An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. The RNAi screening was utilized to identify genes that modify the intracellular accumulation of ATZ and a novel computational pipeline was developed to make high confidence predictions on repurposable drugs. This approach identified glibenclamide (GLB), a sulfonylurea drug that has been used broadly in clinical medicine as an oral hypoglycemic agent. Here we show that GLB promotes autophagic degradation of misfolded ATZ in mammalian cell line models of ATD. Furthermore, an analog of GLB reduces hepatic ATZ accumulation and hepatic fibrosis in a mouse model in vivo without affecting blood glucose or insulin levels. These results provide support for a drug discovery strategy using simple organisms as human disease models combined with genetic and computational screening methods. They also show that GLB and/or at least one of its analogs can be immediately tested to arrest the progression of human ATD liver disease.</div

The effect of incentives in web surveys: Application and ethical considerations

Although researchers use internet-based surveys more often than ever in their research, there is little research on the effect of incentives on response rate, speed and cost. This study attempts to fill in some of the blanks by comparing the different incentives offered to respondents of web-based surveys. The results indicate that offering a luggage tag to each respondent and including them in a draw for a bigger value prize (a personal digital assistant) yields the highest response rate. In terms of response speed, there are no significant differences among each incentive group. The most expensive group in terms of costs was the combination of luggage tag and prize draw

Local government’s role in promoting city hospitality: a meta-ethnography with a public management perspective

Purpose – Adopting a public-management perspective, this study aims to conduct a meta-ethnography to discern local government’s role in city hospitality in terms of promoting the welcome the city gives its guests, filling a gap in research into the subject. Design/methodology/approach – The authors used the seven-step iterative approach of Noblit and Hare’s meta-ethnography. By conducting a systematic search in the major bibliographic databases, ten qualitative studies on city hospitality were identified that met the criteria to be included. Concepts alluding to a local government’s role in city hospitality were coded in NVivo 11 software, translated and interpreted through the lens of public management. A total of 14 semi-structured interviews with experts were also conducted to further validate the meta-ethnography findings. Findings – Six interrelated, third-order constructs were developed and conceptualized into an articulated model describing local government’s role in city hospitality from a public-management perspective: advocating, co-creating, strategizing, planning and implementing city hospitality, and promoting it into a sustainable tourism development. The model, also substantiated by expert feedback, describes local government actions to promote city hospitality and achieve sustainable tourism. It highlights a responsive, proactive and collaborative role for local government as a key actor responsible for the strategic management and co-creation of city hospitality. Research limitations/implications – The study introduces public governance cues into a city hospitality context, with theoretical and practical implications for hospitality and tourism researchers, businesses, politicians, public managers, city officials and destination marketing/management practitioners. Originality/value – The study proposes an original conceptual model that serves as an overarching framework and operative tool for understanding and practicing city hospitality in a contemporary public-management perspective. This lays the foundations for the development of a broadened notion of hospitality management, extended from the traditional context of the hospitality industry to that of the city or place. The study also showcases how meta-ethnography can be an effective methodology in business, management and accounting research, within which it is still a novelty

Deep Learning Development Environment in Virtual Reality

Virtual reality (VR) offers immersive visualization and intuitive interaction. We leverage VR to enable any biomedical professional to deploy a deep learning (DL) model for image classification. While DL models can be powerful tools for data analysis, they are also challenging to understand and develop. To make deep learning more accessible and intuitive, we have built a virtual reality-based DL development environment. Within our environment, the user can move tangible objects to construct a neural network only using their hands. Our software automatically translates these configurations into a trainable model and then reports its resulting accuracy on a test dataset in real-time. Furthermore, we have enriched the virtual objects with visualizations of the model's components such that users can achieve insight about the DL models that they are developing. With this approach, we bridge the gap between professionals in different fields of expertise while offering a novel perspective for model analysis and data interaction. We further suggest that techniques of development and visualization in deep learning can benefit by integrating virtual reality

The GBT Project

The GigaBit Transceiver (GBT) architecture and transmission protocol has been proposed for data transmission in the physics experiments of the future upgrade of the LHC accelerator, the SLHC. Due to the high beam luminosity planned for the SLHC, the experiments will require high data rate links and electronic components capable of sustaining high radiation doses. The GBT ASICs address this issue implementing a radiation-hard bi-directional 4.8 Gb/s optical fibre link between the counting room and the experiments. The paper describes in detail the GBT-SERDES architecture and presents an overview of the various components that constitute the GBT chipset

The impact of technology in hotels: A case study of Istanbul and Ankara hotels

[No abstract available

Perspectives on care and communication involving incurably ill Turkish and Moroccan patients, relatives and professionals: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>Our aim was to obtain a clearer picture of the relevant care experiences and care perceptions of incurably ill Turkish and Moroccan patients, their relatives and professional care providers, as well as of communication and decision-making patterns at the end of life. The ultimate objective is to improve palliative care for Turkish and Moroccan immigrants in the Netherlands, by taking account of socio-cultural factors in the guidelines for palliative care.</p> <p>Methods</p> <p>A systematic literature review was undertaken. The data sources were seventeen national and international literature databases, four Dutch journals dedicated to palliative care and 37 websites of relevant national and international organizations. All the references found were checked to see whether they met the structured inclusion criteria. Inclusion was limited to publications dealing with primary empirical research on the relationship between socio-cultural factors and the health or care situation of Turkish or Moroccan patients with an oncological or incurable disease. The selection was made by first reading the titles and abstracts and subsequently the full texts. The process of deciding which studies to include was carried out by two reviewers independently. A generic appraisal instrument was applied to assess the methodological quality.</p> <p>Results</p> <p>Fifty-seven studies were found that reported findings for the countries of origin (mainly Turkey) and the immigrant host countries (mainly the Netherlands). The central themes were experiences and perceptions of family care, professional care, end-of-life care and communication. Family care is considered a duty, even when such care becomes a severe burden for the main female family caregiver in particular. Professional hospital care is preferred by many of the patients and relatives because they are looking for a cure and security. End-of-life care is strongly influenced by the continuing hope for recovery. Relatives are often quite influential in end-of-life decisions, such as the decision to withdraw or withhold treatments. The diagnosis, prognosis and end-of-life decisions are seldom discussed with the patient, and communication about pain and mental problems is often limited. Language barriers and the dominance of the family may exacerbate communication problems.</p> <p>Conclusions</p> <p>This review confirms the view that family members of patients with a Turkish or Moroccan background have a central role in care, communication and decision making at the end of life. This, in combination with their continuing hope for the patient’s recovery may inhibit open communication between patients, relatives and professionals as partners in palliative care. This implies that organizations and professionals involved in palliative care should take patients’ socio-cultural characteristics into account and incorporate cultural sensitivity into care standards and care practices<it>.</it></p

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe