want to take part in life story work and that some people may even find it distressing; the importance of being led by the person with dementia themselves; the need for training and support for staff, carers and volunteers; and the potential for life story work to celebrate the person’s life today and look to the future

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma