In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Relating near-Earth observations of an interplanetary coronal mass ejection to the conditions at its site of origin in the solar corona

A halo coronal mass ejection (CME) was detected on January 20, 2004. We use solar remote sensing data (SOHO, Culgoora) and near-Earth in situ data (Cluster) to identify the CME source event and show that it was a long duration flare in which a magnetic flux rope was ejected, carrying overlying coronal arcade material along with it. We demonstrate that signatures of both the arcade material and the flux rope material are clearly identifiable in the Cluster and ACE data, indicating that the magnetic field orientations changed little as the material traveled to the Earth, and that the methods we used to infer coronal magnetic field configurations are effective

Coronal jets, magnetic topologies, and the production of interplanetary electron streams

We investigate the acceleration source of the impulsive solar energetic particle (SEP) events on 2007 January 24. Combining the in situ electron measurements and remote-sensing solar observations, as well as the calculated magnetic fields obtained from a potential-field source-surface model, we demonstrate that the jets associated with the hard X-ray flares and type-III radio bursts, rather than the slow and partial coronal mass ejections, are closely related to the production of interplanetary electron streams. The jets, originated from the well-connected active region (AR 10939) whose magnetic polarity structure favors the eruption, are observed to be forming in a coronal site, extending to a few solar radii, and having a good temporal correlation with the electron solar release. The open-field lines near the jet site are rooted in a negative polarity, along which energetic particles escape from the flaring AR to the near-Earth space, consistent with the in situ electron pitch angle distribution. The analysis enables us to propose a coronal magnetic topology relating the impulsive SEP events to their solar source

Garden varieties: how attractive are recommended garden plants to butterflies?

One way the public can engage in insect conservation is through wildlife gardening, including the growing of insect-friendly flowers as sources of nectar. However, plant varieties differ in the types of insects they attract. To determine which garden plants attracted which butterflies, we counted butterflies nectaring on 11 varieties of summer-flowering garden plants in a rural garden in East Sussex, UK. These plants were all from a list of 100 varieties considered attractive to British butterflies, and included the five varieties specifically listed by the UK charity Butterfly Conservation as best for summer nectar. A total of 2659 flower visits from 14 butterfly and one moth species were observed. We performed a principal components analysis which showed contrasting patterns between the species attracted to Origanum vulgare and Buddleia davidii. The “butterfly bush” Buddleia attracted many nymphalines, such as the peacock, Inachis io, but very few satyrines such as the gatekeeper, Pyronia tithonus, which mostly visited Origanum. Eupatorium cannibinum had the highest Simpson’s Diversity score of 0.75, while Buddleia and Origanum were lower, scoring 0.66 and 0.50 respectively. No one plant was good at attracting all observed butterfly species, as each attracted only a subset of the butterfly community. We conclude that to create a butterfly-friendly garden, a variety of plant species are required as nectar sources for butterflies. Furthermore, garden plant recommendations can probably benefit from being more precise as to the species of butterfly they attract

Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in Leydig cells

Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared with littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed after human chorionic gonadotropin stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase to 17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17-hydroxyprogesterone accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse steroid 17-hydroxylase/17,20-lyase is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings

Superstructure Aerodynamics of the Type 26 Global Combat Ship

The Type 26 City class Global Combat Ship is the latest design of UK frigate. Construction of the first ship, HMS Glasgow, began in July 2017 and the expectation is that it will enter service in the mid-2020s as a replacement for the Royal Navy’s Type 23 Duke class frigates. The main contractor for the design and construction of the ship is BAE Systems Maritime – Naval Ships. The Type 26 superstructure is characterised by its smooth sloping surfaces that are continuous along the ship from the fore deck to the flight deck. The tumblehome design reduces the ship’s radar cross-section, as does the minimisation of curved surfaces and internal corners. The Type 26 also has a bulky mast, also with flat sloping sides, while the funnel casing around the gas turbine exhaust uptake is located aft of the main mast and relatively low on the superstructure. In comparison, the earlier Type 23 has a much more fragmented superstructure with few geometric features for reduced radar reflection; it also has a more slender mast from which the anemometers are mounted, and the exhaust uptakes are higher. Overall the aerodynamics of the stealthy Type 26 frigate will be very different to the previous Type 23, and this will affect the operational envelope of the ship’s helicopters. Recognising the importance of superstructure aerodynamics to the ship design, the University of Liverpool has been working closely with colleagues from BAE to ensure that the air flow over the ship was considered as the superstructure design evolved. The paper will describe how, within the design cycle, Computational Fluid Dynamics (CFD) has been used to analyse the unsteady flow over the full-scale ship. It will show how CFD, together with helicopter flight dynamics modelling, was used to inform design options for the superstructure geometry ahead of the landing deck. CFD was also used to inform options for locating the ship’s anemometers and has been used to predict the dispersion of the ship’s engine exhaust gases and the air temperature distribution in the vicinity of the flight deck. </jats:p

