Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries

PMCID: PMC3570554This 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

Virtual signatures of dark sectors in Higgs couplings

Where collider searches for resonant invisible particles loose steam, dark sectors might leave their trace as virtual effects in precision observables. Here we explore this option in the framework of Higgs portal models, where a sector of dark fermions interacts with the standard model through a strong renormalizable coupling to the Higgs boson. We show that precise measurements of Higgs-gauge and triple Higgs interactions can probe dark fermions up to the TeV scale through virtual corrections. Observation prospects at the LHC and future lepton colliders are discussed for the so-called singlet-doublet model of Majorana fermions, a generalization of the bino-higgsino scenario in supersymmetry. We advocate a two-fold search strategy for dark sectors through direct and indirect observables.Comment: 20 pages, 7 figures, 1 tabl

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

Rationale: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. Objective: To answer this question, we generated a mouse with endothelial cell (EC)–specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter–enhancer. Methods and Results: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase–dependent generation of superoxide, whereas insulin-stimulated and shear stress–stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress–induced eNOS activation in hIRECO EC. Conclusions: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress–induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.This work was supported by the British Heart Foundation, London, UK, and the Diabetes Research and Wellness Foundation, Portsmouth, UK

A Methodological Reflection: Deconstructing Cultural Elements for Enhancing Cross-cultural Appreciation of Chinese Intangible Cultural Heritage

This paper presents a practical method of deconstructing cultural elements based on the Human Computer Interaction (HCI) perspective to enhance cross-cultural appreciation of Chinese Intangible Cultural Heritage (ICH). The author pioneered this approach during conducting two case studies as a means to enhance appreciation and engagement with Chinese ICH, such as the extraction of elements from traditional Chinese painting and puppetry with potential to support cross-cultural appreciation, as well as the establishment of an elements archive. Through integrating a series of HCI research methods, this approach provides a specific foundational framework that assists non-Chinese people to better understand the cultural significance of Chinese ICH

Long-term, high frequency in situ measurements of intertidal mussel bed temperatures using biomimetic sensors

At a proximal level, the physiological impacts of global climate change on ectothermic organisms are manifest as changes in body temperatures. Especially for plants and animals exposed to direct solar radiation, body temperatures can be substantially different from air temperatures. We deployed biomimetic sensors that approximate the thermal characteristics of intertidal mussels at 71 sites worldwide, from 1998-present. Loggers recorded temperatures at 10-30 min intervals nearly continuously at multiple intertidal elevations. Comparisons against direct measurements of mussel tissue temperature indicated errors of similar to 2.0-2.5 degrees C, during daily fluctuations that often exceeded 15 degrees-20 degrees C. Geographic patterns in thermal stress based on biomimetic logger measurements were generally far more complex than anticipated based only on 'habitat-level' measurements of air or sea surface temperature. This unique data set provides an opportunity to link physiological measurements with spatially-and temporally-explicit field observations of body temperature

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Assessing the congruence of thermal niche estimations derived from distribution and physiological data. A test using diving beetles.

A basic aim of ecology is to understand the determinants of organismal distribution, the niche concept and species distribution models providing key frameworks to approach the problem. As temperature is one of the most important factors affecting species distribution, the estimation of thermal limits is crucially important for inferring range constraints. It is expectable that thermal physiology data derived from laboratory experiments and species' occurrences may express different aspects of the species' niche. However, there is no study systematically testing this prediction in a given taxonomic group while controlling by potential phylogenetic inertia. We estimate the thermal niches of twelve Palaearctic diving beetles species using physiological data derived from experimental analyses in order to examine the extent to which these coincided with those estimated from distribution models based on observed occurrences. We found that thermal niche estimates derived from both approaches lack general congruence, and these results were similar before and after controlling by phylogeny. The congruence between potential distributions obtained from the two different procedures was also explored, and we found again that the percentage of agreement were not very high (~60%). We confirm that both thermal niche estimates derived from geographical and physiological data are likely to misrepresent the true range of climatic variation that these diving beetles are able to tolerate, and so these procedures could be considered as incomplete but complementary estimations of an inaccessible reality