Albumin-enriched Fibrin Hydrogel Embedded in Active Ferromagnetic Networks Improves Osteoblast Differentiation and Vascular Self-organisation

Porous coatings on prosthetic implants encourage implant fixation. Enhanced fixation may be achieved using a magneto-active porous coating that can deform elastically in vivo on application of an external magnetic field, straining in-growing bone. Such coating, made of 444 ferritic stainless steel fibres, was previously characterised in terms of its mechanical and cellular responses. In this work, co-cultures of human osteoblasts and endothelial cells were seeded into a novel fibrin-based hydrogel embedded in a 444 ferritic stainless steel fibre network. Albumin was successfully incorporated into fibrin hydrogels improving the specific permeability and the diffusion of fluorescently-tagged dextrans without affecting their Young’s modulus. The beneficial effect of albumin was demonstrated by the upregulation of osteogenic and angiogenic gene expression. Furthermore, mineralisation, extracellular matrix production and formation of vessel-like structures were enhanced in albumin-enriched fibrin hydrogels compared to fibrin hydrogels. Collectively, the results indicate that the albumin-enriched fibrin hydrogel is a promising bio-matrix for bone tissue engineering and orthopaedic applications.EPSRC (EP/R511675/1) Blavatnik Family Foundation. Reuben Foundation. WD Armstrong Studentship Isaac Newton Trust Rosetrees Trust (M787)

The views of older women towards mammographic screening: a qualitative and quantitative study

Purpose: Mammographic screening has improved breast cancer survival in the screened age group. This improved survival has not been seen in older women (>70 years) where screening uptake is low. This study explores the views, knowledge and attitudes of older women towards screening. Methods: Women (>70) were interviewed about breast screening. Interview findings informed the development of a questionnaire which was sent to 1000 women (>70) to quantify their views regarding screening. Results: Twenty-six women were interviewed and a questionnaire designed. The questionnaire response rate was 48.3% (479/992). Over half (52.9%, 241/456) of respondents were unaware they could request mammography by voluntary self-referral and were unaware of how to arrange this. Most (81.5% 383/470) had not attended breast screening since turning 70. Most (75.6%, 343/454) felt screening was beneficial and would attend if invited. Most, (90.1%, 412/457) felt screening should be offered to all women regardless of age or health. Conclusions: There is a lack of knowledge about screening in older women. The majority felt that invitation to screening should be extended to the older age group regardless of age or health. The current under-utilised system of voluntary self referral is not supported by older women

Enhancing the therapeutic activity of hyperimmune IgG against chikungunya virus using FcγRIIIa affinity chromatography

INTRODUCTION: Chikungunya virus (CHIKV) is a re-emerging mosquito transmitted alphavirus of global concern. Neutralizing antibodies and antibody Fc-effector functions have been shown to reduce CHIKV disease and infection in animals. However, the ability to improve the therapeutic activity of CHIKV-specific polyclonal IgG by enhancing Fc-effector functions through modulation of IgG subclass and glycoforms remains unknown. Here, we evaluated the protective efficacy of CHIKV-immune IgG enriched for binding to Fc-gamma receptor IIIa (FcγRIIIa) to select for IgG with enhanced Fc effector functions. METHODS: Total IgG was isolated from CHIKV-immune convalescent donors with and without additional purification by FcγRIIIa affinity chromatography. The enriched IgG was characterized in biophysical and biological assays and assessed for therapeutic efficacy during CHIKV infection in mice. RESULTS: FcγRIIIa-column purification enriched for afucosylated IgG glycoforms. In vitro characterization showed the enriched CHIKV-immune IgG had enhanced human FcγRIIIa and mouse FcγRIV affinity and FcγR-mediated effector function without reducing virus neutralization in cellular assays. When administered as post-exposure therapy in mice, CHIKV-immune IgG enriched in afucosylated glycoforms promoted reduction in viral load. DISCUSSION: Our study provides evidence that, in mice, increasing Fc engagement of FcγRs on effector cells, by leveraging FcγRIIIa-affinity chromatography, enhanced the antiviral activity of CHIKV-immune IgG and reveals a path to produce more effective therapeutics against these and potentially other emerging viruses

Functionalisation of a heat-derived and bio-inert albumin hydrogel with extracellular matrix by air plasma treatment

Funder: Cambridge Commonwealth, European and International Trust; doi: https://doi.org/10.13039/501100003343Funder: Trinity College, University of Cambridge; doi: https://doi.org/10.13039/501100000727Funder: Blavatnik Family Foundation; doi: https://doi.org/10.13039/100011643Funder: Reuben FoundationFunder: Worshipful Council of EngineersFunder: Isaac Newton Trust; doi: https://doi.org/10.13039/501100004815Abstract: Albumin-based hydrogels are increasingly attractive in tissue engineering because they provide a xeno-free, biocompatible and potentially patient-specific platform for tissue engineering and drug delivery. The majority of research on albumin hydrogels has focused on bovine serum albumin (BSA), leaving human serum albumin (HSA) comparatively understudied. Different gelation methods are usually employed for HSA and BSA, and variations in the amino acid sequences of HSA and BSA exist; these account for differences in the hydrogel properties. Heat-induced gelation of aqueous HSA is the easiest method of synthesizing HSA hydrogels however hydrogel opacity and poor cell attachment limit their usefulness in downstream applications. Here, a solution to this problem is presented. Stable and translucent HSA hydrogels were created by controlled thermal gelation and the addition of sodium chloride. The resulting bio-inert hydrogel was then subjected to air plasma treatment which functionalised its surface, enabling the attachment of basement membrane matrix (Geltrex). In vitro survival and proliferation studies of foetal human osteoblasts subsequently demonstrated good biocompatibility of functionalised albumin hydrogels compared to untreated samples. Thus, air plasma treatment enables functionalisation of inert heat-derived HSA hydrogels with extracellular matrix proteins and these may be used as a xeno-free platform for biomedical research or cell therapy

Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells

Marcus Altfeld and colleagues suggest that the exhaustion of virus-specific CD8+ T cells during chronic HIV infection likely results from the persistence of antigen

Altered distribution of mucosal NK cells during HIV infection

The human gut mucosa is a major site of HIV infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells play an important role in control of HIV infection but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here we show two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (IEL) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective KIR/HLA genotypes. Both IEL and LP NK cells were significantly expanded in immunologic non-responsive (INR) patients, who incompletely recovered CD4+ T cells on HAART. These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut

Impaired perception of facial motion in autism spectrum disorder

Copyright: © 2014 O’Brien 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.This article has been made available through the Brunel Open Access Publishing Fund.Facial motion is a special type of biological motion that transmits cues for socio-emotional communication and enables the discrimination of properties such as gender and identity. We used animated average faces to examine the ability of adults with autism spectrum disorders (ASD) to perceive facial motion. Participants completed increasingly difficult tasks involving the discrimination of (1) sequences of facial motion, (2) the identity of individuals based on their facial motion and (3) the gender of individuals. Stimuli were presented in both upright and upside-down orientations to test for the difference in inversion effects often found when comparing ASD with controls in face perception. The ASD group’s performance was impaired relative to the control group in all three tasks and unlike the control group, the individuals with ASD failed to show an inversion effect. These results point to a deficit in facial biological motion processing in people with autism, which we suggest is linked to deficits in lower level motion processing we have previously reported

Machine Learning Methods Enable Predictive Modeling of Antibody Feature:Function Relationships in RV144 Vaccinees

The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine release). We demonstrate via cross-validation that classification and regression approaches can effectively use the antibody features to robustly predict qualitative and quantitative functional outcomes. This integration of antibody feature and function data within a machine learning framework provides a new, objective approach to discovering and assessing multivariate immune correlates.U.S. Military HIV Research ProgramCollaboration for AIDS Vaccine Discover (OPP1032817)National Institutes of Health (U.S.) (3R01AI080289-02S1)National Institutes of Health (U.S.) (5R01AI080289-03)United States. Army Medical Research and Materiel Command (National Institute of Allergy and Infectious Diseases (U.S.) Interagency Agreement Y1-AI-2642-12)Henry M. Jackson Foundation for the Advancement of Military Medicine (U.S.) (United States. Dept. of Defense Cooperative Agreement W81XWH-07-2-0067