Political observers agree that parties in European parliamentary democracies are more likely than previously to give party members opportunities to vote in decisions about party policies or ...personnel. Observers are less agreed about the implications of these apparent procedural trends. Some, including Peter Mair, saw them as evidence of the hollowing-out of party democracies; others have seen them as enhancing citizens' opportunities for meaningful political participation. Because this is ultimately an empirical question as well as a normative one, these radically conflicting interpretations make it crucial to examine which interpretation is best supported by usage to date This is the task we undertake in this article. We use data from the Political Party Database Project (PPDB) to investigate the extent to which parties in 26 European countries have adopted and employed intra-party ballots. We also ask whether there is evidence that such procedures are changing intra-party relationships. We find that balloting of party members is indeed widely used, but it is by no means universal. We find much less support for the implication that such ballots are associated with less competitive contests, or that the new devices are generally used in ways that devalue party-member bonds.
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and ...proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.
A series of tert-butyl-substituted pincer ligands based on 1,3-diaminobenzene and 3-aminophenol scaffolds, tBu4PXCYP (1e, X = Y = NH; 1f, X = NH; Y = O) and the corresponding iridium hydridochloro ...complexes (tBu4PXCYP)IrHCl (2e, X = Y = NH; 2f, X = NH; Y = O) were prepared with moderate yields and high purity and were fully characterized by 1H and 31P NMR spectroscopy. Unsymmetrical hybrid pincer ligands R2PNCOPtBu2 (1g, R = isopropyl; 1h, R = cyclohexyl) were prepared conveniently in high yield via a one-pot procedure by judiciously choosing reaction conditions and base; the corresponding iridium hydrido chloro complexes iPr2PNCOPtBu2IrHCl (2g) and Cy2PNCOPtBu2IrHCl (2h) were synthesized by the reaction of IrCl(COE)22 with ligands. X-ray crystallography reveals that these iridium pincer complexes adopt similar square-pyramidal geometries and exhibit strong intermolecular hydrogen bonding between the NH linker and chloride ions of the adjacent iridium complex in the solid state. 1H NMR chemical shifts of tert-butyl based pincer ligated iridium hydrides move downfield when the electronegativity of the linker between the benzene backbone and phosphine moiety increases for 2a, 2e, 2f, and 2b. Accordingly the corresponding iridium pincer carbonyl complexes (tBu4PXCYP)Ir(CO), 3a, 3e, 3f, and 3b show a blue shift in the CO stretching frequency. The activities of iridium complexes containing NH linkers were briefly examined for transfer dehydrogenation from cyclooctane to tert-butylethylene; (iPr2PNCOPtBu2)IrHCl (2g) exhibits the highest activity among all tested iridium pincer complexes, including the most studied (tBu4PCP)IrHCl (2a) and (tBu4POCOP)IrHCl (2b). The enhanced catalytic activity could be related to combined electronic and steric effects of the NH/O hybrid linker and different alkyl groups at phosphorus. This new class of iridium pincer complexes could have great implications in catalytic transformation of polar compounds due to the strong hydrogen-bond-donating ability of the NH linker.
Introduction
Mental health problems are a considerable public health issue and spending time in nature has been promoted as a way to access a range of psychological benefits leading to the ...development of nature‐based interventions for people with severe and enduring mental health problems. Less, however, is understood about the potential benefits and efficacy of day‐to‐day routine access to outdoor green and blue spaces for mental health service users.
Methods
Using a mixed‐methods design between April and October 2021, we explored the benefits and barriers to spending time outdoors with a purposive sample of mental health service users (N = 11) using qualitative interviews and an online general population survey (N = 1791). Qualitative evidence highlighted the restorative benefits of nature and identified a number of barriers associated with fears around personal safety, social anxiety, fatigue and lack of motivation. COVID‐19 had also restricted access to green and blue spaces. Having social contact and support encouraged people to spend time outdoors. In the quantitative survey, self‐report and standardised measures (the Patient Health Questionnaire and the Warwick–Edinburgh Wellbeing Scale) were used to assess past and current mental wellbeing.
Findings
Statistically significant differences were found between wellbeing and the use of green and blue spaces. Those with mental health problems spent time outdoors because they: felt guilty; wanted to reduce their anxiety; or rely on someone for encouragement. Those without mental health problems endorsed more positively framed reasons including relaxation, improving physical health or getting exercise. Barriers for people with mental health problems involved safety concerns, feeling anxious and having a poor self‐image. These findings give insight into motivations for an outdoor activity to help inform the design of public mental health interventions.
Conclusion
Further work is required to improve access and safety to promote the benefits of green and blue spaces for everyone.
Patient or Public Contribution
The research team included expert experienced researchers with a mental health service provider (Praxis Care) and they were involved in the development of the research idea, funding application, design, data collection, analysis, writing up and dissemination activities.
Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) ...in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1’s role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cell-cycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.
Significance This work addresses a key question in the field of liver receptor homolog-1 (LRH-1) pathophysiology in colorectal cancer (CRC)—namely, does LRH-1 contribute exclusively to tumorigenesis, or does LRH-1 also drive established CRC tumor growth? These two models have widely different implications for pharmaceutical targeting in CRC. To our knowledge, our work is the first to demonstrate that silencing of LRH-1 in established human CRC cell lines impairs proliferation though G0/G1 phase prolongation. Our microarray gene expression analysis shows that loss of LRH-1 expression yields alterations in diverse cellular pathways consistent with the critical role of LRH-1 in CRC. Taken together, our study suggests that a subset of CRC patients could benefit from selective antagonism of LRH-1.
Operando EPR under elevated ethylene pressure supported by in situ XAS was for the first time applied to discriminate between active and deactivating Cr species in ethylene tetramerization. Starting ...from Cr(III) in the Cr(acac)3 precursor, a (PNP)Cr(II)(CH3)2 complex is most likely formed upon adding PNP and MMAO, which is regarded as the active species that converts ethylene to 1-octene by passing a reversible redox cycle, while reduction to Cr(I) leads to deactivation.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, ...structure−activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by ∼50%.
Iron-based Fischer–Tropsch synthesis (FTS) catalysts evolve in situ on exposure to synthesis gas (CO & H
2
) forming a mixture of iron oxides, iron carbides and carbonaceous deposits. Recently, the ...application of inelastic neutron scattering has shown the progressive formation of a hydrocarbonaceous overlayer during this catalyst conditioning period. The evolving nature of the catalyst alters the proportion of phases present within the catalyst, which may influence the transport of hydrogen within the reaction system. Preliminary quasi-elastic neutron scattering (QENS) measurements are used to investigate hydrogen diffusion within an un-promoted iron FTS catalyst that has experienced varying levels of time-on-stream (0, 12 and 24 h) of ambient pressure CO hydrogenation at 623 K. Measurements on the catalyst samples in the absence of hydrogen show the unreacted sample (t = 0 h) to exhibit little increase in motion over the temperature range studied, whereas the t = 12 and 24 h samples exhibit a pronounced change in motion with temperature. The contrast is attributed to the presence of the afore-mentioned hydrocarbonaceous overlayer. Measurements on the samples in the presence of liquid hydrogen show hydrogen diffusional characteristics to be modified as a function of the catalyst conditioning process but, due to the complexity of the evolving catalyst matrix, the hydrogen motion cannot be attributed to a particular phase or component of the catalyst. Problems in the use of hydrogen as a probe molecule in this instance are briefly considered. Coincident neutron diffraction studies undertaken alongside the QENS measurements confirm the transition from hematite pre-catalyst to that of Hägg carbide during the course of extended times-on-stream.
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