138 research outputs found
Time variable effectiveness and cost-benefits of different nature-based solution types and design for drought and flood management
We would like to acknowledge financial support from the UK Natural Environment Research Council (project NE/P010334/1) and Chivas Brothers via a CASE industrial studentship. Mark Wilkinson received funding from the Rural & Environment Science & Analytical Services Division of the Scottish Government programme. Drs Luca Fabris and Aaron Neill are thanked for advice on modelling and David Drummond, Dr Katya Dimitrova-Petrova, Martyn Roberts and Eva Loerke are thanked for assistance with fieldwork. Trevor Buckley and staff at the Glenlivet Distillery are thanked for on-site assistance and supply of data and abstraction records. We thank Audrey Innes for her support with the laboratory analysis. Finally, many thanks to DHI for providing the software for MIKE 11/MIKE SHE used in the hydrological simulations.Peer reviewedPublisher PD
Assessing the role of location and scale of Nature Based Solutions for the enhancement of low flows
Acknowledgements We would like to acknowledge financial support from the UK Natural Environment Research Council (project NE/P010334/1) and Chivas Brothers via a CASE industrial studentship. Mark Wilkinson received funding from the Rural & Environment Science & Analytical Services Division of the Scottish Government programme. Dr Luca Fabris and Dr Aaron Neill are thanked for advice on modelling and David Drummond, Dr Katya Dimitrova-Petrova, Martyn Roberts and Eva Loerke are thanked for assistance with fieldwork. Trevor Buckley and staff at the Glenlivet Distillery are thanked for on-site assistance and supply of data and abstraction records. We thank Audrey Innes for her support with the laboratory analysis. Finally, many thanks to DHI for providing the software for MIKE 11/MIKE SHE used in the hydrological simulations.Peer reviewedPublisher PD
Comparison of the microbial population in rabbits and guinea pigs by next generation sequencing
<div><p>This study aimed to determine the microbial composition of faeces from two groups of caecotrophagic animals; rabbits and guinea pigs. In addition the study aimed to determine the community present in the different organs in the rabbit. DNA was extracted from seven of the organs in wild rabbits (n = 5) and from faecal samples from domesticated rabbits (n = 6) and guinea pigs (n = 6). Partial regions of the small ribosomal sub-unit were amplified by PCR and then the sequences present in each sample were determined by next generation sequencing. Differences were detected between samples from rabbit and guinea pig faeces, suggesting that there is not a microbial community common to caecotrophagic animals. Differences were also detected in the different regions of the rabbits’ digestive tracts. As with previous work, many of the organisms detected were Firmicutes or unclassified species and there was a lack of Fibrobacteres, but for the first time we observed a high number of Bacteroidetes in rabbit samples. This work re-iterates high levels of Firmicutes and unclassified species are present in the rabbit gut, together with low number of Fibrobacteres. This suggests that in the rabbit gut, organisms other than the Fibrobacteres must be responsible for fibre digestion. However observation of high numbers of Bacteroidetes suggests that this phylum may indeed have a role to play in digestion in the rabbit gut.</p></div
Characterization of a Novel Small Molecule Subtype Specific Estrogen-Related Receptor α Antagonist in MCF-7 Breast Cancer Cells
The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) is a member of the nuclear receptor superfamily. It was identified through a search for genes encoding proteins related to estrogen receptor alpha (ERalpha). An endogenous ligand has not been found. Novel ERRalpha antagonists that are highly specific for binding to the ligand binding domain (LBD) of ERRalpha have been recently reported. Research suggests that ERRalpha may be a novel drug target to treat breast cancer and/or metabolic disorders and this has led to an effort to characterize the mechanisms of action of N-[(2Z)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5H dibenzo[a,d][7]annulen-5-amine, a novel ERRalpha specific antagonist.We demonstrate this ERRalpha ligand inhibits ERRalpha transcriptional activity in MCF-7 cells by luciferase assay but does not affect mRNA levels measured by real-time RT-PCR. Also, ERalpha (ESR1) mRNA levels were not affected upon treatment with the ERRalpha antagonist, but other ERRalpha (ESRRA) target genes such as pS2 (TFF1), osteopontin (SPP1), and aromatase (CYP19A1) mRNA levels decreased. In vitro, the ERRalpha antagonist prevents the constitutive interaction between ERRalpha and nuclear receptor coactivators. Furthermore, we use Western blots to demonstrate ERRalpha protein degradation via the ubiquitin proteasome pathway is increased by the ERRalpha-subtype specific antagonist. We demonstrate by chromatin immunoprecipitation (ChIP) that the interaction between ACADM, ESRRA, and TFF1 endogenous gene promoters and ERRalpha protein is decreased when cells are treated with the ligand. Knocking-down ERRalpha (shRNA) led to similar genomic effects seen when MCF-7 cells were treated with our ERRalpha antagonist.We report the mechanism of action of a novel ERRalpha specific antagonist that inhibits transcriptional activity of ERRalpha, disrupts the constitutive interaction between ERRalpha and nuclear coactivators, and induces proteasome-dependent ERRalpha protein degradation. Additionally, we confirmed that knocking-down ERRalpha lead to similar genomic effects demonstrated in vitro when treated with the ERRalpha specific antagonist
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<p>Percentage of each phylum present in fresh faecal samples collected from domesticated rabbits and rectal samples collected from wild rabbits together with the percentage of sequences which could not be classified within a particular phylum.</p
FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion
Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation
The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities
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