Assessing visual function following transplantation of mouse ESC-derived rod photoreceptor precursors

Photoreceptor replacement therapy is a promising strategy for treating retinal degenerative diseases leading to blindness. Previous work by our lab has demonstrated proof-of-concept that mouse embryonic stem cells (ESCs) can be differentiated, in a 3D culture system, into post-mitotic rod photoreceptor precursors for transplantation. However, rescue of visual function following transplantation of ESC-derived rod precursors has yet to be demonstrated. This project therefore sought to optimise the transplantation of mouse ESC-derived rod photoreceptor precursors into mouse models of retinal disease, define the optimal developmental stage for transplantation in an endogenous photoreceptor reporter ESC line, and thereafter, assess the extent to which visual function is restored in recipient animals post-transplantation. We assessed different aspects of optimising the transplantation protocol, such as dissociation method, AAV2 virus pseudotype used for labelling photoreceptors, and host immune suppression, and also characterised photoreceptor differentiation in a Crx.GFP ESC line. Additionally, we developed a multi-electrode array (MEA) set up and stimulus protocol that allowed us to detect visual responses from retinal explants. These studies demonstrated the generation of large numbers of healthy, developmentally-homogenous mouse ESC-derived rod photoreceptors for transplantation, and resulted in a significantly increased number of donor-reporter labelled cells observed in the host outer nuclear layer (ONL) following transplantation. Most importantly, using the MEA, we were able to demonstrate for the first time that mouse ESC-derived photoreceptor precursors were capable of transmitting light-evoked responses following transplantation into a mouse model of severe retinal degeneration. Taken together, these are encouraging first steps towards the use of stem cells for photoreceptor replacement therapy in retinal degenerative diseases

Vegetarian diets, maybe not as healthy as you think

Many are approaching vegetarianism as a viable diet option in recent years, presuming that adopting a vegetarian diet would provide health benefits. This paper explores the possibilities of physical and mental effects that vegetarianism may have on humans and its extent by the use of regression analysis. To measure the possible impacts vegetarian diets may hold on both the physiology and physical aspects of humans, we have utilized the measures of life expectancy and prevalence of depression respectively. Cross-sectional data were examined from sources such as the World Health Organization, Our World In Data and the World Bank, with figures on vegetarian adoption rates to be made available on Statista. Current studies on mental health impacts are inconclusive, and many relied on survey data to produce findings. The utilization of cross-sectional data on a macro basis would allow our study to account for regional differences whilst providing an objective result. This study aims to raise awareness of the positive and negative impacts of a vegetarian diet, to assist people to make informed decisions. This would be essential as plant-based diets have been receiving more attention in the media

Effect of COVID-19 on presentations of decompensated liver disease in Scotland

BACKGROUND AND AIMS: SARS-CoV-2 and consequent pandemic has presented unique challenges. Beyond the direct COVID-related mortality in those with liver disease, we sought to determine the effect of lockdown on people with liver disease in Scotland. The effect of lockdown on those with alcohol-related disease is of interest; and whether there were associated implications for a change in alcohol intake and consequent presentations with decompensated disease. METHODS: We performed a retrospective analysis of patients admitted to seven Scottish hospitals with a history of liver disease between 1 April and 30 April 2020 and compared across the same time in 2017, 2018 and 2019. We also repeated an intermediate assessment based on a single centre to examine for delayed effects between 1 April and 31 July 2020. RESULTS: We found that results and outcomes for patients admitted in 2020 were similar to those in previous years in terms of morbidity, mortality, and length of stay. In the Scotland-wide cohort: admission MELD (Model for End-stage Liver Disease) (16 (12–22) vs 15 (12–19); p=0.141), inpatient mortality ((10.9% vs 8.6%); p=0.499) and length of stay (8 days (4–15) vs 7 days (4–13); p=0.140). In the Edinburgh cohort: admission MELD (17 (12–23) vs 17 (13–21); p=0.805), inpatient mortality ((13.7% vs 10.1%; p=0.373) and length of stay (7 days (4–14) vs 7 days (3.5–14); p=0.525)). CONCLUSION: This assessment of immediate and medium-term lockdown impacts on those with chronic liver disease suggested a minimal effect on the presentation of decompensated liver disease to secondary care

Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration

The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1−/− mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation

Recapitulation of Human Retinal Development from Human Pluripotent Stem Cells Generates Transplantable Populations of Cone Photoreceptors

