Close Encounters of the Weak Kind: Investigations of Electron-Electron Interactions between Dissimilar Spins in Hybrid Rotaxanes.

We report a family of hybrid [2]rotaxanes based on inorganic [Cr7NiF8(O2C t Bu)16]- ("{Cr7Ni}") rings templated about organic threads that are terminated at one end with pyridyl groups. These rotaxanes can be coordinated to [Cu(hfac)2] (where Hhfac = 1,1,1,5,5,5-hexafluoroacetylacetone), to give 1:1 or 1:2 Cu:{Cr7Ni} adducts: {[Cu(hfac)2](py-CH2NH2CH2CH2Ph)[Cr7NiF8(O2C t Bu)16]}, {[Cu(hfac)2][py-CH2NH2CH2CH3][Cr7NiF8(O2C t Bu)16]}, {[Cu(hfac)2]([py-CH2CH2NH2CH2C6H4SCH3][Cr7NiF8(O2C t Bu)16])2}, {[Cu(hfac)2]([py-C6H4-CH2NH2(CH2)4Ph][Cr7NiF8(O2C t Bu)16])2}, and {[Cu(hfac)2]([3-py-CH2CH2NH2(CH2)3SCH3][Cr7NiF8(O2C t Bu)16])2}, the structures of which have been determined by X-ray diffraction. The {Cr7Ni} rings and CuII ions both have electronic spin S = 1/2, but with very different g-values. Continuous-wave EPR spectroscopy reveals the exchange interactions between these dissimilar spins, and hence the communication between the different molecular components that comprise these supramolecular systems. The interactions are weak such that we observe AX or AX2 type spectra. The connectivity between the {Cr7Ni} ring and thread terminus is varied such that the magnitude of the exchange interaction J can be tuned. The coupling is shown to be dominated by through-bond rather than through-space mechanisms

Comparison of the predictive nature of the genomic allergen rapid detection (GARD) assay with mammalian assays in determining the skin sensitisation potential of agrochemical active ingredients.

Alternatives to mammalian testing are highly desirable to predict the skin sensitisation potential of agrochemical active ingredients (AI). The GARD assay, a stimulated, dendritic cell-like, cell line measuring genomic signatures, was evaluated using twelve AIs (seven sensitisers and five non-sensitisers) and the results compared with historical results from guinea pig or local lymph node assay (LLNA) studies. Initial GARD results suggested 11/12 AIs were sensitisers and six concurred with mammalian data. Conformal predictions changed one AI to a non-sensitiser. An AI identified as non-sensitising in the GARD assay was considered a potent sensitiser in the LLNA. In total 7/12 GARD results corresponded with mammalian data. AI chemistries might not be comparable to the GARD training set in terms of applicability domains. Whilst the GARD assay can replace mammalian tests for skin sensitisation evaluation for compounds including cosmetic ingredients, further work in agrochemical chemistries is needed for this assay to be a viable replacement to animal testing. The work conducted here is, however, considered exploratory research and the methodology needs further development to be validated for agrochemicals. Mammalian and other alternative assays for regulatory safety assessments of AIs must provide confidence to assign the appropriate classification for human health protection

The (Mis)appropriation of HIV/AIDS advocacy strategies in Global Mental Health: towards a more nuanced approach

Background: Mental health is increasingly finding a place on global health and international development agendas. Advocates for Global Mental Health (GMH), and international organizations such as the World Health Organization (WHO) and the World Bank, argue that treatments available in high-income countries should also be made available in low- and middle-income countries. Such arguments are often made by comparing mental health to infectious diseases, including the relative disease and economic burdens they impose, and pointing to the applicability of the right to access treatment for mental health, not only infectious diseases. HIV/AIDS advocacy in particular has been held up by GMH advocates as offering an appropriate strategy for generating global commitment. Discussion: There is a need to assess how health issues are framed not only in relation to social goods outside of health (such as human rights, security or development), but also in relation to other health or disease models, and how health policy and practice is shaped as a result. The article debates the merits and consequences of likening mental health to HIV/AIDS, and identifies four major problems with the model for GMH advocacy being developed through these analogies: 1. An inappropriately universalizing global approach to context-specific problems; 2. A conception of human rights that focuses on the right to access treatment at the expense of the right to refuse it; 3. A tendency to treat poverty as a psychiatric issue, rather than recognizing that mental distress can be the result of poverty and other forms of inequality; 4. The prioritization of destigmatization of disease over social justice models. Conclusion: There are significant problems with the wholesale adoption of an (often simplified) version of HIV/AIDS advocacy as a model for GMH. Yet critical engagement with the important and nuanced differences between HIV/AIDS and mental health may nevertheless point to some possibilities for productive engagement and cross-fertilisation between advocates, activists and scholars in both fields

