Role of cellular ion channels in the BK polyomavirus life cycle

BK polyomavirus (BKPyV) is a human pathogen that infects the majority of the population, worldwide, establishing a lifelong infection. Immunocompromised patients following renal transplantation, are likely to suffer from severe clinical complications, including polyomavirus-associated nephropathy (PVAN), which can ultimately lead to kidney graft failure. Currently, there are no direct acting anti-viral compounds targeting BKPyV and the number of renal transplants is increasing significantly. Therefore, there is an urgent need to understand the viral life cycle in order to identify potential targets that can be exploited for therapeutic development. Ion channels play a critical role in kidney physiology by controlling several processes, implicating them as candidate proteins required for BKPyV infection. A pharmacological analysis was performed in which human primary renal epithelial cells were treated with a range of pharmacological modulators of host ion channels and the effect on BKPyV production assayed using a fluorescence-based technique. From this approach, it was identified that the clinically available drug, Glibenclamide is a potent inhibitor of BKPyV infection. Biochemical analysis and molecular-based techniques revealed that the cystic fibrosis transmembrane conductance regulator (CFTR) was the target of Glibenclamide and time-of-addition experiments indicated that CFTR might be required during the entry and trafficking of BKPyV through the cytoplasm. These studies provide the first reported requirement for host ion channels in the BKPyV life cycle. Studies on other related polyomaviruses, including JCPyV, SV40 and Merkel cell polyomavirus determined a cell type-dependent requirement of CFTR in the viruses’ life cycle, highlighting the importance of understanding the role of host ion channels in polyomaviruses’ life cycle. Ion channels are an emerging target for many medical conditions and such compounds that target these may represent a novel strategy for developing therapeutics to treat PVAN and/or other polyomavirus-associated clinical complications

Intelligent personalized ADAS warnings

Purpose Advanced Driver Assistance Systems (ADAS) have been among the key innovations in the automotive market for over a decade, since they promote traffic safety. This tendency is strengthened even more lately, with the introduction of the autonomous vehicles. A plethora of ADAS exist in the market today, using common warning thresholds for all drivers. However, since we are not all driving the same way, by offering common systems for all the drivers, neither the acceptance nor the effectiveness levels of ADAS are optimal. This manuscript attempts to optimize the Collision Avoidance System (CAS) warning, through intelligent personalized algorithms. Methods Starting with the identification of the dynamic parameters for driving behaviour modeling on the longitudinal road axis, the personalization parameters for ADAS are derived that form the basis for the algorithms developed. Also, based on literature studies, the safety boundaries for warning provision by the CAS are set and implemented in the algorithms. Results Specific personalized algorithms for the longitudinal road axis behaviour are developed, based on Time to Collision and Time Headway. The proposed algorithms based on Time Headway were assessed on-road with 10 drivers and were positively evaluated by the majority of the participants, with a varying degree of reliability and usability. Conclusions Based on the results obtained, it can be concluded that with the proposed algorithms, the initial hypothesis of the paper is verified, i.e. personalised warnings would get a greater acceptance by the drivers, of course without braking the safety limits. Further improvements of the algorithm could be achieved, possibly through a better determination of the car following event, since its definition includes a few assumptions. Document type: Articl

Seamless-based Infomobility Applications to Support the Needs of All Travellers

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Feasibility of a wireless health monitoring system for prevention and health assessment of elderly people

The work presented in this paper comprises the methodology and results of a pilot study on the feasibility of a wireless health monitoring system designed under main EU challenges for the promotion of healthy and active ageing. The system is focused on health assessment, prevention and lifestyle promotion of elderly people. Over a hundred participants including elderly users and caregivers tested the system in four pilot sites across Europe. Tests covered several scenarios in senior centers and real home environments, including performance and usability assessment. Results indicated strong satisfactoriness on usability, usefulness and user friendliness, and the acceptable level of reliability obtained supports future investigation on the same direction for further improvement and transfer of conclusions to the real world in the healthcare delivery

A critical analysis of the potential for EU Common Agricultural Policy measures to support wild pollinators on farmland

1. Agricultural intensification and associated loss of high‐quality habitats are key drivers of insect pollinator declines. With the aim of decreasing the environmental impact of agriculture, the 2014 EU Common Agricultural Policy (CAP) defined a set of habitat and landscape features (Ecological Focus Areas: EFAs) farmers could select from as a requirement to receive basic farm payments. To inform the post‐2020 CAP, we performed a European‐scale evaluation to determine how different EFA options vary in their potential to support insect pollinators under standard and pollinator‐friendly management, as well as the extent of farmer uptake. 2. A structured Delphi elicitation process engaged 22 experts from 18 European countries to evaluate EFAs options. By considering life cycle requirements of key pollinating taxa (i.e. bumble bees, solitary bees and hoverflies), each option was evaluated for its potential to provide forage, bee nesting sites and hoverfly larval resources. 3. EFA options varied substantially in the resources they were perceived to provide and their effectiveness varied geographically and temporally. For example, field margins provide relatively good forage throughout the season in Southern and Eastern Europe but lacked early‐season forage in Northern and Western Europe. Under standard management, no single EFA option achieved high scores across resource categories and a scarcity of late season forage was perceived. 4. Experts identified substantial opportunities to improve habitat quality by adopting pollinator‐friendly management. Improving management alone was, however, unlikely to ensure that all pollinator resource requirements were met. Our analyses suggest that a combination of poor management, differences in the inherent pollinator habitat quality and uptake bias towards catch crops and nitrogen‐fixing crops severely limit the potential of EFAs to support pollinators in European agricultural landscapes. 5. Policy Implications. To conserve pollinators and help protect pollination services, our expert elicitation highlights the need to create a variety of interconnected, well‐managed habitats that complement each other in the resources they offer. To achieve this the Common Agricultural Policy post‐2020 should take a holistic view to implementation that integrates the different delivery vehicles aimed at protecting biodiversity (e.g. enhanced conditionality, eco‐schemes and agri‐environment and climate measures). To improve habitat quality we recommend an effective monitoring framework with target‐orientated indicators and to facilitate the spatial targeting of options collaboration between land managers should be incentivised

Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection.

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF) attachment protein (α-SNAP) is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell

BAP1 loss by immunohistochemistry predicts improved survival to first-line platinum and pemetrexed chemotherapy for patients with pleural mesothelioma: A validation study

Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy. Methods: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234). Results: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p \u3c 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p \u3c 0.001) and Australian cohorts (19.6 versus 11.1 mo, p \u3c 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p \u3c 0.01). Conclusions: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification