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No abstract available

What is Hacking’s argument for entity realism?

According to Ian Hacking’s Entity Realism, unobservable entities that scientists carefully manipulate to study other phenomena are real. Although Hacking presents his case in an intuitive, attractive, and persuasive way, his argument remains elusive. I present five possible readings of Hacking’s argument: a no-miracle argument, an indispensability argument, a transcendental argument, a Vichian argument, and a non-argument. I elucidate Hacking’s argument according to each reading, and review their strengths, their weaknesses, and their compatibility with each othe

A bipartite structural organization defines the SERINC family of HIV-1 restriction factors

The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Here, using cryo-EM, we determine the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organized into two subdomains and bisected by a long diagonal helix. A lipid binding groove and clusters of conserved residues highlight potential functional sites. A structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains of SERINC5 as critical for HIV-1-restriction activity. The same regions are also important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein

Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

Local contributions to beta-diversity in urban pond networks: implications for biodiversity conservation and management

Aim: An understanding of how biotic communities are spatially organised is necessary to identify and prioritize habitats within landscape-scale biodiversity conservation. Local Contribution to Beta diversity (LCBD) identifies individual habitats that make a significant contribution to beta-diversity and may have important practical implications, particularly for conservation of habitat networks. In this study, we develop and apply a conservation prioritisation approach based on LCBD of aquatic invertebrate communities from 132 ponds.Location: Five urban settlements in England: Halton, Loughborough, Stockport, Birmingham, Huddersfield. Methods: We partition LCBD into richness difference (nestedness: RichDiffLCBD) and species replacement (turnover: ReplLCBD) and identify key environmental variables driving LCBD. We examine LCBD at two scales relevant to conservation planning: within urban settlements and nationally across England. Results: Significant differences in LCBD values were recorded among the five settlements. In four of the five urban settlements studied, pond sites with the greatest LCBD values typically showed high replacement values. Significant LCBD sites, and sites with high taxonomic diversity together supported more of the regional species pool (70%-97%) than sites with high taxonomic diversity alone (54% to 94%) or what could be protected by the random selection of sites. LCBD was significantly associated with vegetation shading, surface area, altitude and macrophyte cover. Main conclusions: Conservation prioritisation that incorporates LCBD and sites with high taxonomic diversity improves the effectiveness of conservation actions within pond habitat networks, ensures site supporting high biodiversity are protected, and provides a method to define a spatial network of protected sites. Identifying new, effective conservation approaches, particularly in urban areas where resources may be scarce and conflicts regarding land use exist, is essential to ensure biodiversity is fully supported and detrimental anthropogenic effects are reduced

Dispersing the Mists: An Experimental History of Medicine Study into the Quality of Volatile Inhalations

This document is the Accepted Manuscript version. The final publication is available from Mary Ann Liebert, Inc. Publishers at https://doi.org/10.1089/jamp.2016.1357.Background: Dr. Nelson's Improved Inhaler was first marketed with an advertisement in The Lancet in 1865. Revolutionary at the time for its ease of use and patient-friendliness, the inhaler is still in use for self-treatment by many all over the world. On the occasion of its 150th anniversary, this study reports an experimental historical medicine approach to identify evidence for the quality of vapor inhalers. Methods: Through accessing reviews of the device's use by the contemporary medical establishment, it was established that Dr. Nelson's Inhaler enjoyed a reputation of quality and efficacy among reputable physicians generating empirical evidence of clinical performance. There was a general absence of product performance tests during this period. Therefore, modern inhalation performance testing was applied to test the aerosol delivery performance for Friars' Balsam, and its key chemical constituent, benzoic acid (BA). Results: A respirable dose of 59.9 ± 9.0 μg of BA was aerosolized in a 10 minutes period from a dose of 3.3 mL Friars' Balsam (equivalent to 35.1 ± 0.2 mg of BA) in 375 mL of steaming water using the glass twin stage impinger at a flow rate of 60 L·min−1. The respirable dose from a standardized aqueous BA inhalation formulation increased from 115.9 ± 10.6 to 200.2 ± 19.9 μg by increasing the simulated inhalation period from 5 to 10 minutes. When tested with a simulated inhalation maneuver (500 mL tidal volume, 13 minutes−1 respiration rate, 1:2 inspiratory:expiratory ratio) a respirable dose of 112.8 ± 40.3 μg was produced. Conclusions: This work has highlighted the potential for aerosol drug delivery using steam inhalers that are popular with patients. Physicians should therefore be aware of the potential for lung dosing with irritants when patients self-medicate using the Nelson Inhaler with vaporizing formulations such as Friars' Balsam.Peer reviewedFinal Accepted Versio

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Influence of wall friction on flow regimes and scale-up of counter-current swirl spray dryers

The structure of the vortex flow in swirl spray dryers is investigated after having fouled the walls with deposits typical of detergent manufacture. The range of Re and swirl intensity Ω characteristic of industry are studied using three counter-current units of varying scale and design. The friction with the deposits increases the flow turbulence kinetic energy and causes a drastic attenuation of the swirl and as a result, the vortex breaks down in the chamber forming recirculation regions (i.e. areas of reverse flow). Three flow regimes (1) no recirculation, (2) central and (3) annular recirculation have been identified depending on the swirl intensity. New control and scale up strategies are proposed for swirl dryers based in predicting the decay and the flow regime using the unit geometry (i.e. initial swirl intensity Ωi) and experimental decay rates function of the coverage and thickness of deposits. The impact in design and numerical modelling must be stressed. Adequate prediction of the swirl is vital to study fouling and recirculation, which surely play an important part in the dispersion and aggregation of the solid phase. Current models have no means to replicate these phenomena, and yet, in this case neglecting the deposits and assuming smooth walls would result in (a) over-prediction of swirl velocity up to 40-186% (b) under-prediction of turbulent kinetic energy up to 67-85% and (c) failure to recognise recirculation areas