Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells

The POU domain transcription factor OCT4 is a key regulator of pluripotency in the early mammalian embryo and is highly expressed in the inner cell mass of the blastocyst. Consistent with its essential role in maintaining pluripotency, Oct4 expression is rapidly downregulated during formation of the trophoblast lineage. To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. Our data set includes regulators of ACTIVIN, BMP, fibroblast growth factor, and WNT signaling. These pathways are implicated in regulating human ESC differentiation and therefore further validate the results of our analysis. In addition, we identified a number of differentially expressed genes that are involved in epigenetics, chromatin remodeling, apoptosis, and metabolism that may point to underlying molecular mechanisms that regulate pluripotency and trophoblast differentiation in humans. Significant concordance between this data set and previous comparisons between inner cell mass and trophectoderm in human embryos indicates that the study of human ESC differentiation in vitro represents a useful model of early embryonic differentiation in humans

Novel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Ayme-Gripp syndrome)

Published online: 08 May 2017Background: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son. Method: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother. Result: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases. Conclusion: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.Shari Javadiyan, Jamie E. Craig, Shiwani Sharma, Karen M. Lower, Theresa Casey, Eric Haan, Emmanuelle Souzeau and Kathryn P. Burdo

Expanding the role of participatory mapping to assess ecosystem service provision in local coastal environments

There has been increasing international effort to better understand the diversity and quality of marine natural capital, ecosystem services and their associated societal benefits. However, there is an evidence gap as to how these benefits are identified at the local scale, where benefits are provided and to whom, trade-offs in development decisions, and understanding how benefits support well-being. Often the benefits of conservation are poorly understood at the local scale, are not effectively integrated into policy and are rarely included meaningfully in public discourse. This paper addresses this disjuncture and responds to the demand for improving dialogue with local communities and stakeholders. Participatory GIS mapping is used as a direct means of co-producing knowledge with stakeholder and community interests. This paper drives a shift from development of participatory approaches to adaptive applications in real-world case studies of local, national and international policy relevance. The results from four sites along the UK North Sea coast are presented. This paper showcases a robust stakeholder-driven approach that can be used to inform marine planning, conservation management and coastal development. Although the demonstration sites are UK-focused, the methodology presented is of global significance and can be applied across spatial and temporal scales

Increasing forest loss worldwide from invasive pests requires new trade regulations

Loss of forests due to non-native invasive pests (including insects, nematodes, and pathogens) is a global phenomenon with profound population, community, ecosystem, and economic impacts. We review the magnitude of pest-associated forest loss worldwide and discuss the major ecological and evolutionary causes and consequences of these invasions. After compiling and analyzing a dataset of pest invasions from 21 countries, we show that the number of forest pest invasions recorded for a given country has a significant positive relationship with trade (as indicated by gross domestic product) and is not associated with the amount of forested land within that country. We recommend revisions to existing international protocols for preventing pest entry and proliferation, including prohibiting shipments of non-essential plants and plant products unless quarantined. Because invasions often originate from taxa that are scientifically described only after their introduction, current phytosanitary regulations – which target specific, already named organisms – are ineffective

Recurrent mutation in the crystallin alpha A gene associated with inherited paediatric cataract

© 2016 Javadiyan et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Cataract is a major cause of childhood blindness worldwide. The purpose of this study was to determine the genetic cause of paediatric cataract in a South Australian family with a bilateral lamellar paediatric cataract displaying variable phenotypes. Case presentation: Fifty-one genes implicated in congenital cataract in human or mouse were sequenced in an affected individual from an Australian (Caucasian) family using a custom Ampliseq library on the Ion Torrent Personal Genome Machine. Reads were mapped against the human genome (hg19) and variants called with the Torrent Suite software. Variants were annotated to dbSNP 137 using Ion Reporter (IR 1.6.2) and were prioritised for validation if they were novel or rare and were predicted to be protein changing. We identified a previously reported oligomerization disrupting mutation, c.62G > A (p.R21Q), in the Crystallin alpha A (CRYAA) gene segregating in this three generation family. No other novel or rare coding mutations were detected in the known cataract genes sequenced. Microsatellite markers were used to compare the haplotypes between the family reported here and a previously published family with the same segregating mutation. Haplotype analysis indicated a potential common ancestry between the two South Australian families with this mutation. The work strengthens the genotype-phenotype correlations between this functional mutation in the crystallin alpha A (CRYAA) gene and paediatric cataract. Conclusion: The p.R21Q mutation is the most likely cause of paediatric cataract i

A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32

Background: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family.Methods: Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations. Results: Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. Conclusions: The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.Kathryn Hattersley, Kate J Laurie, Jan E Liebelt, Jozef Gecz, Shane R Durkin, Jamie E Craig and Kathryn P Burdo

Paraoxonase 2 protein is spatially expressed in the human placenta and selectively reduced in labour

Humans parturition involves interaction of hormonal, neurological, mechanical stretch and inflammatory pathways and the placenta plays a crucial role. The paraoxonases (PONs 1–3) protect against oxidative damage and lipid peroxidation, modulation of endoplasmic reticulum stress and regulation of apoptosis. Nothing is known about the role of PON2 in the placenta and labour. Since PON2 plays a role in oxidative stress and inflammation, both features of labour, we hypothesised that placental PON2 expression would alter during labour. PON2 was examined in placentas obtained from women who delivered by cesarean section and were not in labour and compared to the equivalent zone of placentas obtained from women who delivered vaginally following an uncomplicated labour. Samples were obtained from 12 sites within each placenta: 4 equally spaced apart pieces were sampled from the inner, middle and outer placental regions. PON2 expression was investigated by Western blotting and real time PCR. Two PON2 forms, one at 62 kDa and one at 43 kDa were found in all samples. No difference in protein expression of either isoform was found between the three sites in either the labour or non-labour group. At the middle site there was a highly significant decrease in PON2 expression in the labour group when compared to the non-labour group for both the 62 kDa form (p = 0.02) and the 43 kDa form (p = 0.006). No spatial differences were found within placentas at the mRNA level in either labour or non-labour. There was, paradoxically, an increase in PON2 mRNA in the labour group at the middle site only. This is the first report to describe changes in PON2 in the placenta in labour. The physiological and pathological significance of these remains to be elucidated but since PON2 is anti-inflammatory further studies are warranted to understand its role

Early impact of COVID-19 outbreak on eye care: Insights from EUROCOVCAT group

The recent outbreak of coronavirus disease 2019 (COVID-19) has been declared a public health emergency worldwide. The scientific community has put in much effort and published studies that described COVID-19’s biology, transmission, clinical diagnosis, candidate therapeutics, and vaccines. However, to date, only a few data are available on the impact of COVID-19 pandemic on ophthalmological care in different health care systems, its future consequences in terms of disability, and access to sight-saving cures for many patients. To reduce human-to-human transmission of the virus and also ensure supply of infrastructures, human resources, and disposable medical devices to many regions, it is crucial to assess risks and postpone non-essential outpatient visits and elective surgical procedures, especially in older patients and those with comorbidities. This delay or suspension in essential eye procedures may cause significant and rapid vision impairment to irreversible blindness. Determining the risk-benefit profile of treating these ocular pathologies is a public health issue of supreme priority, even though many patients benefiting from therapeutic treatments are elderly, who are more vulnerable to COVID-19. If not reversible, this process could lead to a dramatic increase in disability and unsustainable social costs for many Governments