Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Induced pluripotent stem cell (iPSC)‐derived retinal organoids provide a platform to study human retinogenesis, disease modeling, and compound screening. Although retinal organoids may represent tissue structures with greater physiological relevance to the in vivo human retina, their generation is not without limitations. Various protocols have been developed to enable development of organoids with all major retinal cell types; however, variability across iPSC lines is often reported. Modulating signaling pathways important for eye formation, such as those involving bone morphogenetic protein 4 (BMP4) and insulin‐like growth factor 1 (IGF1), is a common approach used for the generation of retinal tissue in vitro. We used three human iPSC lines to generate retinal organoids by activating either BMP4 or IGF1 signaling and assessed differentiation efficiency by monitoring morphological changes, gene and protein expression, and function. Our results showed that the ability of iPSC to give rise to retinal organoids in response to IGF1 and BMP4 activation was line‐ and method‐dependent. This demonstrates that careful consideration is needed when choosing a differentiation approach, which would also depend on overall project aims

The effects of a pragmatic exercise intervention in people with multiple sclerosis.

?Background: People with multiple sclerosis (PwMS) are less physically active than the general population. Moderate intensity exercise is likely to be safe and may provide an effective intervention for improving health outcomes for people with mild-to-moderate disability from MS. A robustly designed trial, using a pragmatic approach constructed to be cost-effective and elicit long-lasting behaviour change is required to influence health care practice.Objectives:To determine the feasibility of a pragmatic exercise intervention for PwMS and to determine if this type of intervention can provide a cost effective solution to improving health outcomes and increasing exercise and physical activity at up to nine months follow-up in PwMS compared with usual care alone.Methods: We initially conducted a feasibility randomised controlled trial, recruiting a voluntary sample of 30 PwMS (male n = 4, female n = 26; mean age 40 years; range 24 to 49 years; Expanded Disability Status Scale (EDSS) 0.0 to 5.5). Results from which informed the design of a large-scale randomised controlled trial (RCT). A total of 120 PwMS (male n = 34, female n = 86; mean age 46 years; range 19 to 65 years; EDSS 1.0 to 6.5) were then recruited to a three month exercise intervention (two supervised and one home-based session for first six weeks; one supervised and two home-based session for the final six weeks) plus usual care or usual care alone. Cognitive behavioural strategies were used to promote long-term behaviour change. The primary outcome was self-reported exercise behaviour change (Godin Leisure Time Exercise Questionnaire (GLTEQ)). Secondary outcomes included clinical, functional and quality-of- life (MSQol-54) measures.Results: The feasibility trial demonstrated that attrition was low (6.7% at immediate follow-up and 20% at three months follow-up) and compliance was high (> 75% of all sessions). The main trial reported significant improvements in self-reported exercise behaviour (p = 0.01), fatigue (p < 0.0001) and many MSQol-54 domains (p < 0.03). Only the significant improvements in overall quality of life (p = 0.001), and the sub-domains of emotional wellbeing (p = 0.01) and social function (p = 0.004) were maintained at the nine months follow-up. The probability of the intervention being cost-effective was 0.75 at the threshold of &pound;20,000 per quality adjusted life year (QALY).Conclusion: This pragmatic intervention was not only feasible, but outcomes from the main trial suggest that it is highly likely to be cost effective, leading to improved self-reported exercise behaviour, fatigue and a sustained enhancement of health-related quality of life. This provides a strong evidence base to influence the prescription of exercise into the treatment pathway for PwMS within the NHS

Is the incidence of invasive vulvar cancer increasing in the United States?

OBJECTIVE: To document incidence rates of vulvar cancer, specifically invasive vulvar cancer, from 1973 to 2004 in the United States. METHODS: Nine US cancer registries from the Surveillance, Epidemiology, and End Results (SEER) databases were used to identify women aged 15-84 years, who were first diagnosed with vulvar cancer during 1973-2004. Age-adjusted incidence rates and annual percentage changes were calculated for different time periods, stage of the disease, age, race, and geographic area. RESULTS: During 1973-2004, the incidence of in situ vulvar tumors increased by an average of 3.5% per year (95% CI: 2.9%, 4.1%), while the incidence of invasive tumors increased 1.0% per year (95% CI: 0.6%, 1.4%). An increasing incidence was observed for localized and regional invasive tumors. To at least some degree, the rise of incidence rates of incidence tumors was evident in every age category, race, and geographic region. CONCLUSIONS: Incidence rates of invasive vulvar cancer have increased in the United States during the last three decades. The reasons for this increase are unknown

Global modelling of the early Martian climate under a denser CO2 atmosphere: Water cycle and ice evolution

