MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo

Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls. Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD

Building democracy from below : lessons from Western Uganda

How to achieve democratisation in the neopatrimonial and agrarian environments that predominate in sub-Saharan Africa continues to present a challenge for both development theory and practice. Drawing on intensive fieldwork in Western Uganda, this paper argues that Charles Tilly’s ‘democratisation as process’ provides us with the framework required to explain the ways in which particular kinds of association can advance democratisation from below. Moving beyond the current focus on how elite-bargaining and certain associational forms may contribute to liberal forms of democracy, this approach helps identify the intermediate mechanisms involved in building democracy from below, including the significance of challenging categorical inequalities, notably through the role of producer groups, and of building trust networks, cross-class alliances and synergistic relations between civil and political society. The evidence and mode of analysis deployed here help suggest alternative routes for supporting local efforts to build democracy from below in sub-Saharan Africa

Nest building and circulating testosterone dynamics in male zebra finches, Taeniopygia guttata

Funding: This work was supported by Marie Skłodowska-Curie Actions Fellowships to E.I (PIEF-GA-2013-625457) and M.H (101024039). This work was also supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC) Eastbio Doctoral Training Program to S.C.E and funding from BBSRC to S.D.H (BB/Y001311/1), S.L.M (BB/Y002121/1), and Roslin Institute Strategic Grant funding from BBSRC to S.L.M (BB/P013759/1 and BBS/E/RL/230001C).Despite its fundamental importance for avian reproduction, the hormonal mechanisms supporting nest building remain poorly understood. While nest building by both male and female builders requires circulating sex steroids, it is not clear whether these steroids are required throughout building. We, therefore, sought to determine circulating testosterone dynamics in male zebra finches during early breeding, specifically focusing on the nest building period. We collected plasma samples from two cohorts of birds at three of the following four timepoints: before (baseline), following pairing, during, and after nest building. To dissociate the end of nest building from incubation onset we daily removed any eggs laid and terminated nest building once we had sampled males during nest building. Male circulating testosterone levels remained stable following pairing with a female and throughout nest building. However, testosterone titers dropped once nest building had stopped. We also found evidence to suggest that, following pairing with a female, circulating testosterone titers can predict a male’s future readiness to build. Together, our data suggest that circulating testosterone is important throughout nest building, not decreasing until the end of nest building activities, perhaps through a ‘self-feedback’ mechanism.Peer reviewe

Caring for quality of care: symbolic violence and the bureaucracies of audit.

BACKGROUND: This article considers the moral notion of care in the context of Quality of Care discourses. Whilst care has clear normative implications for the delivery of health care it is less clear how Quality of Care, something that is centrally involved in the governance of UK health care, relates to practice. DISCUSSION: This paper presents a social and ethical analysis of Quality of Care in the light of the moral notion of care and Bourdieu's conception of symbolic violence. We argue that Quality of Care bureaucracies show significant potential for symbolic violence or the domination of practice and health care professionals. This generates problematic, and unintended, consequences that can displace the goals of practice. SUMMARY: Quality of Care bureaucracies may have unintended consequences for the practice of health care. Consistent with feminist conceptions of care, Quality of Care 'audits' should be reconfigured so as to offer a more nuanced and responsive form of evaluation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Neural circuits underlying nest building in male zebra finches

SDH thanks SICB for financial support and the work described here was conducted with the support of EASTBIO DTP from the Biotechnology and Biological Sciences Research Council (BBSRC, to SE), the School of Biology and NSERC (to ZJH), MARIE CURIE (Ares(2016)5869884 to EI), and BBSRC Roslin Institute strategic grant funding (BB/P013759/1, to SLM). EN was supported by the Erasmus Plus student exchange program to SLM.Nest building consists of a series of motor actions, which are concomitant with activity in regions of the anterior motor pathway, the social behaviour network and the reward circuity in nest building adult male zebra finches (Taeniopygia guttata). It is not clear, however, whether this activity is due to nest building, collection and/or manipulation of nest material. To identify which areas of the brain are specifically involved, we used immunohistochemistry to quantify the immediate early gene c-fos in male zebra finches that were nest building (Building), birds given a nestbox but could interact only with tied down nest material (Fixed), and birds that were not given a nestbox or nest material (Control). We investigated the following brain regions: the anterior motor pathway (anterior ventral mesopallium (AMV), anterior nidopallium (AN), anterior striatium (ASt)), areas of the social behaviour network (bed nucleus of the stria terminalis, dorsomedial sub division (BSTmd), lateral septum (LS)), the dopaminergic reward circuitry (ventral tegmental area (VTA)) and the cerebellum. We found that there was greater Fos-ir expression in the BSTmd, LS and AMV with increased material deposition; in LS, AMV ASt and folia VI with increased material carrying; in LS, AMV and ASt with increased nest material tucking; and in LS and all folia (except folium VIII) with increased tugging at tied down material. These data confirm a functional role for areas of the anterior motor pathway, social behaviour network and the cerebellum in nest material collection and manipulation by birdsPostprintPeer reviewe

Addressing Global Ruminant Agricultural Challenges Through Understanding the Rumen Microbiome: Past, Present, and Future

The rumen is a complex ecosystem composed of anaerobic bacteria, protozoa, fungi, methanogenic archaea and phages. These microbes interact closely to breakdown plant material that cannot be digested by humans, whilst providing metabolic energy to the host and, in the case of archaea, producing methane. Consequently, ruminants produce meat and milk, which are rich in high-quality protein, vitamins and minerals, and therefore contribute to food security. As the world population is predicted to reach approximately 9.7 billion by 2050, an increase in ruminant production to satisfy global protein demand is necessary, despite limited land availability, and whilst ensuring environmental impact is minimized. Although challenging, these goals can be met, but depend on our understanding of the rumen microbiome. Attempts to manipulate the rumen microbiome to benefit global agricultural challenges have been ongoing for decades with limited success, mostly due to the lack of a detailed understanding of this microbiome and our limited ability to culture most of these microbes outside the rumen. The potential to manipulate the rumen microbiome and meet global livestock challenges through animal breeding and introduction of dietary interventions during early life have recently emerged as promising new technologies. Our inability to phenotype ruminants in a high-throughput manner has also hampered progress, although the recent increase in "omic" data may allow further development of mathematical models and rumen microbial gene biomarkers as proxies. Advances in computational tools, high-throughput sequencing technologies and cultivation-independent "omics" approaches continue to revolutionize our understanding of the rumen microbiome. This will ultimately provide the knowledge framework needed to solve current and future ruminant livestock challenges.</p

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk