One-Pot Asymmetric Synthesis of Alkylidene 1-Alkylindan-1-ols Using Bronsted Acid and Palladium Catalysis

A one-pot catalytic enantioselective allylboration/Mizoroki–Heck reaction of 2-bromoaryl ketones has been developed for the asymmetric synthesis of 3-methyleneindanes bearing a tertiary alcohol center. Brønsted acid-catalyzed allylboration with a chiral BINOL derivative was followed by a palladium-catalyzed Mizoroki–Heck cyclization, resulting in selective formation of the exo-alkene. This novel protocol provides a concise and scalable approach to 1-alkyl-3-methyleneindan-1-ols in high enantiomeric ratios (up to 96:4 er). The potential of these compounds as chiral building blocks was demonstrated with efficient transformation to optically active diol and amino alcohol scaffolds

Noncontact Material Testing Using Low-Energy Optical Generation and Detection of Acoustic Pulses

We will discuss preliminary results on the use of a low-energy laser and a sensitive laser interferometer for noncontact material testing of metals and nonmetals. There have been numerous reports [1–12] on the use of lasers to generate acoustic signals, but this is the first use of a relatively low-energy tunable laser source and improved interferometer to measure acoustic waveforms in both metals and nonmetals [13]. The use of a laser interferometer for the noncontact detection of acoustic pulses has also been reported previously [14–20], but we now report the use of a sensitive “non-Michelson” interferometer with increased signal-to-noise capabilities. The combination of these features allows noncontact, low-energy optical generation and optical detection in a variety of materials, in potentially hostile environments, and provides accurate accoustic waveforms which can be used to characterize specimens. These results, therefore, begin to demonstrate the feasibility of a portable (entirely) optical system for the nondestructive evaluation of materials

Long-term patterns of body mass and stature evolution within the hominin lineage.

Body size is a central determinant of a species' biology and adaptive strategy, but the number of reliable estimates of hominin body mass and stature have been insufficient to determine long-term patterns and subtle interactions in these size components within our lineage. Here, we analyse 254 body mass and 204 stature estimates from a total of 311 hominin specimens dating from 4.4 Ma to the Holocene using multi-level chronological and taxonomic analytical categories. The results demonstrate complex temporal patterns of body size variation with phases of relative stasis intermitted by periods of rapid increases. The observed trajectories could result from punctuated increases at speciation events, but also differential proliferation of large-bodied taxa or the extinction of small-bodied populations. Combined taxonomic and temporal analyses show that in relation to australopithecines, early Homo is characterized by significantly larger average body mass and stature but retains considerable diversity, including small body sizes. Within later Homo, stature and body mass evolution follow different trajectories: average modern stature is maintained from ca 1.6 Ma, while consistently higher body masses are not established until the Middle Pleistocene at ca 0.5-0.4 Ma, likely caused by directional selection related to colonizing higher latitudes. Selection against small-bodied individuals (less than 40 kg; less than 140 cm) after 1.4 Ma is associated with a decrease in relative size variability in later Homo species compared with earlier Homo and australopithecines. The isolated small-bodied individuals of Homo naledi (ca 0.3 Ma) and Homo floresiensis (ca 100-60 ka) constitute important exceptions to these general patterns, adding further layers of complexity to the evolution of body size within the genus Homo. At the end of the Late Pleistocene and Holocene, body size in Homo sapiens declines on average, but also extends to lower limits not seen in comparable frequency since early Homo

Consequentialism and Virtue

We examine the following consequentialist view of virtue: a trait is a virtue if and only if it has good consequences in some relevant way. We highlight some motivations for this basic account, and offer twelve choice points for filling it out. Next, we explicate Julia Driver’s consequentialist view of virtue in reference to these choice points, and we canvass its merits and demerits. Subsequently, we consider three suggestions that aim to increase the plausibility of her position, and critically analyze them. We conclude that one of those proposed revisions would improve her account. NOTE: I will self-archive the paper after the 24 month embargo period ends. If you want a copy, just email me

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Online brand communities: when consumers are negatively engaged

The goal of the current research is to explore the influence of negative engagement on committing participants in hate online brand communities. To reach this aim, three brands are used to assess this phenomenon (Starbucks, Apple, and McDonald’s), and three related hate online brand communities of such brands are involved. An online questionnaire is developed based on previously validated scales and fulfilled by 300 online members of mentioned communities. Findings reveal the importance of Brand influence, Helping, and Self-expression dimensions on participants to be committed to hating brand communities.info:eu-repo/semantics/acceptedVersio

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature

ackground: Omega-3 (n-3) fatty acid supplementation is becoming increasingly popular. However given its antithrombotic properties the potential for severe adverse events (SAE) such as bleeding has safety implications, particularly in an older adult population. A systematic review of randomized control trials (RCT) was conducted to explore the potential for SAE and non-severe adverse events (non-SAE) associated with n-3 supplementation in older adults. Methods: A comprehensive search strategy using Medline and a variety of other electronic sources was conducted. Studies investigating the oral administration of n-3 fish oil containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or both against a placebo were sourced. The primary outcome of interest included reported SAE associated with n-3 supplementation. Chi-square analyses were conducted on the pooled aggregate of AEs. Results: Of the 398 citations initially retrieved, a total of 10 studies involving 994 older adults aged ≥60 years were included in the review. Daily fish oil doses ranged from 0.03 g to 1.86 g EPA and/or DHA with study durations ranging from 6 to 52 weeks. No SAE were reported and there were no significant differences in the total AE rate between groups (n-3 intervention group: 53/540; 9.8%; placebo group: 28/454; 6.2%; p= 0.07). Non-SAE relating to gastrointestinal (GI) disturbances were the most commonly reported however there was no significant increase in the proportion of GI disturbances reported in participants randomized to the n-3 intervention (n-3 intervention group: 42/540 (7.8%); placebo group: 24/454 (5.3%); p= 0.18). Conclusions: The potential for AEs appear mild-moderate at worst and are unlikely to be of clinical significance. The use of n-3 fatty acids and the potential for SAE should however be further researched to investigate whether this evidence is consistent at higher doses and in other populations. These results also highlight that well-documented data outlining the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. A more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve n-3 supplementation is required.The authors would like to acknowledge funding provided for the ongoing ATLANTIC randomized controlled trial supported by the National Health and Medical Research Council (NHMRC), Australia

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Evaluation of the implementation of a clinical pharmacy service on an acute internal medicine ward in Italy

© 2018 The Author(s). Published by Springer Nature. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background: Successful implementation of clinical pharmacy services is associated with improvement of appropriateness of prescribing. Both high clinical significance of pharmacist interventions and their high acceptance rate mean that potential harm to patients could be avoided. Evidence shows that low acceptance rate of pharmacist interventions can be associated with lack of communication between pharmacists and the rest of the healthcare team. The objective of this study was to evaluate the effect of a structured communication strategy on acceptance rate of interventions made by a clinical pharmacist implementing a ward-based clinical pharmacy service targeting elderly patients at high risk of drug-related problems. Characteristics of interventions made to improve appropriateness of prescribing, their clinical significance and intervention acceptance rate by doctors were recorded. Methods: A clinical pharmacy intervention study was conducted between September 2013 and December 2013 in an internal medicine ward of a teaching hospital. A trained clinical pharmacist provided pharmaceutical care to 94 patients aged over 70 years. The clinical pharmacist used the following communication and marketing tools to implement the service described: Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis; Specific, Measurable, Achievable, Realistic and Timely (SMART) goals; Awareness, Interest, Desire, Action (AIDA) model. Results: A total of 740 interventions were made by the clinical pharmacist. The most common drug classes involved in interventions were: antibacterials for systemic use (11.1%) and anti-parkinson drugs (10.8%). The main drug-related problem categories triggering interventions were: no specific problem (15.9%) and prescription writing error (12.0%). A total of 93.2% of interventions were fully accepted by physicians. After assessment by an external panel 63.2% of interventions (96 interventions/ per month) were considered of moderate clinical significance and 23.4% (36 interventions/ per month) of major clinical significance. The most frequent interventions were to educate a healthcare professional (20.4%) and change dose (16.1%). Conclusions: To our knowledge this is the first study evaluating the effect of a structured communication strategy on acceptance rate of pharmacist interventions. Pharmaceutical care delivered by the clinical pharmacist is likely to have had beneficial outcomes. Clinical pharmacy services like the one described should be implemented widely to increase patient safety.Peer reviewedFinal Published versio