A cobalt complex of a microbial arene oxidation product

We report the first synthesis of a cobalt Cp diene complex wherein the diene is derived by microbial dearomatising dihydroxylation of an aromatic ring. The complex has been characterised crystallographically and its structure is compared to that of an uncomplexed diene precursor

Labrador retrievers under primary veterinary care in the UK: demography, mortality and disorders

Abstract Background Labrador retrievers are reportedly predisposed to many disorders but accurate prevalence information relating to the general population are lacking. This study aimed to describe demography, mortality and commonly recorded diseases in Labrador retrievers under UK veterinary care. Methods The VetCompass™ programme collects electronic patient record data on dogs attending UK primary-care veterinary practices. Demographic analysis covered all33,320 Labrador retrievers in the VetCompass™ database under veterinary care during 2013 while disorder and mortality data were extracted from a random sample of 2074 (6.2%) of these dogs. Results Of the Labrador retrievers with information available, 15,427 (46.4%) were female and 15,252 (53.6%) were male. Females were more likely to be neutered than males (59.7% versus 54.8%, P <  0.001). The overall mean adult bodyweight was 33.0 kg (SD 6.1). Adult males were heavier (35.2 kg, SD 5.9 kg) than adult females (30.4 kg, SD 5.2 kg) (P <  0.001). The median longevity of Labrador retrievers overall was 12.0 years (IQR 9.9–13.8, range 0.0–16.0). The most common recorded colours were black (44.6%), yellow (27.8%) and liver/chocolate (reported from hereon as chocolate) (23.8%). The median longevity of non-chocolate coloured dogs (n = 139, 12.1 years, IQR 10.2–13.9, range 0.0–16.0) was longer than for chocolate coloured animals (n = 34, 10.7 years, IQR 9.0–12.4, range 3.8–15.5) (P = 0.028). Of a random sample of 2074 (6.2%) Labrador retrievers under care in 2013 that had full disorder data extracted, 1277 (61.6%) had at least one disorder recorded. The total number of dogs who died at any date during the study was 176. The most prevalent disorders recorded were otitis externa (n = 215, prevalence 10.4%, 95% CI: 9.1–11.8), overweight/obesity (183, 8.8%, 95% CI: 7.6–10.1) and degenerative joint disease (115, 5.5%, 95% CI: 4.6–6.6). Overweight/obesity was not statistically significantly associated with neutering in females (8.3% of entire versus 12.5% of neutered, P = 0.065) but was associated with neutering in males (4.1% of entire versus 11.4% of neutered, P < 0.001). The prevalence of otitis externa in black dogs was 12.8%, in yellow dogs it was 17.0% but, in chocolate dogs, it rose to 23.4% (P < 0.001). Similarly, the prevalence of pyo-traumatic dermatitis in black dogs was 1.1%, in yellow dogs it was 1.6% but in chocolate dogs it rose to 4.0% (P = 0.011). Conclusions The current study assists prioritisation of health issues within Labrador retrievers. The most common disorders were overweight/obesity, otitis externa and degenerative joint disease. Males were significantly heavier females. These results can alert prospective owners to potential health issues and inform breed-specific wellness checks

The ethics of digital well-being: a multidisciplinary perspective

This chapter serves as an introduction to the edited collection of the same name, which includes chapters that explore digital well-being from a range of disciplinary perspectives, including philosophy, psychology, economics, health care, and education. The purpose of this introductory chapter is to provide a short primer on the different disciplinary approaches to the study of well-being. To supplement this primer, we also invited key experts from several disciplines—philosophy, psychology, public policy, and health care—to share their thoughts on what they believe are the most important open questions and ethical issues for the multi-disciplinary study of digital well-being. We also introduce and discuss several themes that we believe will be fundamental to the ongoing study of digital well-being: digital gratitude, automated interventions, and sustainable co-well-being

Copy Number and Loss of Heterozygosity Detected by SNP Array of Formalin-Fixed Tissues Using Whole-Genome Amplification

The requirement for large amounts of good quality DNA for whole-genome applications prohibits their use for small, laser capture micro-dissected (LCM), and/or rare clinical samples, which are also often formalin-fixed and paraffin-embedded (FFPE). Whole-genome amplification of DNA from these samples could, potentially, overcome these limitations. However, little is known about the artefacts introduced by amplification of FFPE-derived DNA with regard to genotyping, and subsequent copy number and loss of heterozygosity (LOH) analyses. Using a ligation adaptor amplification method, we present data from a total of 22 Affymetrix SNP 6.0 experiments, using matched paired amplified and non-amplified DNA from 10 LCM FFPE normal and dysplastic oral epithelial tissues, and an internal method control. An average of 76.5% of SNPs were called in both matched amplified and non-amplified DNA samples, and concordance was a promising 82.4%. Paired analysis for copy number, LOH, and both combined, showed that copy number changes were reduced in amplified DNA, but were 99.5% concordant when detected, amplifications were the changes most likely to be ‘missed’, only 30% of non-amplified LOH changes were identified in amplified pairs, and when copy number and LOH are combined ∼50% of gene changes detected in the unamplified DNA were also detected in the amplified DNA and within these changes, 86.5% were concordant for both copy number and LOH status. However, there are also changes introduced as ∼20% of changes in the amplified DNA are not detected in the non-amplified DNA. An integrative network biology approach revealed that changes in amplified DNA of dysplastic oral epithelium localize to topologically critical regions of the human protein-protein interaction network, suggesting their functional implication in the pathobiology of this disease. Taken together, our results support the use of amplification of FFPE-derived DNA, provided sufficient samples are used to increase power and compensate for increased error rates

Induction of interleukin-8 preserves the angiogenic response in HIF-1 alpha-deficient colon cancer cells

authorHypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis^1, ^2, ^3, ^4. It represents an attractive therapeutic target^5, ^6 in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy^7. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis^8, ^9. In HIF-1_α knockdown DLD-1 colon cancer cells (DLD-1^HIF-kd), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1_α (DLD-1^HIF-wt). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1^HIF-kd but not DLD-1^HIF-wt cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-_KB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1^HIF-kd but not DLD-1^HIF-wt xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1α may be most effective when IL-8 is simultaneously targeted

An integrated 1D–2D hydraulic modelling approach to assess the sensitivity of a coastal region to compound flooding hazard under climate change

Coastal regions are dynamic areas that often lie at the junction of different natural hazards. Extreme events such as storm surges and high precipitation are significant sources of concern for flood management. As climatic changes and sea-level rise put further pressure on these vulnerable systems, there is a need for a better understanding of the implications of compounding hazards. Recent computational advances in hydraulic modelling offer new opportunities to support decision-making and adaptation. Our research makes use of recently released features in the HEC-RAS version 5.0 software to develop an integrated 1D–2D hydrodynamic model. Using extreme value analysis with the Peaks-Over-Threshold method to define extreme scenarios, the model was applied to the eastern coast of the UK. The sensitivity of the protected wetland known as the Broads to a combination of fluvial, tidal and coastal sources of flooding was assessed, accounting for different rates of twenty-first century sea-level rise up to the year 2100. The 1D–2D approach led to a more detailed representation of inundation in coastal urban areas, while allowing for interactions with more fluvially dominated inland areas to be captured. While flooding was primarily driven by increased sea levels, combined events exacerbated flooded area by 5–40% and average depth by 10–32%, affecting different locations depending on the scenario. The results emphasise the importance of catchment-scale strategies that account for potentially interacting sources of flooding

Assessment of rotatory laxity in anterior cruciate ligament-deficient knees using magnetic resonance imaging with Porto-knee testing device

Purpose Objective evaluation of both antero-posterior translation and rotatory laxity of the knee remains a target to be accomplished. This is true for both preoperative planning and postoperative assessment of different ACL reconstruction emerging techniques. The ideal measurement tool should be simple, accurate and reproducible, while enabling to assess both ‘‘anatomy’’ and ‘‘function’’ during the same examination. The purpose of this study is to evaluate the clinical effectiveness of a new in-housedeveloped testing device, the so-called Porto-knee testing device (PKTD). The PKTD is aimed to be used on the evaluation of both antero-posterior and rotatory laxity of the knee during MRI exams. Methods Between 2008 and 2010, 33 patients with ACLdeficient knees were enrolled for the purpose of this study. All patients were evaluated in the office and under anesthesia with Lachman test, lateral pivot-shift test and anterior drawer test. All cases were studied preoperatively with KT-1000 and MRI with PKTD, and examinations performed by independent observers blinded for clinical evaluation. During MRI, we have used a PKTD that applies antero-posterior translation and permits free tibial rotation through a standardized pressure (46.7 kPa) in the proximal posterior region of the leg. Measurements were taken for both knees and comparing side-to-side. Five patients with partial ruptures were excluded from the group of 33. Results For the 28 remaining patients, 3 women and 25 men, with mean age of 33.4 ± 9.4 years, 13 left and 15 right knees were tested. No significant correlation was noticed for Lachman test and PKTD results (n.s.). Pivot-shift had a strong positive correlation with the difference in anterior translation registered in lateral and medial tibia plateaus of injured knees (cor. coefficient = 0.80; p\0.05), and with the difference in this parameter as compared to side-to-side (cor. coefficient = 0.83; p\0.05). Considering the KT-1000 difference between injured and healthy knees, a very strong positive correlation was found for side-to-side difference in medial (cor. coeffi- cient = 0.73; p\0.05) and lateral (cor. coefficient = 0.5; p\0.05) tibial plateau displacement using PKTD. Conclusion The PKTD proved to be a reliable tool in assessment of antero-posterior translation (comparing with KT-1000) and rotatory laxity (compared with lateral pivotshift under anesthesia) of the ACL-deficient knee during MRI examinatio

Role of cAMP in the promotion of colorectal cancer cell growth by Prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) reaction, stimulates the growth of colonic epithelial cells. It is inferred that the abrogation of prostaglandins' growth-promoting effects as a result of COX inhibition underlies the advantageous effects of non-steroidal anti-inflammatory drugs in colorectal carcinoma (CRC). Despite this appreciation, the underlying molecular mechanisms remain obscure since cell culture studies have yielded discrepant results regarding PGE2's mitogenicity.</p> <p>Methods</p> <p>We have employed several alternative approaches to score cell proliferation and apoptosis of 4 CRC cell lines exposed to PGE2 under various conditions. To investigate the role of cAMP in PGE2's functions, activation of the cAMP pathway was assessed at different levels (changes in cAMP levels and PKA activity) in cells subjected to specific manipulations including the use of specific inhibitors or prostanoid receptor-selective agonists/antagonists.</p> <p>Results</p> <p>Our data document that the dose-response curve to PGE2 is 'bell-shaped', with nano molar concentrations of PGE2 being more mitogenic than micro molar doses. Remarkably, mitogenicity inversely correlates with the ability of PGE2 doses to raise cAMP levels. Consistent with a major role for cAMP, cAMP raising agents and pertussis toxin revert the mitogenic response to PGE2. Accordingly, use of prostanoid receptor-selective agonists argues for the involvement of the EP3 receptor and serum deprivation of HT29 CRC cells specifically raises the levels of Gi-coupled EP3 splice variants.</p> <p>Conclusion</p> <p>The present data indicate that the mitogenic action of low PGE2 doses in CRC cells is mediated via Gi-proteins, most likely through the EP3 receptor subtype, and is superimposed by a second, cAMP-dependent anti-proliferative effect at higher PGE2 doses. We discuss how these findings contribute to rationalize conflictive literature data on the proliferative action of PGE2.</p