Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution

There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4]4+ cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles. In an effort to improve the kinetic stability of these cage architectures here we report the synthesis of two amino substituted tripyridyl 2,6-bis(pyridin-3-ylethynyl)pyridine (tripy) ligands (with amino groups either in the 2-(2A-tripy) or 3-(3A-tripy) positions of the terminal pyridines) and their respective [Pd2(Ltripy)4]4+ cages. These systems have been characterised by 1H, 13C and DOSY NMR spectroscopies, high resolution electrospray mass spectrometry, elemental analysis and, in one case, by X-ray crystallography. It was established, using model palladium(II) N-heterocyclic carbene (NHC) probe complexes, that the amino substituted compounds were stronger donor ligands than the parent system (2A-tripy > 3A-tripy > tripy). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2(2A-tripy)4]4+ proving the most stable. Biological testing on the three ligands and cages against A549 and MDA-MB-231 cell lines showed that only [Pd2(2A-tripy)4]4+ exhibited any appreciable cytotoxicity, with a modest IC50 of 36.4 ± 1.9 μM against the MDA-MB-231 cell line. Unfortunately, the increase in kinetic stability of the [Pd2(Ltripy)4]4+ cages was accompanied by loss of cisplatin-binding ability

NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch

Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01–1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions

Initiation of Psychotropic Medication after Partner Bereavement: A Matched Cohort Study

Background Recent changes to diagnostic criteria for depression in DSM-5 remove the bereavement exclusion, allowing earlier diagnosis following bereavement. Evaluation of the potential effect of this change requires an understanding of existing psychotropic medication prescribing by non-specialists after bereavement. Aims To describe initiation of psychotropic medication in the first year after partner bereavement. Methods In a UK primary care database, we identified 21,122 individuals aged 60 and over with partner bereavement and no psychotropic drug use in the previous year. Prescribing (anxiolytic/hypnotic, antidepressant, antipsychotic) after bereavement was compared to age, sex and practice matched controls. Results The risks of receiving a new psychotropic prescription within two and twelve months of bereavement were 9.5% (95% CI 9.1 to 9.9%) and 17.9% (17.3 to 18.4%) respectively; an excess risk of initiation in the first year of 12.4% compared to non-bereaved controls. Anxiolytic/hypnotic and antidepressant initiation rates were highest in the first two months. In this period, the hazard ratio for initiation of anxiolytics/hypnotics was 16.7 (95% CI 14.7 to 18.9) and for antidepressants was 5.6 (4.7 to 6.7) compared to non-bereaved controls. 13.3% of those started on anxiolytics/hypnotics within two months continued to receive this drug class at one year. The marked variation in background family practice prescribing of anxiolytics/hypnotics was the strongest determinant of their initiation in the first two months after bereavement. Conclusion Almost one in five older people received a new psychotropic drug prescription in the year after bereavement. The early increase and trend in antidepressant use after bereavement suggests some clinicians did not adhere to the bereavement exclusion, with implications for its recent removal in DSM-5. Family practice variation in use of anxiolytics/hypnotics suggests uncertainty over their role in bereavement with the potential for inappropriate long term use

Dimensions of Children's Health Beliefs

Health beliefs interviews were conducted with 250 children aged 6-17 years. A factor analysis of the items resulted in six correlated fac tors which were interpreted as 1) specific health concerns, 2)general health concerns, 3) perceived parental concern, 4) perceived general susceptibility, 5) perceived susceptibility to specific conditions, and 6) perceived seriousness of and susceptibility to disease. Factor scores were computed and two-way analyses of variance (by age and sex of child) were conducted on six sets of factor scores. No significant sex differences or sex by age in teraction effects were noted. Younger children scored significantly higher on "specific health concerns"and "perceived general susceptibility,"while older children scored significantly higher on "perceived parental concern. " Tests of differences among variances showed a tendency for the variability to be greater among younger children. The results are interpreted as pro viding partial support for a model of children's health beliefs and as a basis for further operationalization of concepts which are central to an understand ing of motivated health behavior. Implications for practice are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66657/2/10.1177_109019818000700304.pd

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer. Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights. Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms. Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2–2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086–1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06–1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04–1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4. Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study

Does attending a large science event enthuse young people about science careers?

A survey was conducted during the University of Manchester’s 2014 ‘Science Extravaganza’, which saw the participation of over 900 Key Stage 3 (ages 11–14) students in a range of interactive demonstrations, all run by active University researchers. The findings of this study suggest that a new approach is necessary in order to use these large science events to actively engage with school students about the career opportunities afforded by science subjects. Recommendations for such an approach are suggested, including the better briefing of researchers, and the invitation of scientists from outside academia to attend and interact with the school students

Comment on 'Geoengineering with seagrasses: Is credit due where credit is given?'

Over the past decade scientists around the world have sought to estimate the capacity of seagrass meadows to sequester carbon, and thereby understand their role in climate change mitigation. The number of studies reporting on seagrass carbon accumulation rates is still limited, but growing scientific evidence supports the hypothesis that seagrasses have been efficiently locking away CO2 for decades to millennia (e.g. Macreadie et al 2014, Mateo et al 1997, Serrano et al 2012). Johannessen and Macdonald (2016), however, challenge the role of seagrasses as carbon traps, claiming that gains in carbon storage by seagrasses may be \u27illusionary\u27 and that \u27their contribution to the global burial of carbon has not yet been established\u27. The authors warn that misunderstandings of how sediments receive, process and store carbon have led to an overestimation of carbon burial by seagrasses. Here we would like to clarify some of the questions raised by Johannessen and Macdonald (2016), with the aim to promote discussion within the scientific community about the evidence for carbon sequestration by seagrasses with a view to awarding carbon credits

External sources of clean technology: evidence from the clean development mechanism

New technology is fundamental to sustainable development. However, inventors from industrialized countries often refuse technology transfer because they worry about reverse-engineering. When can clean technology transfer succeed? We develop a formal model of the political economy of North–South technology transfer. According to the model, technology transfer is possible if (1) the technology in focus has limited global commercial potential or (2) the host developing country does not have the capacity to absorb new technologies for commercial use. If both conditions fail, inventors from industrialized countries worry about the adverse competitiveness effects of reverse-engineering, so technology transfer fails. Data analysis of technology transfer in 4,894 projects implemented under the Kyoto Protocol’s Clean Development Mechanism during the 2004–2010 period provides evidence in support of the model

V_H replacement in rearranged immunoglobulin genes

Examples suggesting that all or part of the V&lt;sub&gt;H&lt;/sub&gt; segment of a rearranged V&lt;sub&gt;H&lt;/sub&gt;DJ&lt;sub&gt;H&lt;/sub&gt; may be replaced by all or part of another V&lt;sub&gt;H&lt;/sub&gt; have been appearing since the 1980s. Evidence has been presented of two rather different types of replacement. One of these has gained acceptance and has now been clearly demonstrated to occur. The other, proposed more recently, has not yet gained general acceptance because the same effect can be produced by polymerase chain reaction artefact. We review both types of replacement including a critical examination of evidence for the latter. The first type involves RAG proteins and recombination signal sequences (RSS) and occurs in immature B cells. The second was also thought to be brought about by RAG proteins and RSS. However, it has been reported in hypermutating cells which are not thought to express RAG proteins but in which activation-induced cytidine deaminase (AID) has recently been shown to initiate homologous recombination. Re-examination of the published sequences reveals AID target sites in V&lt;sub&gt;H&lt;/sub&gt;-V&lt;sub&gt;H&lt;/sub&gt; junction regions and examples that resemble gene conversion