Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy

Selenoprotein expression in endothelial cells from different human vasculature and species

AbstractSelenium (Se) can protect endothelial cells (EC) from oxidative damage by altering the expression of selenoproteins with antioxidant function such as cytoplasmic glutathione peroxidase (cyGPX), phospholipid hydroperoxide glutathione peroxidase (PHGPX) and thioredoxin reductase (TR). If the role of Se on EC function is to be studied, it is essential that a model system be chosen which reflects selenoprotein expression in human EC derived from vessels prone to developing atheroma. We have used [75Se]-selenite labelling and selenoenzyme measurements to compare the selenoproteins expressed by cultures of EC isolated from different human vasculature with EC bovine and porcine aorta. Only small differences were observed in selenoprotein expression and activity in EC originating from human coronary artery, human umbilical vein (HUVEC), human umbilical artery and the human EC line EAhy926. The selenoprotein profile in HUVEC was consistent over eight passages and HUVEC isolated from four cords also showed little variability. In contrast, EC isolated from pig and bovine aorta showed marked differences in selenoprotein expression when compared to human cells. This study firmly establishes the suitability and consistency of using HUVEC (and possibly the human cell line EAhy926) as a model to study the effects of Se on EC function in relation to atheroma development in the coronary artery. Bovine or porcine EC appear to be an inappropriate model

Ski skating race technique-effect of long distance cross-country ski racing on choice of skating technique in moderate uphill terrain

The aim of this study was to investigate the effect of prolonged ski racing using skating style on technique choice in a transition section among female and male high-level skiers. Fifty three national-to-elite level skiers (20 females: 26.7 \ub1 4.8 years, 167.0 \ub1 6.5 m, 61.0 \ub1 5.1 kg, and 75.5 \ub1 68.8 FIS points; 33 males: 25.2 \ub1 3.5 years, 179.0 \ub1 5.2 cm, 73.1 \ub1 5.7 kg, and 73.7 \ub1 63.2 FIS points) were video recorded along a flat-to-uphill transition section of a course during the 30-km (females) and 50-km (males) races at the 2018 Norwegian National Championships. Across laps, section speeds decreased (P < 0.001) in all skiers, with the best-ranked skiers faster than the lowest-ranked (P < 0.001), and males faster than females in the first and middle laps. Section speed within each lap was associated with race performance (r = 0.76-0.86, P < 0.001 in females and r = 0.87-0.89, P < 0.001 in males). The prevalence of Gear 2 (G2) increased, while Gear 3 (G3) use decreased (both P < 0.001) across the subsequent laps, with females preferring G2 more than males in lap one (P = 0.027). In long-distance skate-style skiing, transition performance is representative of race performance and skiers decrease the use of the often-faster G3 technique while increasing the use of the slower G2 technique due to prolonged exercise. Especially female skiers should consider adding some flat-to-uphill G3 practice into established training, specifically early in the session before fatigue may occur

Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota

Background: The soil-transmitted helminth (STH), Trichuris trichiura colonises the human large intestine where it may modify inflammatory responses, an effect possibly mediated through alterations in the intestinal microbiota. We hypothesised that patent T. trichiura infections would be associated with altered faecal microbiota and that anthelmintic treatment would induce a microbiota resembling more closely that observed in uninfected individuals. Materials and Methods: School children in Ecuador were screened for STH infections and allocated to 3 groups: uninfected, T. trichiura only, and mixed infections with T. trichiura and Ascaris lumbricoides. A sample of uninfected children and those with T. trichiura infections only were given anthelmintic treatment. Bacterial community profiles in faecal samples were studied by 454 pyrosequencing of 16 S rRNA genes. Results: Microbiota analyses of faeces were done for 97 children: 30 were uninfected, 17 were infected with T. trichiura, and 50 with T. trichiura and A. lumbricoides. Post-treatment samples were analyzed for 14 children initially infected with T. trichiura alone and for 21 uninfected children. Treatment resulted in 100% cure of STH infections. Comparisons of the microbiota at different taxonomic levels showed no statistically significant differences in composition between uninfected children and those with T. trichiura infections. We observed a decreased proportional abundance of a few bacterial genera from the Clostridia class of Firmicutes and a reduced bacterial diversity among children with mixed infections compared to the other two groups, indicating a possible specific effect of A. lumbricoides infection. Anthelmintic treatment of children with T. trichiura did not alter faecal microbiota composition. Discussion: Our data indicate that patent human infections with T. trichiura may have no effect on faecal microbiota but that A. lumbricoides colonisation might be associated with a disturbed microbiota. Our results also catalogue the microbiota of rural Ecuadorians and indicate differences with individuals from more urban industrialised societies

Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis

It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2

Food from the Oceans - How can more food and biomass be obtained from the oceans in a way that does not deprive future generations of their benefits?

Food from the Oceans is the first Evidence Review Report published by the SAPEA consortium. SAPEA is an integral part of the European Scientific Advice Mechanism (SAM) and this report demonstrates the outstanding commitment and knowledge of experts who were nominated by academies and learned societies. Interdisciplinarity and world-class expertise from across Europe are SAPEA’s core strengths. We assembled two international working groups for Food from the Oceans, covering both the natural sciences and the humanities/social sciences. We were delighted with SAPEA’s collaboration with the High-Level Group of Scientific Advisers (HLG), which has proved so effective in Food from the Oceans. Our Evidence Review Report informs the Scientific Opinion of the HLG. They are published together, and the aim is for them to be used by the European Commission in planning and policymaking across a range of areas. Academia Europaea performed the role of Lead Academy for the Food from the Oceans Evidence Review Report. It acted as project manager, ensuring that deadlines were met, and outputs were of the highest quality standard. By working well with academies and experts we have met all milestones leading up to and including the final deliverable, the Evidence Review Report itself. We also took a novel approach to public engagement, with encouraging results. In Food from the Oceans, we believe we have established an attractive model for future SAPEA projects. We would like to thank everyone involved in making Food from the Oceans a success and express our sincere gratitude to those who have worked hard throughout 2017

Evolution of the geomagnetic daily variation at Tatuoca, Brazil, from 1957 to 2019: a transition from Sq to EEJ

The magnetic equator in the Brazilian region has moved over 1,100 km northward since 1957, passing the geomagnetic observatory Tatuoca (TTB), in northern Brazil, around 2013. We recovered and processed TTB hourly mean values of the geomagnetic field horizontal (H) component from 1957 until 2019, allowing the investigation of long‐term changes in the daily variation due to the influence of secular variation, solar activity, season, and lunar phase. The H day‐to‐day variability and the occurrence of the counter electrojet at TTB were also investigated. Until the 1990s, ionospheric solar quiet currents dominated the quiet‐time daily variation at TTB. After 2000, the magnitude of the daily variation became appreciably greater due to the equatorial electrojet (EEJ) contribution. The H seasonal and day‐to‐day variability increased as the magnetic equator approached, but their amplitudes normalized to the average daily variation remained at similar levels. Meanwhile, the amplitude of the lunar variation, normalized in the same way, increased from 5% to 12%. Within the EEJ region, the occurrence rate of the morning counter electrojet (MCEJ) increased with proximity to the magnetic equator, while the afternoon counter electrojet (ACEJ) did not. EEJ currents derived from CHAMP and Swarm satellite data revealed that the MCEJ rate varies with magnetic latitude within the EEJ region while the ACEJ rate is largely constant. Simulations with the Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model based on different geomagnetic main field configurations suggest that long‐term changes in the geomagnetic daily variation at TTB can be attributed to the main field secular variation

Global response to pandemic flu: more research needed on a critical front

If and when sustained human-to-human transmission of H5N1 becomes a reality, the world will no longer be dealing with sporadic avian flu borne along migratory flight paths of birds, but aviation flu – winged at subsonic speed along commercial air conduits to every corner of planet Earth. Given that air transportation is the one feature that most differentiates present day transmission scenarios from those in 1918, our present inability to prevent spread of influenza by international air travel, as reckoned by the World Health Organization, constitutes a major weakness in the current global preparedness plan against pandemic flu. Despite the lessons of SARS, it is surprising that aviation-related health policy options have not been more rigorously evaluated, or scientific research aimed at strengthening public health measures on the air transportation front, more energetically pursued