Catalytic and mechanistic studies into the epoxidation of styrenes using manganese complexes of structurally similar polyamine ligands

The synthesis and catalytic activity of manganese(ii) complexes of two polyamine ligands is reported which highlights how a small structural change in the ligand affects the overall catalytic behaviour.</p

Biotin-tagged fluorescent sensor to visualize "mobile' Zn2+ in cancer cells

A cancer cell-targeting fluorescent sensor has been developed to image mobile Zn2+ by introducing a biotin group. It shows a highly selective response to Zn2+ in vitro, no toxicity in cellulo and images 'mobile' Zn2+ specifically in cancer cells. We believe this probe has the potential to help improve our understanding of the role of Zn2+ in the processes of cancer initiation and development

Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study

Background: In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness. Aim: The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy. Design: This was an observational comparative effectiveness study. Setting: The setting was NHS adult general intensive care units in England and Wales. Participants: Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017. Interventions: Exposure – continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator – continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned. Outcome measures: Primary effectiveness – all-cause mortality at 90 days. Primary economic – incremental net monetary benefit at 1 year. Secondary outcomes – mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit. Data sources: Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study. Results: Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of –£2376 (95% confidence interval –£3841 to –£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%. Limitations: Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends. Conclusions: The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data. Future work: (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. Trial registration: This trial is registered as ClinicalTrials.gov NCT03545750

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0–24; 3,045 ng · h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0–24 (3,036 ng · h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies

Does designation as a UNESCO World Heritage Site influence tourist evaluation of a local destination?

The purpose of this study is to explore whether the UNESCO World Heritage Site (WHS) designation affects tourists’ evaluation of the local destination hosting the site, building on a large sample of about 0.8 million tourists who visited Italy over the period 1997-2015. We find that the inscription onto the UNESCO World Heritage List exerts surprisingly a negative effect on the overall evaluation of the destination and also on the evaluation of its artistic assets though the magnitude of the latter is lower. The effect is heterogeneous across visitors, depending on evaluation levels, as well as origin/destinations and demographics. Nonetheless, the presence of multiple WHSs in the same destination tends to increase evaluation suggesting that destination stakeholders with previous experience in dealing with WHS designations are better equipped to manage the complicated relationship between tourism and preservation. Managerial and policy-making implications are discussed

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival

1. Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design. 2. We evaluated two-dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angle SD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (midpoint: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance). 3. In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleye Sander vitreus, common carp Cyprinus carpio and channel catfish Ictalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted. 4. By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids

Explaining the human resource management preferences of employees: A study of Chinese workers

The forces of globalization, technology and the differences or similarities in institutional systems place substantial pressure on convergence and divergence in HRM practices. Moreover, local customs and the responses from employees also pose serious constraints on the degree of convergence or divergence (Rowley and Benson 2002). In other words, there is what might be termed an upward influence coming from the employees. Although companies may benchmark HRM ‘best practices’, the actual adoption and success of these practices depends, to a large extent, on perceptions and acceptance from employees. However, the opinions of non-managerial employees have been largely neglected in the studies of HRM (Cooke 2009; Legge 1995; Guest 2002; Edgar and Geare 2005; Qiao, Khilji and Wang 2009). Cooke (2009), after reviewing studies on HRM in China published between 1998 and 2007 in major business and management journals, reported that two-thirds of the studies had collected data from managers and most of them relied on managers as the sole source for information. Since the information has mainly been provided by managers, there is the potential for bias because feedback from the managers probably reflects the ideal or ‘best practices’ of HRM that those managers want to implement, rather than the actual HR policies or practices being used in the organization. Thus Cooke (2009, p.19) argued that ‘unless we can broaden our research catchment to include views from the widest range of stakeholders, particularly the employees, our understanding of HRM in China remains partial, from management’s lens’. This study explores the HR preferences of Chinese employees, both non-managerial and managerial ones, based on a sample of 2852 questionnaires from companies in China. A number of questions are explored. For example, what do they think of a ‘promotion-from-within’ policy? Do they prefer an individual-based bonus or a group-based bonus? Do they prefer a ‘downward performance appraisal method’ or a ‘multi-source performance appraisal method’? The research findings shows a strong ‘group orientation’ and a great emphasis on ‘soft factors’ such as seniority, loyalty and connections in many HRM areas. The debate on whether Chinese HRM will converge or diverge towards the Western models is still ongoing. Many argue that there could be further convergence towards the Western practices because globalization may place substantial pressure on firms to standardize practices and policies (see Chen, Lawler and Bae 2005). Others argue that HRM is highly context specific in which institutional and cultural forces have enduring influences (see Rowley and Cooke 2010), which indicates a divergent perspective. The third group supports a ‘cross-vergence’ view which argues that there will be signs of convergence in certain areas but Chinese HRM will keep its ‘Chinese characteristics’ (Cooke 2005, 2010; Yeung, Warner and Rowley 2008; Warner 2009a, b). This study supports the ‘cross-vergence’ perspective. It is argued that certain areas of Chinese HRM are converging to the Western model, but the influence of traditional Chinese personnel practices remains strong. A ‘group orientation’, a major emphasis on ‘soft factors’ and a trade union presence is likely to remain as the three main features of Chinese HRM in the long-term