The trans influence in unsymmetrical pincer palladacycles: an experimental and computational study

A library of unsymmetrical SCN pincer palladacycles, [ClPd{2-pyr-6-(RSCH2)C6H3}], R = Et, Pr, Ph, p-MePh, and p-MeOPh, pyr = pyridine, has been synthesized via C–H bond activation, and used, along with PCN and N’CN unsymmetrical pincer palladacycles previously synthesized by the authors, to determine the extent to which the trans influence is exhibited in unsymmetrical pincer palladacycles. The trans influence is quantified by analysis of structural changes in the X-ray crystal and density functional theory (DFT) optimized structures and a topological analysis of the electron density using quantum theory of atoms in molecules (QTAIM) to determine the strength of the Pd-donor atom interaction. It is found that the trans influence is controlled by the nature of the donor atom and although the substituents on the donor-ligand affect the Pd-donor atom interaction through the varied electronic and steric constraints, they do not influence the bonding of the ligand trans to it. The data indicate that the strength of the trans influence is P > S > N. Furthermore, the synthetic route to the family of SCN pincer palladacycles presented demonstrates the potential of late stage derivitization for the effective synthesis of ligands towards unsymmetrical pincer palladacycles

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL

Dietary sugars and cardiometabolic risk: Systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids

ABSTRACT Background: Dietary sugars have been suggested as a cause of obesity, several chronic diseases, and a range of cardiometabolic risk factors, but there is no convincing evidence of a causal relation between sugars and risk factors other than body weight. Objective: We conducted a systematic review and meta-analysis of randomized controlled trials that examined effects of the modification of dietary free sugars on blood pressure and lipids. Design: Systematic searches were conducted in OVID Medline, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature, and Web of Science databases (to August 2013) to identify studies that reported intakes of free sugars and at least one lipid or blood pressure outcome. The minimum trial duration was 2 wk. We pooled data by using inverse-variance methods with random-effects models. Results: A total of 39 of 11,517 trials identified were included; 37 trials reported lipid outcomes, and 12 trials reported blood pressure outcomes. Higher compared with lower sugar intakes significantly raised triglyceride concentrations [mean difference (MD): 0.11 mmol/L; 95% CI: 0.07, 0.15 mmol/L; P , 0.0001], total cholesterol (MD: 0.16 mmol/L; 95% CI: 0.10, 0.24 mmol/L; P , 0.0001), lowdensity lipoprotein cholesterol (0.12 mmol/L; 95% CI: 0.05, 0.19 mmol/L; P = 0.0001), and high-density lipoprotein cholesterol (MD: 0.02 mmol/L; 95% CI: 0.00, 0.03 mmol/L; P = 0.03). Subgroup analyses showed the most marked relation between sugar intakes and lipids in studies in which efforts were made to ensure an energy balance and when no difference in weight change was reported. Potential explanatory factors, including a weight change, in most instances explained ,15% of the heterogeneity between studies (I 2 = 36-75%). The effect of sugar intake on blood pressure was greatest in trials $8 wk in duration [MD: 6.9 mm Hg (95% CI: 3.4, 10.3 mm Hg; P , 0.001) for systolic blood pressure and 5.6 mm Hg (95% CI: 2.5, 8.8 mm Hg; P = 0.0005) for diastolic blood pressure]. Conclusions: Dietary sugars influence blood pressure and serum lipids. The relation is independent of effects of sugars on body weight. Protocols for this review were registered separately for effects of sugars on blood pressure and lipids in the PROSPERO International prospective register of systematic reviews as PROS-PERO 2012: CRD42012002379 and 2012: CRD42012002437, respectively. Am J Clin Nut

Pojamide: An HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells.

A ferrocene containing ortho-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide, 2b (Pojamide) displayed nanomolar potency vs. HDAC3. Compared to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and Romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC 1 & 3 inhibition is desirable to achieve maximum anti-cancer benefits. Additionally, we explored Pojamide-induced redox-pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside) and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage attributed to activation to an Fe(III) species

Dental periodontal procedures: a systematic review of contamination (splatter, droplets and aerosol) in relation to COVID-19

Introduction The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic has had a significant effect on the delivery of routine dentistry; and in particular, periodontal care across the world. This systematic review examines the literature relating to splatter, droplet settle and aerosol for periodontal procedures and forms part of a wider body of research to understand the risk of contamination in relation to periodontal care procedures relevant to COVID-19. Methods A search of the literature was carried out using key terms and MeSH words relating to the review questions. Sources included Medline (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials, Scopus, Web of Science and LILACS, ClinicalTrials.Gov. Studies meeting inclusion criteria were screened in duplicate and data extraction was carried out using a template. All studies were assessed for methodological quality and sensitivity. Narrative synthesis was undertaken. Results Fifty studies were included in the review with procedures including ultrasonic scaling (n = 44), air polishing (n = 4), prophylaxis (n = 2) and hand scaling (n = 3). Outcomes included bacterial (colony-forming units e.g. on settle plates) or blood contamination (e.g. visible splatter) and non bacterial, non blood (e.g. chemiluminescence or coloured dyes) contamination. All studies found contamination at all sites although the contamination associated with hand scaling was very low. Contamination was identified in all of the studies even where suction was used at baseline. Higher power settings created greater contamination. Distribution of contamination varied in relation to operator position and was found on the operator, patient and assistant with higher levels around the head of the operator and the mouth and chest of the patient. Settle was identified 30 min after treatments had finished but returned to background levels when measured at or after an hour. The evidence was generally low to medium quality and likely to underestimate contamination. Conclusion Ultrasonic scaling, air polishing and prophylaxis procedures produce contamination (splatter, droplets and aerosol) in the presence of suction, with a small amount of evidence showing droplets taking between 30 min and 1 h to settle. Consideration should be given to infection control, areas of cleaning particularly around the patient and appropriate personal protective equipment, with particular attention to respiratory, facial and body protection for these procedures. In addition, the use of lower power settings should be considered to reduce the amount and spread of contamination