Retinal Vascular Tortuosity and Diameter Associations with Adiposity and Components of Body Composition.

OBJECTIVE: The aim of this study was to assess whether adiposity or body composition relates to microvascular characteristics of the retina, indicative of cardiometabolic function. METHODS: A fully automated QUARTZ software processed retinal images from 68,550 UK Biobank participants (aged 40-69 years). Differences in retinal vessel diameter and tortuosity with body composition measures from the Tanita analyzer were obtained by using multilevel regression analyses adjusted for age, sex, ethnicity, clinic, smoking, and Townsend deprivation index. RESULTS: Venular tortuosity and diameter increased by approximately 2% (P < 10-300 ) and 0.6 μm (P < 10-6 ), respectively, per SD increase in BMI, waist circumference index, waist-hip ratio, total body fat mass index, and fat-free mass index (FFMI). Venular associations with adiposity persisted after adjustment for FFMI, whereas associations with FFMI were weakened by FMI adjustment. Arteriolar diameter (not tortuosity) narrowing with FFMI was independent of adiposity (-0.6 μm; -0.7 to -0.4 μm per SD increment of FFMI), while adiposity associations with arteriolar diameter were largely nonsignificant after adjustment for FFMI. CONCLUSIONS: This demonstrates, on an unprecedented scale, that venular tortuosity and diameter are more strongly associated with adiposity, whereas arteriolar diameter relates more strongly to fat-free mass. Different attributes of the retinal microvasculature may reflect distinct roles of body composition and fatness on the cardiometabolic system

Fruit, vegetable and vitamin C intakes and plasma vitamin C: cross-sectional associations with insulin resistance and glycaemia in 9-10 year-old children.

AIM: To examine whether low circulating vitamin C concentrations and low fruit and vegetable intakes were associated with insulin resistance and other Type 2 diabetes risk markers in childhood. METHODS: We conducted a cross-sectional, school-based study in 2025 UK children aged 9-10 years, predominantly of white European, South-Asian and black African origin. A 24-h dietary recall was used to assess fruit, vegetable and vitamin C intakes. Height, weight and fat mass were measured and a fasting blood sample collected to measure plasma vitamin C concentrations and Type 2 diabetes risk markers. RESULTS: In analyses adjusting for confounding variables (including socio-economic status), a one interquartile range higher plasma vitamin C concentration (30.9 μmol/l) was associated with a 9.6% (95% CI 6.5, 12.6%) lower homeostatic model assessment of insulin resistance value, 0.8% (95% CI 0.4, 1.2%) lower fasting glucose, 4.5% (95% CI 3.2, 5.9%) lower urate and 2.2% (95% CI 0.9, 3.4%) higher HDL cholesterol. HbA1c concentration was 0.6% (95% CI 0.2, 1.0%) higher. Dietary fruit, vegetable and total vitamin C intakes were not associated with any Type 2 diabetes risk markers. Lower plasma vitamin C concentrations in South-Asian and black African-Caribbean children could partly explain their higher insulin resistance. CONCLUSIONS: Lower plasma vitamin C concentrations are associated with insulin resistance and could partly explain ethnic differences in insulin resistance. Experimental studies are needed to establish whether increasing plasma vitamin C can help prevent Type 2 diabetes at an early stage

Associations of Retinal Microvascular Diameters and Tortuosity With Blood Pressure and Arterial Stiffness: United Kingdom Biobank.

To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment. A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index. Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (-0.9 µm; -0.94, -0.87 µm per 10 mmHg), mean arterial pressure (-1.5 µm; -1.5, -1.5 µm per 10 mmHg), PP (-0.7 µm; -0.8, -0.7 µm per 10 mmHg), and arterial stiffness index (-0.12 µm; -0.14, -0.09 µm per ms/m2). Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index. These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease