Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells.

Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na(+)/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications

Characteristics of a functional programming language

Journal ArticleA programming language kernel is presented where an algorithm is a function defined through a functional expression. The only data structure introduced is an object that may be an atom or a sequence of objects. A number of functional forms are defined, with a notation close to ordinary mathematical notation, and their usage is demonstrated through several examples. The language allows a high degree of parallelism in an underlying interpreting machine

Multilingualism and verbal short-term/working memory: Evidence from academics.

To date, the evidence regarding the effect of bilingualism/multilingualism on short-term memory (STM) and working memory (WM) capacity is inconclusive. This study investigates whether multilingualism has a positive effect on the verbal STM and WM capacity of neuro typical middle-aged and older individuals. Eighty-two L1-Norwegian sequential bilingual/ multilingual academics were tested with tasks measuring verbal STM/WM capacity. Degree of bilingualism/multilingualism for each participant was estimated based on a comprehensive questionnaire. Different measures of bilingualism/multilingualism were used. Data on potentially influencing non-linguistic factors were also collected. Correlation and regression analyses showed that multilingualism impacts both verbal STM and verbal WM. All analyses showed that number of known foreign languages was the strongest predictor of verbal STM and WM capacity. The results are discussed considering recent studies on the impact of bilingualism on STM/WM and on recent proposals regarding the mechanism underlying so-called bilingual advantage.publishedVersio

Peekaboo: A Hub-Based Approach to Enable Transparency in Data Processing within Smart Homes (Extended Technical Report)

We present Peekaboo, a new privacy-sensitive architecture for smart homes that leverages an in-home hub to pre-process and minimize outgoing data in a structured and enforceable manner before sending it to external cloud servers. Peekaboo's key innovations are (1) abstracting common data pre-processing functionality into a small and fixed set of chainable operators, and (2) requiring that developers explicitly declare desired data collection behaviors (e.g., data granularity, destinations, conditions) in an application manifest, which also specifies how the operators are chained together. Given a manifest, Peekaboo assembles and executes a pre-processing pipeline using operators pre-loaded on the hub. In doing so, developers can collect smart home data on a need-to-know basis; third-party auditors can verify data collection behaviors; and the hub itself can offer a number of centralized privacy features to users across apps and devices, without additional effort from app developers. We present the design and implementation of Peekaboo, along with an evaluation of its coverage of smart home scenarios, system performance, data minimization, and example built-in privacy features.Comment: 18 page

P171Elevated free fetal haemoglobin threatens vasculoprotection in the fetal circulation of preeclamptic pregnancy

Placental up-regulation of free fetal haemoglobin (fHbF) occurs in preeclamptic (PE) pregnancy. Heme oxygenase-1 (HO-1) is an important vasculoprotective enzyme in the catabolism of the associated heme porphyrin structure. We have previously shown that fHbF negatively influences the vasculoprotective capacity of the fetal circulation. Here we study fHbF levels in the fetal cord blood of pregnancies complicated by PE; a pathology associated with dysregulated fetoplacental vascular tone. We have previously shown that fHbF binds nitric oxide (NO) to elicit elevated vascular resistance in the fetoplacental circulation, using ex vivo human dual placental perfusion and in vitro placental endothelial cell shear stress studies. Furthermore, fHbF causes morphological changes to the fetoplacental endothelium. Here we hypothesise that elevated levels of fHbF in fetal plasma associated with placental pathology contribute to fetoplacental hypertension. Purpose: To evaluate and derive a robust cord blood collection and processing protocol for the accurate measurement of fetal plasma fHbF levels in normal and PE pregnancies. Methods: Fetal venous cord blood was collected by syringe and needle, or Vacutainer method into either EDTA or citrate tubes, within 10 minutes of partum. Plasma recovery occurred immediately, or after 30 minutes, prior to centrifugation at 2000g x 10 min at room temperature. Following evaluation to reduce mechanical haemolysis, newly collected normal & PE plasma (n=13 & 6, respectively) was subjected to ELISAs for HbF and HO-1. Results: Venipuncture collection of cord venous blood taken from the cord-placenta insertion point by Vacutainer system with a 21G needle, into citrate collection tubes with immediate centrifugation prevented mechanical haemolysis. There was no difference in plasma HO-1 between groups (medians = 5.9 & 5.3 ng/mL; normal & PE, respectively; Mann-Whitney). Whilst there was no difference in fHbF between groups (Mann-Whitney), variability was high in the PE group and there were some very high values for fHbF compared to the normal range, whilst fHbF values in the control group were within a tighter lower range (medians & ranges = 45.9 & 0-206 and 118.8 & 29-640 μg/mL). Conclusion: Fetal plasma HO-1 levels appear stable in preeclamptic fetal plasma, permitting fHbF to remain unchecked in some cases. High pathophysiological levels of fHbF in some cases of PE pregnancies are capable of evoking elevated vascular resistance within the fetoplacental circulation, caused by nitric oxide sequestration and disruption to the endothelium. Further evaluation is require

