A single residue substitution in the receptor-binding domain of H5N1 hemagglutinin is critical for packaging into pseudotyped lentiviral particles

© 2012 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Serological studies for influenza infection and vaccine response often involve microneutralization and hemagglutination inhibition assays to evaluate neutralizing antibodies against human and avian influenza viruses, including H5N1. We have previously characterized lentiviral particles pseudotyped with H5-HA (H5pp) and validated an H5pp-based assay as a safe alternative for high-throughput serological studies in BSL-2 facilities. Here we show that H5-HAs from different clades do not always give rise to efficient production of H5pp and the underlying mechanisms are addressed. Methodology/Findings: We have carried out mutational analysis to delineate the molecular determinants responsible for efficient packaging of HA from A/Cambodia/40808/2005 (H5Cam) and A/Anhui/1/2005 (H5Anh) into H5pp. Our results demonstrate that a single A134V mutation in the 130-loop of the receptor binding domain is sufficient to render H5Anh the ability to generate H5Anh-pp efficiently, whereas the reverse V134A mutation greatly hampers production of H5Cam-pp. Although protein expression in total cell lysates is similar for H5Anh and H5Cam, cell surface expression of H5Cam is detected at a significantly higher level than that of H5Anh. We further demonstrate by several independent lines of evidence that the behaviour of H5Anh can be explained by a stronger binding to sialic acid receptors implicating residue 134. Conclusions: We have identified a single A134V mutation as the molecular determinant in H5-HA for efficient incorporation into H5pp envelope and delineated the underlying mechanism. The reduced binding to sialic acid receptors as a result of the A134V mutation not only exerts a critical influence in pseudotyping efficiency of H5-HA, but has also an impact at the whole virus level. Because A134V substitution has been reported as a naturally occurring mutation in human host, our results may have implications for the understanding of human host adaptation of avian influenza H5N1 virusesThis work was supported by grants from the Research Fund for the Control of Infectious Diseases of Hong Kong (RFCID#08070972), the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China), the French Ministry of Health, and the RESPARI project of the Institut Pasteur International Network

Dao, harmony and personhood: towards a Confucian ethics of technology

A closer look at the theories and questions in philosophy of technology and ethics of technology shows the absence and marginality of non-Western philosophical traditions in the discussions. Although, increasingly, some philosophers have sought to introduce non-Western philosophical traditions into the debates, there are few systematic attempts to construct and articulate general accounts of ethics and technology based on other philosophical traditions. This situation is understandable, for the questions of modern sciences and technologies appear to be originated from the West; at the same time, the situation is undesirable. The overall aim of this paper, therefore, is to introduce an alternative account of ethics of technology based on the Confucian tradition. In doing so, it is hoped that the current paper can initiate a relatively uncharted field in philosophy of technology and ethics of technology

Co-morbidity and polypharmacy in Parkinson's Disease:insights from a large Scottish primary care database

Background: Parkinson’s disease is complicated by comorbidity and polypharmacy, but the extent and patterns of these are unclear. We describe comorbidity and polypharmacy in patients with and without Parkinson’s disease across 31 other physical, and seven mental health conditions. Methods: We analysed primary health-care data on 510,502 adults aged 55 and over. We generated standardised prevalence rates by age-groups, gender, and neighbourhood deprivation, then calculated age, sex and deprivation adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for those with PD compared to those without, for the prevalence, and number of conditions. Results: Two thousand six hundred forty (0.5%) had Parkinson’s disease, of whom only 7.4% had no other conditions compared with 22.9% of controls (adjusted OR [aOR] 0.43, 95% 0.38–0.49). The Parkinson’s group had more conditions, with the biggest difference found for seven or more conditions (PD 12.1% vs. controls 3.9%; aOR 2.08 95% CI 1.84–2.35). 12 of the 31 physical conditions and five of the seven mental health conditions were significantly more prevalent in the PD group. 44.5% with Parkinson’s disease were on five to nine repeat prescriptions compared to 24.5% of controls (aOR 1.40; 95% CI 1.28 to 1.53) and 19.2% on ten or more compared to 6.2% of controls (aOR 1.90; 95% CI 1.68 to 2.15). Conclusions: Parkinson’s disease is associated with substantial physical and mental co-morbidity. Polypharmacy is also a significant issue due to the complex nature of the disease and associated treatments