Conformational Flexibility of Hybrid [3]- and [4]-Rotaxanes

The synthesis, structures, and properties of [4]- and [3]-rotaxane complexes are reported where [2]-rotaxanes, formed from heterometallic {Cr7Ni} rings, are bound to a fluoride-centered {CrNi2} triangle. The compounds have been characterized by single-crystal X-ray diffraction and have the formulas [CrNi2(F)(O2CtBu)6]{(BH)[Cr7NiF8(O2CtBu)16]}3 (3) and [CrNi2(F)(O2CtBu)6(THF)]{(BH)[Cr7NiF8(O2CtBu)16]}2 (4), where B = py-CH2CH2NHCH2C6H4SCH3. The [4]-rotaxane 3 is an isosceles triangle of three [2]-rotaxanes bound to the central triangle while the [3]-rotaxane 4 contains only two [2]-rotaxanes bound to the central triangle. Studies of the behavior of 3 and 4 in solution by small-angle X-ray scattering and atomistic molecular dynamic simulations show that the structure of 3 is similar to that found in the crystal but that 4 has a different conformation to the crystal. Continuous wave and pulsed electron paramagnetic resonance spectroscopy was used to study the structures present and demonstrate that in frozen solutions (at 5 K) 4 forms more extended molecules than 3 and with a wider range of conformations

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA

Limited diversity associated with duplicated class II MHC-DRB genes in the red squirrel population in the United Kingdom compared with continental Europe

The red squirrel (Sciurus vulgaris) population in the United Kingdom has declined over the last century and is now on the UK endangered species list. This is the result of competition from the eastern grey squirrel (S. carolinensis) which was introduced in the 19th century. However, recent evidence suggests that the rate of population decline is enhanced by squirrelpox disease, caused by a viral infection carried asymptomatically by grey squirrels but to which red squirrels are highly susceptible. Population genetic diversity provides some resilience to rapidly evolving or exotic pathogens. There is currently no data on genetic diversity of extant UK squirrel populations with respect to genes involved in disease resistance. Diversity is highest at loci involved in the immune response including genes clustered within the major histocompatibility complex (MHC). Using the class II DRB locus as a marker for diversity across the MHC region we genotyped 110 red squirrels from locations in the UK and continentalEurope. Twenty four Scvu-DRB alleles at two functional loci; Scvu-DRB1 and Scvu- DRB2, were identified. High levels of diversity were identified at both loci in the continental populations. In contrast, no diversity was observed at the Scvu-DRB2 locus in the mainland UK population while a high level of homozygosity was observed at the Scvu-DRB1 locus. The red squirrel population in the UK appears to lack the extensive MHC diversity associated with continental populations, a feature which may have contributed to their rapid decline

Looking through the 'window of opportunity': is there a new paradigm of podiatry care on the horizon in early rheumatoid arthritis?

Over the past decade there have been significant advances in the clinical understanding and care of rheumatoid arthritis (RA). Major paradigm changes include earlier disease detection and introduction of therapy, and 'tight control' of follow-up driven by regular measurement of disease activity parameters. The advent of tumour necrosis factor (TNF) inhibitors and other biologic therapies have further revolutionised care. Low disease state and remission with prevention of joint damage and irreversible disability are achievable therapeutic goals. Consequently new opportunities exist for all health professionals to contribute towards these advances. For podiatrists relevant issues range from greater awareness of current concepts including early referral guidelines through to the application of specialist skills to manage localised, residual disease activity and associated functional impairments. Here we describe a new paradigm of podiatry care in early RA. This is driven by current evidence that indicates that even in low disease activity states destruction of foot joints may be progressive and associated with accumulating disability. The paradigm parallels the medical model comprising early detection, targeted therapy, a new concept of tight control of foot arthritis, and disease monitoring