Phaeobacter gallaeciensis Reduces Vibrio anguillarum in Cultures of Microalgae and Rotifers, and Prevents Vibriosis in Cod Larvae

Phaeobacter gallaeciensis can antagonize fish-pathogenic bacteria in vitro, and the purpose of this study was to evaluate the organism as a probiont for marine fish larvae and their feed cultures. An in vivo mechanism of action of the antagonistic probiotic bacterium is suggested using a non-antagonistic mutant. P. gallaeciensis was readily established in axenic cultures of the two microalgae Tetraselmis suecica and Nannochloropsis oculata, and of the rotifer Brachionus plicatilis. P. gallaeciensis reached densities of 107 cfu/ml and did not adversely affect growth of algae or rotifers. Vibrio anguillarum was significantly reduced by wild-type P. gallaeciensis, when introduced into these cultures. A P. gallaeciensis mutant that did not produce the antibacterial compound tropodithietic acid (TDA) did not reduce V. anguillarum numbers, suggesting that production of the antibacterial compound is important for the antagonistic properties of P. gallaeciensis. The ability of P. gallaeciensis to protect fish larvae from vibriosis was determined in a bath challenge experiment using a multidish system with 1 larva per well. Unchallenged larvae reached 40% accumulated mortality which increased to 100% when infected with V. anguillarum. P. gallaeciensis reduced the mortality of challenged cod larvae (Gadus morhua) to 10%, significantly below the levels of both the challenged and the unchallenged larvae. The TDA mutant reduced mortality of the cod larvae in some of the replicates, although to a much lesser extent than the wild type. It is concluded that P. gallaeciensis is a promising probiont in marine larviculture and that TDA production likely contributes to its probiotic effect

The cortical responses to evoked clinical pain in patients with hip osteoarthritis

Experimental models have been used extensively to evaluate pain using e.g., visual analogue scales or electroencephalography (EEG). Stimulation using tonic pain has been shown to better mimic the unpleasantness of chronic pain, but has mainly been evoked by non-clinical stimuli. This study aims to, evaluate the EEG during clinical pain in patients scheduled for total hip replacement with control and resting conditions.The hip scheduled for replacement was moved by the examiner to evoke pain for 30 seconds while recording EEG. The control condition entailed movement of the opposite hip in a similar fashion and holding it for 30 seconds. In addition, EEG was recorded during the resting condition with open eyes. The relative spectral content was calculated from the EEG as well as functional connectivity using phase-lag index for frequency bands delta (1-4Hz), theta (4-8Hz), alpha (8-12Hz) and beta (12-32Hz). A mixed model was used for statistical comparison between the three recording conditions.Spectral content differed between conditions in all bands. Functional connectivity differed in delta and theta frequency bands. Post-hoc analysis revealed differences between the painful and control condition in delta, theta and beta for spectral content. Pain during the hip rotation was correlated to the theta (r = -0.24 P = 0.03) and beta (r = 0.25 P = 0.02) content in the EEG.EEG differences during hip movements in the affected and unaffected hip appeared in the spectral beta and theta content. This was correlated to the reported pain perceived, pointing towards pain specific brain activity related to clinical pain

Radiographer gender and breast-screening uptake

BreastCheck, the Irish National Breast Screening Programme, screens women aged 50–64. Radiographer recruitment has been a challenge; doubling of numbers is required for full national expansion; to date females are employed. The aim was to document attitudes to male radiographers and effect on return for subsequent screening. In all 85.8% of a random sample of 2000 women recently screened by BreastCheck completed a postal questionnaire. The commonest reaction women felt they would have if there were a male radiographer was embarrassment; significantly greater among those attending a static unit (45.6%) than mobile (38.4%) and in younger women (46%) than older (38.7%). Nine per cent would not have proceeded if the radiographer was male and 9% would only have proceeded if female chaperone present. In all 17.5% (95% CI 15.7–19.4%) agreed that ‘If there were male radiographers I would not return for another screening appointment'; 18.3% were unsure. One-quarter agreed ‘if I heard there could be male radiographers it would change my opinion of BreastCheck for the worse'. The proportions agreeing with these statements did not vary significantly by screening unit type, age group, area of residence or insurance status. This is the largest published study to date of this important issue; the correct balance between equality and programme performance must be identified

Shifting Home Energy Consumption Through a Holistic Understanding of the Home System of Practice

This chapter describes the concept of the home system of practice, which can be used to provide a deeper understanding of the social system of the home and inform long-term solutions for enabling domestic energy reduction. More traditional methods have attempted to persuade occupants to change behaviour through the use of information campaigns and feedback technology. However, these interventions are usually short lived as they ignore the underlying reasons for practices to occur. A more effective solution is through practice-oriented design, which co-creates innovative technology with the user. In addition, the emergence and use of automated technology enables practices to act independently of the user. Yet, the success of automation is also reliant on an understanding of the home system of practice, occupant needs and skills