Un/writing the landscape, re/figuring the body

Kelly + Jones' research interests in the process and engagement with writing has shifted away from the production of text. Instead, their research enquiry now focuses on a broader visual and performed investigation into site and the materiality of writing and the place of the body as a scripting phenomena that writes itself into being in proximity to myriad otherness. To do this they have tested out abandoning any form of recognisable text, subverted written language by returning to the gesture, developed an approach that engages with writing instinctively and the materiality whose mark-making predates fixivity. As a result of this enquiry, new material has been generated and formed a new body of work – existing as an area of investigation where writing has become the milieu in which our collaboration operates. The research process is an organic and intermittent collaboration that bubbles in the gaps and suddenly erupts into different spaces and contexts. To this end, Kelly + Jones state that the enquiry has produced the following contributions: Originality - Site specific practice usually engages with one site and most theory and cultural commentary would attest to this. They have created a dialogue between two diverse sites that have expanded each other’s terms and created a conceptual third site that does not belong fully to either and has its own terms. They have decentralised the research opening it up to other researchers at various stages in their career without hierarchy. They have moved outside of the Fine Art community gaining fresh insight into their theoretical framework and site knowledge e.g geographer Professor Helen Walkington who brought new insight about the presence of flint within chalk beds and their significance around human activity. Kelly +Jones practice is of significance as they have created a research cascade which continues to grow and spread outwards. This is evidenced in the zoom research meeting transcript which brought together different research voices from student to Professorship with a specialism in Higher Education pedagogy. Significance in expanded research models that decentralise and strip hierarchy. They have expanded the discourse between site and the body …by splitting the singularity attached to ideas of site/locus in an environmental sense and have also presented the body as a multiple and shifting site as opposed to a fixed entity. In contrast to existing discourse on writing it draws attention to the political implication of the act of writing rather than what is written. What are the conditions and gestures that precede writing? What is the troubled and fruitful relationship between writing and subjectivity, resistance and personhood. We have repurposed the traditional idea of exhibiting visual art as display and as fixed point to exhibiting as research and as touch – to feel the way to the next level, to allow others to intervene and alter course, expand discourse. We chose a response model (listening to the sites rather than demonstrating it with planned gestures). This allowed new and unexpected experience to rise 'which were intimately connected to the presence that live work offers, rather than projection.The publication is an output for this new body of practice as research. The publication takes the form of a newspaper framework and features an edited series of texts, performative gestures and provocations that has been written and edited by Kelly + Jones. It also ‘draws-down’ on several research activities and influences from Kelly + Jones presented in the form of the solo exhibition at The Glass Tank in 2020. The seers-in-residence programme carried out as part of their exhibition at The Glass Tank provided a unique opportunity for research-generation in the form of a series of conversations with invited academics and researchers to be Seers (Professor Helen Walkington, Janice Howard, Deborah Pill and Kate Mahony, Oxford Brookes University). The publication includes essays by Professor Jennie Klein, University of Ohio and Joanne Lee, Sheffield Hallam University. The publication has been internationally peer reviewed and the National Library of Norway has a collection of 7 copies of the publication now on file due to international academic and artistic interests in the publication. The publication has been commissioned by Bergen Performing Arts publishing arm - PABlish.University of Ohio Performance Art Bergen University of Derby Oxford Brookes Universit

Elaboration of tetra-orthogonally-substituted aromatic scaffolds towards novel EGFR-kinase inhibitors

Nitration of three regioisomers of bromo-fluorobenzaldehyde proceeds regioselectively, notably with H2SO4/HNO3 at 0 °C. The thereby synthesized tetrasubstituted aromatics, endowed with orthogonal substituents, can be elaborated via Pd-catalysed coupling, reduction and reductive amination reactions. As a test-case, these compounds were converted into EGFR inhibitors related to Gefitinib, whose activity was rationalised by docking studies

CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin

Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8− skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1). In contrast, CCR8− skin T cells are heterogeneous and comprise variable numbers of exhausted (programmed cell death protein 1+), senescent (CD57+, killer cell lectin-like receptor subfamily G member 1+), and effector (T-bethi, Eomeshi) T cells. Importantly, conventional and high-throughput sequencing of expressed TCR β-chain (TRB) gene rearrangements showed that these CCR8-defined populations are clonotypically distinct, suggesting unique ontogenies in response to separate antigenic challenges and/or stimulatory conditions. Moreover, CCR8+ and CCR8− skin T cells were phenotypically stable in vitro and displayed similar levels of telomere erosion, further supporting the likelihood of a nonlinear differentiation pathway. On the basis of these results, we propose that long-lived memory T cells in human skin can be defined by the expression of CCR8

Goal-oriented cognitive rehabilitation for early-stage Alzheimer's and related dementias: the GREAT RCT

This is the author accepted manuscript. The final version is available from NIHR Journals Library via the DOI in this record.The published version is available in ORE at http://hdl.handle.net/10871/36867This study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme; PI Professor L Clare; HTA reference 11/15/04