Further development of The Ebbsfleet Water Management System Dynamics Model: Adjusting representation of processes and system boundaries, incentivising stakeholder re-engagement, and exploring the potential for University teaching

This is the final version. Available from WIT Press via the DOI in this record. System Dynamics Model (SDM) that explores sustainable urban water management. The model is open-source compiled using Vensim software, which is free for non-commercial use. This paper demonstrates that the current SDM and the modelling approach are open to adjustment, which is illustrated by introducing a link between water tariffs and environmental awareness. The increase in water tariffs leads not only to the obvious increase in water bills, but also to an increase in Environmental Awareness, and consequently, to increases in the use of water efficiency devices, grey water acceptability, and grey water reuse. A range of further modifications is suggested, including expanding representation of sustainable drainage systems (SuDS) to consider resultant improvements in stormwater quality as well as quantity. This would recognise the indirect benefits of improved stormwater quality on biodiversity in the River Ebbsfleet, which is the receiving watercourse. This study intends to encourage knowledge transfer, by facilitating and incentivising the use and further development of the SDM by stakeholders and a wider community of end-users, including practitioners, academics and the public. While SDM is particularly suited to analysis of indirect relations, benefits and trade-offs among system constituents, other approaches provide viable alternatives and we discuss the potential for re-implementing our findings in other interactive modelling software packages and programming languages. We also explore the scope for linking the adapted SDM to other models. Finally, we consider the utility of the Ebbsfleet SDM in teaching, learning and knowledge transfer. We conclude that students, practitioners and other stakeholders could not only enhance their understanding of urban water management complexity, but also gain valuable system modelling skills based on using the SDM to support kinaesthetic learning. Ultimately, society benefits when the level of knowledge and analytical thinking skills of its members are enhanced.Engineering and Physical Sciences Research Council (EPSRC)Engineering and Physical Sciences Research Council (EPSRC)Engineering and Physical Sciences Research Council (EPSRC

Solar-like oscillations in low-luminosity red giants: first results from Kepler

We have measured solar-like oscillations in red giants using time-series photometry from the first 34 days of science operations of the Kepler Mission. The light curves, obtained with 30-minute sampling, reveal clear oscillations in a large sample of G and K giants, extending in luminosity from the red clump down to the bottom of the giant branch. We confirm a strong correlation between the large separation of the oscillations (Delta nu) and the frequency of maximum power (nu_max). We focus on a sample of 50 low-luminosity stars (nu_max > 100 muHz, L <~ 30 L_sun) having high signal-to-noise ratios and showing the unambiguous signature of solar-like oscillations. These are H-shell-burning stars, whose oscillations should be valuable for testing models of stellar evolution and for constraining the star-formation rate in the local disk. We use a new technique to compare stars on a single echelle diagram by scaling their frequencies and find well-defined ridges corresponding to radial and non-radial oscillations, including clear evidence for modes with angular degree l=3. Measuring the small separation between l=0 and l=2 allows us to plot the so-called C-D diagram of delta nu_02 versus Delta nu. The small separation delta nu_01 of l=1 from the midpoint of adjacent l=0 modes is negative, contrary to the Sun and solar-type stars. The ridge for l=1 is notably broadened, which we attribute to mixed modes, confirming theoretical predictions for low-luminosity giants. Overall, the results demonstrate the tremendous potential of Kepler data for asteroseismology of red giants.Comment: accepted by ApJ Letters, to appear in special Kepler issue. Updated reference

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma

Fight For Sight Fellowship, UK; National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHSFoundation Trust and UCL Institute of Ophthalmology. J.W. and C.C. acknowledge support from Cancer Research UK Centre of Excellence Award to Barts Cancer Centre [C16420/A18066

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets

Detection of solar-like oscillations from Kepler photometry of the open cluster NGC 6819

Asteroseismology of stars in clusters has been a long-sought goal because the assumption of a common age, distance and initial chemical composition allows strong tests of the theory of stellar evolution. We report results from the first 34 days of science data from the Kepler Mission for the open cluster NGC 6819 -- one of four clusters in the field of view. We obtain the first clear detections of solar-like oscillations in the cluster red giants and are able to measure the large frequency separation and the frequency of maximum oscillation power. We find that the asteroseismic parameters allow us to test cluster-membership of the stars, and even with the limited seismic data in hand, we can already identify four possible non-members despite their having a better than 80% membership probability from radial velocity measurements. We are also able to determine the oscillation amplitudes for stars that span about two orders of magnitude in luminosity and find good agreement with the prediction that oscillation amplitudes scale as the luminosity to the power of 0.7. These early results demonstrate the unique potential of asteroseismology of the stellar clusters observed by Kepler.Comment: 5 pages, 4 figures, accepted by ApJ (Lett.

Obesity and PCOS radically alters the snRNA composition of follicular fluid extracellular vesicles

IntroductionThe ovarian follicle consists of the oocyte, somatic cells, and follicular fluid (FF). Proper signalling between these compartments is required for optimal folliculogenesis. The association between polycystic ovarian syndrome (PCOS) and extracellular vesicular small non-coding RNAs (snRNAs) signatures in follicular fluid (FF) and how this relates to adiposity is unknown. The purpose of this study was to determine whether FF extracellular vesicle (FFEV)-derived snRNAs are differentially expressed (DE) between PCOS and non-PCOS subjects; and if these differences are vesicle-specific and/or adiposity-dependent.MethodsFF and granulosa cells (GC) were collected from 35 patients matched by demographic and stimulation parameters. FFEVs were isolated and snRNA libraries were constructed, sequenced, and analyzed.ResultsmiRNAs were the most abundant biotype present, with specific enrichment in exosomes (EX), whereas in GCs long non-coding RNAs were the most abundant biotype. In obese PCOS vs. lean PCOS, pathway analysis revealed target genes involved in cell survival and apoptosis, leukocyte differentiation and migration, JAK/STAT, and MAPK signalling. In obese PCOS FFEVs were selectively enriched (FFEVs vs. GCs) for miRNAs targeting p53 signalling, cell survival and apoptosis, FOXO, Hippo, TNF, and MAPK signalling.DiscussionWe provide comprehensive profiling of snRNAs in FFEVs and GCs of PCOS and non-PCOS patients, highlighting the effect of adiposity on these findings. We hypothesize that the selective packaging and release of miRNAs specifically targeting anti-apoptotic genes into the FF may be an attempt by the follicle to reduce the apoptotic pressure of the GCs and stave off premature apoptosis of the follicle observed in PCOS

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Structural Basis for Interaction of O-Acetylserine Sulfhydrylase and Serine Acetyltransferase in the Arabidopsis Cysteine Synthase Complex

In plants, association of O-acetylserine sulfhydrylase (OASS) and Ser acetyltransferase (SAT) into the Cys synthase complex plays a regulatory role in sulfur assimilation and Cys biosynthesis. We determined the crystal structure of Arabidopsis thaliana OASS (At-OASS) bound with a peptide corresponding to the C-terminal 10 residues of Arabidopsis SAT (C10 peptide) at 2.9-Å resolution. Hydrogen bonding interactions with key active site residues (Thr-74, Ser-75, and Gln-147) lock the C10 peptide in the binding site. C10 peptide binding blocks access to OASS catalytic residues, explaining how complex formation downregulates OASS activity. Comparison with bacterial OASS suggests that structural plasticity in the active site allows binding of SAT C termini with dissimilar sequences at structurally similar OASS active sites. Calorimetric analysis of the effect of active site mutations (T74S, S75A, S75T, and Q147A) demonstrates that these residues are important for C10 peptide binding and that changes at these positions disrupt communication between active sites in the homodimeric enzyme. We also demonstrate that the C-terminal Ile of the C10 peptide is required for molecular recognition by At-OASS. These results provide new insights into the molecular mechanism underlying formation of the Cys synthase complex and provide a structural basis for the biochemical regulation of Cys biosynthesis in plants