Ultrastructural and immunocytochemical evidence for the reorganisation of the milk fat globule membrane after secretion.

This paper reports a detailed ultrastructural and immunocytochemical investigation of the structure of the milk fat globule membrane (MFGM) in a variety of species. The process follows the same pattern in all mammals so far investigated. The initial (or primary) MFGM immediately on release from the mammary cell is a continuous unit membrane with a thin underlying layer of cytoplasmic origin and a monolayer of phospholipid separating it from the core lipid. This structure changes rapidly as the milk fat globule (MFG) moves into the alveolar lumen. The unit membrane plus the underlying layer of cytoplasm modifies drastically into discontinuous patches and networks. These are superimposed upon a continuous apparently structureless sheet of electron dense material stabilising the MFG and similar to that which bounded the lipid in the cell. The underlying layer of the patches increases in electron density and immunocytochemistry demonstrates localisation of MFGM proteins in this layer. In four species, the dense material shows ordered paracrystalline molecular arrays in section and en face views. All the arrays show the same basic pattern and unit size as determined by optical diffraction. Similar patches, networks and arrays are present on the surface of expressed MFG. Negative staining of lipid-extracted expressed MFGs shows similar patches and networks of membrane. These also occasionally show the crystalline arrays and label with MFGM protein antibodies. Similar networks and strands of plasma membrane on the MFG surface are shown by our CLSM examination of unfixed expressed MFG from mice genetically modified to express a fluorescent molecule as a normal plasma membrane constituent.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer

Dynamics of precipitation pattern formation at geothermal hot springs

We formulate and model the dynamics of spatial patterns arising during the precipitation of calcium carbonate from a supersaturated shallow water flow. The model describes the formation of travertine deposits at geothermal hot springs and rimstone dams of calcite in caves. We find explicit solutions for travertine domes at low flow rates, identify the linear instabilities which generate dam and pond formation on sloped substrates, and present simulations of statistical landscape evolution

Author Correction: Development of a sensitive, quantitative assay with broad subtype specificity for detection of total HIV-1 nucleic acids in plasma and PBMC

Correction to: Scientific Reports https://doi.org/10.1038/s41598-021-03016-1, published online 28 January 202

Modes of sea-water intrusion during transgression.

Analytical methods and numerical experiments are used to study salinization of groundwater in response to sea level rise. The system that is studied involves a saturated porous medium with an inclined upper surface. The upper surface is progressively inundated during sea level rise to simulate transgression, the landward migration of the shoreline. Four "modes" of seawater intrusion are distinguished: (1) horizontal intrusion for slow transgression and a relatively high-permeability (sand/silt) substrate, (2) vertical intrusion by seawater fingering for fast transgression and a sand/silt substrate, (3) vertical intrusion by diffusion for fast transgression and a low-permeability (clay) substrate, (4) vertical intrusion by combined diffusion and low-salinity fingering for fast transgression and a clay layer at the seafloor overlying an aquifer. These four modes are characterized by the development of very distinctive transition zones between the fresh and salt groundwater domains. An analytical expression is derived for the critical transgression rate which separates horizontal (mode 1) from dominantly vertical (modes 2-4) intrusion. For modes 3 and 4, salinization significantly lags behind sea level rise. The results are consistent with observations of fossil fresh/brackish groundwater beneath many continental shelves and shallow seas

Conducting retrospective impact analysis to inform a medical research charity’s funding strategies: The case of Asthma UK

© 2013 Hanney et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.BACKGROUND: Debate is intensifying about how to assess the full range of impacts from medical research. Complexity increases when assessing the diverse funding streams of funders such as Asthma UK, a charitable patient organisation supporting medical research to benefit people with asthma. This paper aims to describe the various impacts identified from a range of Asthma UK research, and explore how Asthma UK utilised the characteristics of successful funding approaches to inform future research strategies. METHODS: We adapted the Payback Framework, using it both in a survey and to help structure interviews, documentary analysis, and case studies. We sent surveys to 153 lead researchers of projects, plus 10 past research fellows, and also conducted 14 detailed case studies. These covered nine projects and two fellowships, in addition to the innovative case studies on the professorial chairs (funded since 1988) and the MRC-Asthma UK Centre in Allergic Mechanisms of Asthma (the ‘Centre’) which together facilitated a comprehensive analysis of the whole funding portfolio. We organised each case study to capture whatever academic and wider societal impacts (or payback) might have arisen given the diverse timescales, size of funding involved, and extent to which Asthma UK funding contributed to the impacts. RESULTS: Projects recorded an average of four peer-reviewed journal articles. Together the chairs reported over 500 papers. All streams of funding attracted follow-on funding. Each of the various categories of societal impacts arose from only a minority of individual projects and fellowships. Some of the research portfolio is influencing asthma-related clinical guidelines, and some contributing to product development. The latter includes potentially major breakthroughs in asthma therapies (in immunotherapy, and new inhaled drugs) trialled by university spin-out companies. Such research-informed guidelines and medicines can, in turn, contribute to health improvements. The role of the chairs and the pioneering collaborative Centre is shown as being particularly important. CONCLUSIONS: We systematically demonstrate that all types of Asthma UK’s research funding assessed are making impacts at different levels, but the main societal impacts from projects and fellowships come from a minority of those funded. Asthma UK used the study’s findings, especially in relation to the Centre, to inform research funding strategies to promote the achievement of impact.This study was funded by Asthma UK

Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

The feasibility of determining the impact of primary health care research projects using the Payback Framework

<p>Abstract</p> <p>Background</p> <p>Primary health care research is under pressure to be accountable to funders in terms of benefits for practice and policy. However, methods to assess the impact of primary health care research must be appropriate to use with the diverse topics, settings and approaches of this sector. This project explored the feasibility of using the Buxton and Hanney Payback Framework to determine the impact of a stratified random sample (n = 4) of competitively funded, primary health care research projects.</p> <p>Methods</p> <p>The project conducted telephone interviews based on the Payback Framework with leaders of the research teams and nominated users of their research, used bibliometric methods for assessing impact through publication outputs and obtained documentary evidence of impact where possible. The purpose was to determine the effectiveness of the data collection methods and the applicability of the Payback Framework, and any other issues which arose around the assessment of impact of primary health care research.</p> <p>Results and discussion</p> <p>The thirteen interviews were resource intensive to organise conduct and analyse but provided better information about impact than bibliometric analysis or documentary analysis. Bibliometric analysis of the papers published from the four projects was hampered by the inclusion of only one of the journals in major citation indexes. Document analysis provided more evidence of dissemination than of impact.</p> <p>The payback framework and logic model were a sound basis for assessing impact. Chief investigators and nominated users of research provided substantial information relevant to the impact categories closest to their spheres of influence and awareness, but less about the impact their research had on the wider health sector, population health or economic benefits. An additional category of impact emerged from the interviews, that of strengthening research networks which could enhance the impact of later work. The framework provided rich information about the pathways to impact, better understanding of which may enhance impact.</p> <p>Conclusion</p> <p>It is feasible to use the Buxton and Hanney Payback framework and logic model to determine the proximal impacts of primary health care research. Though resource intensive, telephone interviews of chief investigators and nominated users provided rich information.</p