Remarks on the Concept of Critique in Habermasian Thought

The main purpose of this paper is to examine the concept of critique in Habermasian thought. Given that the concept of critique is a central theoretical category in the work of the Frankfurt School, it comes as a surprise that little in the way of a systematic account which sheds light on the multifaceted meanings of the concept of critique in Habermas’s oeuvre can be found in the literature. This paper aims to fill this gap by exploring the various meanings that Habermas attributes to the concept of critique in 10 key thematic areas of his writings: (1) the public sphere, (2) knowledge, (3) language, (4) morality, (5) ethics, (6) evolution, (7) legitimation, (8) democracy, (9) religion, and (10) modernity. On the basis of a detailed analysis of Habermas’s multifaceted concerns with the nature and function of critique, the study seeks to demonstrate that the concept of critique can be considered not only as a constitutive element but also as a normative cornerstone of Habermasian thought. The paper draws to a close by reflecting on some of the limitations of Habermas’s conception of critique, arguing that in order to be truly critical in the Habermasian sense we need to turn the subject of critique into an object of critique

The German MultiCare-study: Patterns of multimorbidity in primary health care – protocol of a prospective cohort study

Background Multimorbidity is a highly frequent condition in older people, but well designed longitudinal studies on the impact of multimorbidity on patients and the health care system have been remarkably scarce in numbers until today. Little is known about the long term impact of multimorbidity on the patients' life expectancy, functional status and quality of life as well as health care utilization over time. As a consequence, there is little help for GPs in adjusting care for these patients, even though studies suggest that adhering to present clinical practice guidelines in the care of patients with multimorbidity may have adverse effects. Methods The study is designed as a multicentre prospective, observational cohort study of 3.050 patients aged 65 to 85 at baseline with at least three different diagnoses out of a list of 29 illnesses and syndromes. The patients will be recruited in approx. 120 to 150 GP surgeries in 8 study centres distributed across Germany. Information about the patients' morbidity will be collected mainly in GP interviews and from chart reviews. Functional status, resources/risk factors, health care utilization and additional morbidity data will be assessed in patient interviews, in which a multitude of well established standardized questionnaires and tests will be performed. Discussion The main aim of the cohort study is to monitor the course of the illness process and to analyse for which reasons medical conditions are stable, deteriorating or only temporarily present. First, clusters of combinations of diseases/disorders (multimorbidity patterns) with a comparable impact (e.g. on quality of life and/or functional status) will be identified. Then the development of these clusters over time will be analysed, especially with regard to prognostic variables and the somatic, psychological and social consequences as well as the utilization of health care resources. The results will allow the development of an instrument for prediction of the deterioration of the illness process and point at possibilities of prevention. The practical consequences of the study results for primary care will be analysed in expert focus groups in order to develop strategies for the inclusion of the aspects of multimorbidity in primary care guidelines

Social Perception of the Nasal Dorsal Contour in Male Rhinoplasty

Importance:  The social perception of nasal dorsal modification for male rhinoplasty is poorly understood.Objective:  To investigate the association of modifying the male nasal dorsum with the perception of such social attributes as youth, approachability, healthiness, masculinity/femininity, intelligence, successfulness, and leadership.Design, Setting, and Participants:  Using computer simulation software, 12 images with varied combinations of the nasal dorsal shape, nasofrontal angle (NFA), and nasolabial angle (NLA) were generated from a photograph of a male volunteer’s face in profile. These photographs were then sent to participants at a university clinic who were English-speaking adult internet users who were masked to the purpose of the study, which asked them to value different social attributes regarding the face in the photograph in a 16-question survey. The study was conducted in September 2018 and the data were analyzed thereafter until March 2019.Exposures:  Twelve photographs embedded in a 16-question survey.Main Outcomes and Measures:  Population proportions of responses and χ2 test and graphical analysis based on 95% confidence intervals.Results:  Of 503 respondents (survey provision rate, 100%), 412 (81.9%) were women, 386 (76.7%) were white, 32 (6.4%) were Hispanic or Latinx, 63 (12.5%) were black/African American, 10 (2.0%) were Asian/Pacific Islander, and the median age was 46 years (interquartile range, 32-61 years). The man with ski slope–shaped nose with an NFA of 130° and NLA of 97° was often associated with frequently perceived positive characteristics; specifically, he was judged to be the most attractive (95% CI, 18%-26%; P Conclusions and Relevance:  A reduced dorsal slope combined with more acute NFAs and NLAs was associated with positively perceived social attributes. The results may be of interest to rhinoplasty surgeons and their male patients when planning changes to the nasal dorsal contour.Level of Evidence:  NA.</p