We discuss 3D global simulations of the early Martian climate that we have performed assuming a faint young Sun and denser CO2 atmosphere. We include a self-consistent representation of the water cycle, with atmosphere-surface interactions, atmospheric transport, and the radiative effects of CO2 and H2O gas and clouds taken into account. We find that for atmospheric pressures greater than a fraction of a bar, the adiabatic cooling effect causes temperatures in the southern highland valley network regions to fall significantly below the global average. Long-term climate evolution simulations indicate that in these circumstances, water ice is transported to the highlands from low-lying regions for a wide range of orbital obliquities, regardless of the extent of the Tharsis bulge. In addition, an extended water ice cap forms on the southern pole, approximately corresponding to the location of the Noachian/Hesperian era Dorsa Argentea Formation. Even for a multiple-bar CO2 atmosphere, conditions are too cold to allow long-term surface liquid water. Limited melting occurs on warm summer days in some locations, but only for surface albedo and thermal inertia conditions that may be unrealistic for water ice. Nonetheless, meteorite impacts and volcanism could potentially cause intense episodic melting under such conditions. Because ice migration to higher altitudes is a robust mechanism for recharging highland water sources after such events, we suggest that this globally sub-zero, `icy highlands' scenario for the late Noachian climate may be sufficient to explain most of the fluvial geology without the need to invoke additional long-term warming mechanisms or an early warm, wet Mars.Comment: Minor revisions to text, one new table, figs. 1,3 11 and 18 redon

Cervical and Vulvar Cancer Risk in Relation to the Joint Effects of Cigarette Smoking and Genetic Variation in Interleukin 2.

Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1790-9)

DataSHIELD – new directions and dimensions

In disciplines such as biomedicine and social sciences, sharing and combining sensitive individual-level data is often prohibited by ethical-legal or governance constraints and other barriers such as the control of intellectual property or the huge sample sizes. DataSHIELD (Data Aggregation Through Anonymous Summary-statistics from Harmonised Individual-levEL Databases) is a distributed approach that allows the analysis of sensitive individual-level data from one study, and the co-analysis of such data from several studies simultaneously without physically pooling them or disclosing any data. Following initial proof of principle, a stable DataSHIELD platform has now been implemented in a number of epidemiological consortia. This paper reports three new applications of DataSHIELD including application to post-publication sensitive data analysis, text data analysis and privacy protected data visualisation. Expansion of DataSHIELD analytic functionality and application to additional data types demonstrate the broad applications of the software beyond biomedical sciences

Concert recording 2016-04-03

[Track 01]. Fanfare pour précéder \u27La Péri\u27 / Paul Dukas -- [Track 02]. French dances revisted. I ; [Track 03]. II ; [Track 04]. III ; [Track 05]. IV ; [Track 06]. V ; [Track 07]. VI / Adam Gorb -- [Track 08]. Danses sacrée et profane / Claude Debussy -- [Track 09]. Dance mix / Rob Smith

Incorporating microglia‐like cells in human induced pluripotent stem cell‐derived retinal organoids

Microglia are the primary resident immune cells in the retina. They regulate neuronal survival and synaptic pruning making them essential for normal development. Following injury, they mediate adaptive responses and under pathological conditions they can trigger neurodegeneration exacerbating the effect of a disease. Retinal organoids derived from human induced pluripotent stem cells (hiPSCs) are increasingly being used for a range of applications, including disease modelling, development of new therapies and in the study of retinogenesis. Despite many similarities to the retinas developed in vivo, they lack some key physiological features, including immune cells. We engineered an hiPSC co-culture system containing retinal organoids and microglia-like (iMG) cells and tested their retinal invasion capacity and function. We incorporated iMG into retinal organoids at 13 weeks and tested their effect on function and development at 15 and 22 weeks of differentiation. Our key findings showed that iMG cells were able to respond to endotoxin challenge in monocultures and when co-cultured with the organoids. We show that retinal organoids developed normally and retained their ability to generate spiking activity in response to light. Thus, this new co-culture immunocompetent in vitro retinal model provides a platform with greater relevance to the in vivo human retina

Complex geomorphologic assemblage of terrains in association with the banded terrain in Hellas basin, Mars

Hellas basin acts as a major sink for the southern highlands of Mars and is likely to have recorded several episodes of sedimentation and erosion. The north-western part of the basin displays a potentially unique Amazonian landscape domain in the deepest part of Hellas, called “banded terrain”, which is a deposit characterized by an alternation of narrow band shapes and inter-bands displaying a sinuous and relatively smooth surface texture suggesting a viscous flow origin. Here we use high-resolution (HiRISE and CTX) images to assess the geomorphological interaction of the banded terrain with the surrounding geomorphologic domains in the NW interior of Hellas to gain a better understanding of the geological evolution of the region as a whole. Our analysis reveals that the banded terrain is associated with six geomorphologic domains: a central plateau named Alpheus Colles, plain deposits (P1 and P2), reticulate (RT1 and RT2) and honeycomb terrains. Based on the analysis of the geomorphology of these domains and their cross-cutting relationships, we show that no widespread deposition post-dates the formation of the banded terrain, which implies that this domain is the youngest and latest deposit of the interior of Hellas. Therefore, the level of geologic activity in the NW Hellas during the Amazonian appears to have been relatively low and restricted to modification of the landscape through mechanical weathering, aeolian and periglacial processes. Thermophysical data and cross-cutting relationships support hypotheses of modification of the honeycomb terrain via vertical rise of diapirs such as ice diapirism, and the formation of the plain deposits through deposition and remobilization of an ice-rich mantle deposit. Finally, the observed gradual transition between honeycomb and banded terrain suggests that the banded terrain may have covered a larger area of the NW interior of Hellas in the past than previously thought. This has implications on the understanding of the evolution of the deepest part of Hellas