The geology of the Ballina Syncline

In early Visean times subsidence began in the Ballina area, and a basin of sedimentation developed whose form and nature were largely controlled by the caledonoid structural lines of the basement. During the first phase of deposition most of the sediments which entered the basin were derived from the north-west, and accumulated in a large delta. Sedimentation and subsidence were greatest near Ballycastle where about 2,000 feet of sandstones, siltstones, shales and limestones are preserved. At Dromore West and Keenagh only a few hundred feet of deltaic deposits occur, and farther east, at Skreen only a few tens of feet. The beds of this delta are referred to the Carboniferous Sandstone. The fauna which they contain indicates a Visean age, probably C2S1. The beds succeeding the deltaic sediments are referred to the Ballina Limestone, and are a series of bedded limestones with thin shale partings. The lateral variation in the thickness of the deltaic beds suggests that the Ballina Limestone facies spread northwestwards when the rate of supply of terrigenous material tb the delta diminished. A sandy-oolitic facies of the Ballina Limestone which occurred near what is now the Ox Mountains Range suggests that a contemporary anticlinal axis was located there. The fauna of the Ballina Limestone consists mainly of corals and brachiopods, and these indicate a lower Visean age, also probably C2S1. Armorican earth movements caused the development of faults and folds in a pattern which was in large measure controlled by the Caledonoid structures of the underlying rocks. Structurally the Ballina Syncline is an area of Carboniferous rocks preserved by downthrow between large faults. In the western part folding is slight, but the rocks have been dislocated by large faults. In the east there are several folds, usually broad with low dips, but occasionally with dips as steep as 5

Enhancing rAAV production by HEK293 cells via metabolic profiling

Viral vector manufacturing is expensive and time-consuming. Demand for rAAV-based vectors has risen massively in the past decade and continues to rise thanks to urgent healthcare supply demand. The industry is, however, currently missing a cost-effective and robust manufacturing strategy. One of the major downsides of rAAV production is the high percentage of “empty” vector particles being produced and harvested. In addition to complicating downstream purification processes, this characteristic limits the efficiency of rAAV manufacture and presents uncertainties for scale-up. Efficiency of the manufacturing process is largely dependent on the productivity of the production cell line. Much emphasis has been put into understanding the effects of recombinant protein production on mammalian cell lines (e.g., CHO, HeLa, HEK293) but relatively little is known about the effects of viral vector production on cell biology and behaviour. Over the years, many clones have been derived, isolated and engineered from HEK293 to induce improvements in productivity and efficiency. However, the high cost of production and licensing, the expression of potentially undesired elements (e.g., T-antigen) and regulatory approval processes for next generation cell lines, hinders their use in clinical manufacturing. Increased understanding of HEK293 in relation to existing processes and process control offers realistic opportunity to enhance the efficiency of rAAV manufacturing. Our aim is to identify and understand the critical parameters that contribute to setting the productivity in HEK293 cells (in terms of final yield and abundance of full capsids), ranging from the metabolic requirements prior to and during viral vector production, to cell culture parameter optimisation to maintain the cells in an optimal state of health. We tested several commercially available media for rAAV9 production and selected the candidate that provided the best yield and quality of viral vector. With this medium as our baseline, we investigated the metabolism during a period of culture via extracellular metabolic profiling of control and rAAV producing cells. The analysis revealed the rapid use of several amino acids over the first 24 hr post-inoculation and the subsequent generation of metabolites indicative of metabolic profiles associated with cell growth. rAAV9 producing cells show lower rates of amino acid and glucose consumption than control cells but the profile of metabolism was not significantly changed as a result of transfection/production of rAAV9. These data were used to design medium supplements and the effect of supplement addition on cell proliferation, viability and rAAV production/quality was assessed. Specific combinations of amino acids generated an increased cell density (up to 9.3x106 cells/mL at 5 days post-inoculation compared to 4.4x106 cells/mL for cells in non-supplemented medium). This was associated with retention of improved viability in the presence of the supplement. In addition, the metabolic profiling we undertook indicated the build-up of potentially toxic/growth inhibitory metabolites during the period of stock cell preparations prior to setting up transfections. In various dilution experiments we were able to optimise the pre-treatment, cell density and dilution protocol to generate predictable and reproducible efficiencies of transfection, cell growth and rAAV production. Overall, our data contributes metabolic insights to process conditions that generate HEK293 cells of appropriate health and defined parameters to robust and enhanced production of rAAV, providing work schemes that are also appropriate to the manufacture of further types of viral vectors

Hydrodynamics and phosphorus loading in an urbanized river channel influences response to future managed change: insights from advection-dispersion modelling

There is a need to understand what makes certain targeted measures for in-river phosphorus load reduction more effective than others. Therefore, this paper investigates multiple development scenarios in a small lowland polluted river draining an urban area (The Cut, Bracknell, UK), using an advection-dispersion model (ADModel-P). A comparative analysis is presented whereby changes in concentrations and fluxes of soluble reactive phosphorus (SRP) and organic phosphorus (OP) have been attributed to specific transformations (mineralization, sedimentation, resuspension, adsorption-desorption, and algal uptake) and correlated to controlling factors. Under present day conditions the river stretch is a net source of SRP (10.4 % increase in mean concentration) implying a release of previously accumulated material. Scenarios with the greatest impact are those based on managed reduction of phosphorus load in sources (e.g., 20 % increase in afforestation causes an in-river SRP and OP reduction of 1.3 % to 12.6 %) followed by scenarios involving changes in water temperature (e.g., 1 °C decrease leads to in-river SRP reduction around 3.1 %). Measures involving increased river residence time show the lowest effects (e.g., 16 % decrease in velocity results in under 0.02 % in-river SRP and OP reduction). For better understanding downstream persistence of phosphorus pollution and the effectiveness of mitigation measures the research demonstrates the importance of establishing when and where reaches are net adsorbers or desorbers, and whether sedimentation or resuspension is important

Monitoring of methane in groundwater from the Vale of Pickering, UK: temporal variability and source discrimination

Groundwater abstracted from aquifers in the Vale of Pickering, North Yorkshire, UK and monitored over the period 2015–2022, shows evidence of variable but commonly high concentrations of dissolved CH4. Sampled groundwater from the Jurassic organic-rich Kimmeridge Clay Formation (boreholes up to 180 m depth) has concentrations up to 57 mg/L, and concentrations up to 59 mg/L are found in groundwater from underlying confined Corallian Group limestone (borehole depths 50–227 m). The high concentrations are mainly from boreholes in the central parts of the vale. Small concentrations of ethane (C2H6, up to 800 μg/L) have been found in the Kimmeridge Clay and confined Corallian groundwaters, and of propane (C3H8, up to 160 μg/L) in deeper boreholes (110–180 m) from these formations. The concentrations are typically higher in groundwater from the deeper boreholes and vary with hydrostatic pressure, reflecting the pressure control on CH4 solubility. The occurrences contrast with groundwater from shallow Quaternary superficial deposits which have low CH4 concentrations (up to 0.39 mg/L), and with the unconfined and semi-confined sections of the Corallian aquifer (up to 0.7 mg/L) around the margins of the vale. Groundwater from the Quaternary, Kimmeridge Clay formations and to a small extent the confined Corallian aquifer, supports local private-water supplies, that from the peripheral unconfined sections of Corallian also supports public supply for towns and villages across the region. Dissolved methane/ethane (C1/C2) ratios and stable-isotopic compositions (δ13C-CH4, δ2H-CH4 and δ13C-CO2) suggest that the high-CH4 groundwater from both the Kimmeridge Clay and confined Corallian formations derives overwhelmingly from biogenic reactions, the methanogenesis pathway by CO2 reduction. A small minority of groundwater samples shows a more enriched δ13C-CH4 composition (−50 to −44 ‰) which has been interpreted as due to anaerobic or aerobic methylotrophic oxidation in situ or post-sampling oxidation, rather than derivation by a thermogenic route. Few of the existing groundwater sites are proximal to abandoned or disused conventional hydrocarbon wells that exist in the region, and little evidence has been found for an influence on groundwater dissolved gases from these sites. The Vale of Pickering has also been under recent consideration for development of an unconventional hydrocarbon (shale-gas) resource. In this context, the monitoring of dissolved gases has been an important step in establishing the high-CH4 baseline of groundwaters from Jurassic deposits in the region and in apportioning their sources and mechanisms of genesis

Sensors in the stream: the high-frequency wave of the present

New scientific understanding is catalysed by novel technologies that enhance measurement precision, resolution or type, and that provide new tools to test and develop theory. Over the last 50 years, technology has transformed the hydrologic sciences by enabling direct measurements of watershed fluxes (evapotranspiration, streamflow) at time scales and spatial extents aligned with variation in physical drivers. High frequency water quality measurements, increasingly obtained by in-situ water quality sensors, are extending that transformation. Widely available sensors for some physical (temperature) and chemical (conductivity, dissolved oxygen) attributes have become integral to aquatic science, and emerging sensors for nutrients, dissolved CO2, turbidity, algal pigments, and dissolved organic matter are now enabling observations of watersheds and streams at timescales commensurate with their fundamental hydrological, energetic, elemental, and biological drivers. Here we synthesize insights from emerging technologies across a suite of applications, and envision future advances, enabled by sensors, in our ability to understand, predict, and restore watershed and stream systems

Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility

Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case–control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study

Challenges of Reducing Phosphorus Based Water Eutrophication in the Agricultural Landscapes of Northwest Europe

ISI Document Delivery No.: HJ7HC Times Cited: 1 Cited Reference Count: 180 Bol, Roland Gruau, Gerard Mellander, Per-Erik Dupas, Remi Bechmann, Marianne Skarbovik, Eva Bieroza, Magdalena Djodjic, Faruk Glendell, Miriam Jordan, Philip Van der Grift, Bas Rode, Michael Smolders, Erik Verbeeck, Mieke Gu, Sen Klumpp, Erwin Pohle, Ina Fresne, Maelle Gascuel-Odoux, Chantal van der Grift, Bas/0000-0003-4069-6703 INSU-CNRS Earth Sciences and Astronomy Observatory of Rennes (OSUR); Loire-Brittany Water Agency (AELB); French Catchment Network Observatory (SOERE Reseau des Bassins Versants) The INSU-CNRS Earth Sciences and Astronomy Observatory of Rennes (OSUR), the Loire-Brittany Water Agency (AELB), and the French Catchment Network Observatory (SOERE Reseau des Bassins Versants) are thanked for their financial support to the international workshop meeting which was held in Rennes (France) between 24th and 26th October 2017 and whose outputs and discussions have served as a basis for constructing this paper. 1 0 Frontiers media sa Lausanne 2296-7745In this paper, we outline several recent insights for the priorities and challenges for future research for reducing phosphorus (P) based water eutrophication in the agricultural landscapes of Northwest Europe. We highlight that new research efforts best be focused on headwater catchments as they are a key influence on the initial chemistry of the larger river catchments, and here many management interventions are most effectively made. We emphasize the lack of understanding on how climate change will impact on P losses from agricultural landscapes. Particularly, the capability to disentangle current and future trends in P fluxes, due to climate change itself, from climate driven changes in agricultural management practices and P inputs. Knowing that, future climatic change trajectories for Western Europe will accelerate the release of the most bioavailable soil P. We stress the ambiguities created by the large varieties of sources and storage/transfer processes involved in P emissions in landscapes and the need to develop specific data treatment methods or tracers able to circumvent them, thereby helping catchment managers to identify the ultimate P sources that most contribute to diffuse P emissions. We point out that soil and aqueous P exist not only in various chemical forms, but also in range of less considered physical forms e. g., dissolved, nanoparticulate, colloidal and other particulates, all affected differently by climate as well as other environmental factors, and require bespoke mitigation measures. We support increased high resolution monitoring of headwater catchments, to not only help verify the effectiveness of catchments mitigation strategies, but also add data to further develop new water quality models (e.g., those include Fe-P interactions) which can deal with climate and land use change effects within an uncertainty framework. We finally conclude that there is a crucial need for more integrative research efforts to deal with our incomplete understanding of the mechanisms and processes associated with the identification of critical source areas, P mobilization, delivery and biogeochemical processing, as otherwise even highintensity and high-resolution research efforts will only reveal an incomplete picture of the full global impact of the terrestrial derived P on downstream aquatic and marine ecosystems

Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications.

Methylation of cytosine deoxynucleotides generates 5-methylcytosine (m(5)dC), a well-established epigenetic mark. However, in higher eukaryotes much less is known about modifications affecting other deoxynucleotides. Here, we report the detection of N(6)-methyldeoxyadenosine (m(6)dA) in vertebrate DNA, specifically in Xenopus laevis but also in other species including mouse and human. Our methylome analysis reveals that m(6)dA is widely distributed across the eukaryotic genome and is present in different cell types but is commonly depleted from gene exons. Thus, direct DNA modifications might be more widespread than previously thought.M.J.K. was supported by the Long-Term Human Frontiers Fellowship (LT000149/2010-L), the Medical Research Council grant (G1001690), and by the Isaac Newton Trust Fellowship (R G76588). The work was sponsored by the Biotechnology and Biological Sciences Research Council grant BB/M022994/1 (J.B.G. and M.J.K.). The Gurdon laboratory is funded by the grant 101050/Z/13/Z (J.B.G.) from the Wellcome Trust, and is supported by the Gurdon Institute core grants, namely by the Wellcome Trust Core Grant (092096/Z/10/Z) and by the Cancer Research UK Grant (C6946/A14492). C.R.B. and G.E.A. are funded by the Wellcome Trust Core Grant. We are grateful to D. Simpson and R. Jones-Green for preparing X. laevis eggs and oocytes, F. Miller for providing us with M. musculus tissue, T. Dyl for X. laevis eggs and D. rerio samples, and to Gurdon laboratory members for their critical comments. We thank U. Ruether for providing us with M. musculus kidney DNA (Entwicklungs- und Molekularbiologie der Tiere, Heinrich Heine Universitaet Duesseldorf, Germany). We also thank J. Ahringer, S. Jackson, A. Bannister and T. Kouzarides for critical input and advice, M. Sciacovelli and E. Gaude for suggestions.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.314