Transplantation of rod photoreceptors, derived either from neonatal retinae or pluripotent stem cells (PSCs), can restore rod-mediated visual function in murine models of inherited blindness. However, humans depend more upon cone photoreceptors that are required for daylight, color, and high-acuity vision. Indeed, macular retinopathies involving loss of cones are leading causes of blindness. An essential step for developing stem cell-based therapies for maculopathies is the ability to generate transplantable human cones from renewable sources. Here, we report a modified 2D/3D protocol for generating hPSC-derived neural retinal vesicles with well-formed ONL-like structures containing cones and rods bearing inner segments and connecting cilia, nascent outer segments, and presynaptic structures. This differentiation system recapitulates human photoreceptor development, allowing the isolation and transplantation of a pure population of stage-matched cones. Purified human long/medium cones survive and become incorporated within the adult mouse retina, supporting the potential of photoreceptor transplantation for treating retinal degeneration

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism

Single-cell multi-omics analysis of the immune response in COVID-19

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Funder: University College London, Birkbeck MRC Doctoral Training ProgrammeFunder: The Jikei University School of MedicineFunder: Action Medical Research (GN2779)Funder: NIHR Clinical Lectureship (CL-2017-01-004)Funder: NIHR (ACF-2018-01-004) and the BMA FoundationFunder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194)Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944)Funder: Barbour FoundationFunder: ERC Consolidator and EU MRG-Grammar awardsFunder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002)Funder: European Molecular Biology Laboratory (EMBL)Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy

Who we are and what we want

Feminist standpoints are forms of knowledge that serve as critical insight about how a dominant society thinks and structures itself in relation to the oppression of marginalized groups. This research discusses the use of Third World feminist epistemology as theory and method in gender digital divide research to establish the consciousness of Appalachian women left behind in the information society and to enable them to define how information and communication technologies can be used effectively and meaningfully in their struggles to improve their situations. This paper draws from findings of an ethnographic study that examines how women in West Virginia negotiate the complexity of their identities as mothers, wives and workers, alongside the structural factors that create the conditions for them to engage in computer learning and use. It also discusses how non-economic concerns become central in discussions about their experiences and lives and identifies opportunities that will help them transcend their marginalized positions

Teaching style, ICT experience and teachers’ attitudes toward teaching with Web 2.0

Emphasis on 21st Century Skills development has increased expectations on teachers to take advantages of emerging technologies to support student learning. Yet it is not clear whether teachers are well equipped with the necessary skills, support, and positive attitudes toward integrating them in their practices. Even though student-centered teachers are considered receptive to collaborative technologies and likely to use technology meaningfully in teaching, to what extent teaching style influences their Web 2.0 adaption requires further investigation. This study attempts to identify K12 teachers’ attitudes toward the use of Web 2.0 technologies in their teaching. 161 teachers from eight middle and high schools in both rural and urban locations of West Virginia participated in this cross sectional survey study. Overall, the findings indicate that while teachers are fairly proficient in their computer and internet skills and have fairly high computer self-efficacy, their workload and a structured and standardized curriculum were inhibitors of Web 2.0 adoption. Age, self-efficacy, workload, and views about Web 2.0 in teaching were observed to be significant factors predicting teachers’ likelihood to find Web 2.0 appealing for teaching. Teaching style was not a significant predictor. The findings suggest infrastructural improvements, workload adjustments, and increased professional development opportunities allowing teachers to observe, discuss, and practice Web 2.0 technologies in their particular disciplines

The urban–rural gap: project-based learning with Web 2.0 among West Virginian teachers

To overcome the digital divide in West Virginia, schools are urged to integrate emerging information and communication technologies (ICTs) such as Web 2.0 and alternative pedagogies to develop students’ twenty-first-century skills. Yet, the potential effects of the digital divide on technology integration have not necessarily been part of planning for professional development programmes. As a first step to identify the potential digital divide between rural and urban school settings, this study examined West Virginian teachers’ Web 2.0 access levels – namely, motivation, physical, skills and usage accesses. Analysis of the survey responses from 161 teachers suggested that the divide persisted at physical and usage access levels, signifying teachers’ unique needs and conditions for the use of emerging technologies. While teachers’ usage access was observed to be a significant factor for their Web 2.0-associated project-based learning, attending professional development programmes seemed to minimally benefit such practices.Accepted versio