25 years of epidermal stem cell research.

This is a chronicle of concepts in the field of epidermal stem cell biology and a historic look at their development over time. The past 25 years have seen the evolution of epidermal stem cell science, from first fundamental studies to a sophisticated science. The study of epithelial stem cell biology was aided by the ability to visualize the distribution of stem cells and their progeny through lineage analysis studies. The excellent progress we have made in understanding epidermal stem cell biology is discussed in this article. The challenges we still face in understanding epidermal stem cells include defining molecular markers for stem and progenitor sub-populations, determining the locations and contributions of the different stem cell niches, and mapping regulatory pathways of epidermal stem cell proliferation and differentiation. However, our rapidly evolving understanding of epidermal stem cells has many potential uses that promise to translate into improved patient therapy

Estimation and application of the thermodynamic properties of aqueous phenanthrene and isomers of methylphenanthrene at high temperature

Estimates of standard molal Gibbs energy (ΔGf°) and enthalpy (ΔHf°) of formation, entropy (S°), heat capacity (Cp°) and volume (V°) at 25 °C and 1 bar of aqueous phenanthrene (P) and 1-, 2-, 3-, 4- and 9-methylphenanthrene (1-MP, 2-MP, 3-MP, 4-MP, 9-MP) were made by combining reported standard-state properties of the crystalline compounds, solubilities and enthalpies of phenanthrene and 1-MP, and relative Gibbs energies, enthalpies and entropies of aqueous MP isomers from published quantum chemical simulations. The calculated properties are consistent with greater stabilities of the β isomers (2-MP and 3-MP) relative to the α isomers (1-MP and 9-MP) at 25 °C. However, the metastable equilibrium values of the abundance ratios 2-MP/1-MP (MPR) and (2-MP + 3-MP)/(1-MP + 9-MP) (MPI-3) decrease with temperature, becoming <1 at ~375–455 °C. The thermodynamic model is consistent with observations of reversals of these organic maturity parameters at high temperature in hydrothermal and metamorphic settings. Application of the model to data reported for the Paleoproterozoic Here’s Your Chance (HYC) Pb–Zn–Ag ore deposit (McArthur River, Northern Territory, Australia) indicates a likely effect of high-temperature equilibration on reported values of MPR and MPI-3, but this finding is contingent on the location within the deposit. If metastable equilibrium holds, a third aromatic maturity ratio, 1.5 × (2-MP + 3-MP)/(P + 1-MP + 9-MP) (MPI-1), can be used as a proxy for oxidation potential. Values of log aH2(aq) determined from data reported for HYC and for a sequence of deeply buried source rocks are indicative of more reducing conditions at a given temperature than those inferred from data reported for two sets of samples exposed to contact or regional metamorphism. These results are limiting-case scenarios for the modeled systems that do not account for effects of non-ideal mixing or kinetics, or external sources or transport of the organic matter.Nevertheless, quantifying the temperature dependence of equilibrium constants of organic reactions enables the utilization of organic maturity parameters as relative geothermometers at temperatures higher than the nominal limits of the oil window

Nordic consensus report on asthma management

AbstractThe work with the Nordic consensus report on asthma management started some years ago. The Nordic countries have common socioeconomic conditions. We acknowledge the international as well as other European guidelines providing valuable recommendations. Nevertheless, we felt the need to combine the common Nordic experiences in order to have a local statement of asthma and asthma care, based upon Nordic clinical science and tradition. The work has been rewarding and we acknowledge many valuable contributions from paediatricians, allergologists and lung physicians in all Nordic countries. The response has so far been positive and we feel that the present material reflects the main opinion of Nordic physicians taking care of asthma patients of all ages. However, the asthma and allergy research field is rapidly developing. Thus, this document should merely be regarded as a time-limited contribution to the continuing scientific discussion of this fascinating field

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

textabstractThe classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research

Glibenclamide and metfoRmin versus stAndard Care in gEstational diabeteS (GRACES): a feasibility open label randomised trial

Background: Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. Methods: We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks’ gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes. Results: Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n=13) or metformin and insulin (n=10). Mean (SD) recruitment rate was 0.39(0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6-90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03-1.87]). Conclusions: A large randomised controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic control with glibenclamide and insulin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg-0.22, P =5.5x10-13), T2D (rg-0.27, P =1.1x10-6) and coronary artery disease (rg-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated

Making the microbiome public: Participatory experiments with DNA sequencing in domestic kitchens

Recent rapid increases in the capability and affordability of DNA sequencing have enabled scientists to map the microbiome and to identify its associations with a range of health conditions. Concerns are growing that missing microbes might be behind the current rise in inflammatory disease. Microbial absence and dysbiosis have been linked to a range of hygiene practices, fuelling popular anxiety and confusion about being both too clean and the risk of superbugs. A growing number of microbiology projects allow some publics to engage with DNA sequencing, and enable DIY experiments in microbiome management. Advocates promote this as the democratisation of sequencing. This paper outlines a new methodology for making the microbiome public, and explores the potential of thinking with microbes for social science research. It reports on an interdisciplinary research project, in which a small number of households in Oxford designed and conducted repeated experiments on their kitchen microbiome. These experiments explored the composition of the microbiome and the effects of different hygiene practices. The analysis identifies two challenges of public microbiome research: the mismatch between a vernacular species ontology and the ecological understanding of the microbiome, and the difficulties posed by scientific uncertainty. The reported methodology was able to engage publics in the design and interpretation of experiments, and to work with the surprises generated by open research. Thinking with microbes as ecologies revealed the tensions between an antibiotic and a probiotic approach to domestic hygiene. Public microbiome research needs new metaphors and visualisation tools, and an awareness of the political economic and epistemic barriers that will configure the promised democratisation of sequencing. The conclusion calls for further interdisciplinary and participatory microbiome research to guide the emergence of this new technology

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Energy model, boundary object and societal lens: 35 years of the MARKAL model in the UK

Abstract Technical energy models operate within social systems and those that perform particular social as well as technical functions are more likely to be used. We illustrate this with the example of the MARKAL energy system model in the UK, a model that is also widely used internationally. In the UK, MARKAL modelling has a long history helping underpin government energy and climate policy. We trace the use of the model from its initial development in the mid-1970s to the present day, highlighting attributes that contribute to its role as a successful ‘boundary object’ for different but interconnecting energy policy communities. We suggest that changing images of the energy policy problem have enabled MARKAL to shift from an initial role in identifying technologies to reduce oil dependency to playing a key role in target-oriented climate policy. Furthermore, we argue that the ability of MARKAL to perform different roles for different groups has served to embed and institutionalise the model in the energy policy community. Moreover, the capacity of the model to represent detailed technology options has accorded with a technological focus that has suited prevailing, shared conceptions of the energy-climate policy problem