This case study describes the development of an open research skills framework at the University of York. The framework responds to a need for more comprehensive training, clarity and understanding ...around open research practices across disciplines at York, in line with the University's commitment to the long-term development of an open research culture. The framework was developed by Library, Archives and Learning Services (LALS) in partnership with practitioners from different disciplines across the University's research community. We summarize the background of open research activities at York since 2020, describe how the project was initiated and progressed during the summer of 2022, then provide an overview of the framework itself including areas for future development and consideration. We conclude with some early indicators of usage and reflections on the project, and we hope that this case study will prove useful for research support staff who may be considering developing a similar framework for their own institution. Keywords: open research, open science, research support, research skills, training
•A synthetic lethal screen for Poly(ADP-ribose)glycohydrolase (PARG) is presented.•SiRNA and the PARG inhibitors Gallotannin and PDD00017273 are used.•PARG is synthetically lethal with BRCA1, BRCA2, ...PALB2, FAM175A (ABRAXAS) and BARD1.•PARG inhibition induces DNA damage, stalled replication forks and homologous recombination.•The data support the validity of PARG as a target for therapy.
Poly(ADP-ribosylation) of proteins following DNA damage is well studied and the use of poly(ADP-ribose) polymerase (PARP) inhibitors as therapeutic agents is an exciting prospect for the treatment of many cancers. Poly(ADP-ribose) glycohydrolase (PARG) has endo- and exoglycosidase activities which can cleave glycosidic bonds, rapidly reversing the action of PARP enzymes. Like addition of poly(ADP-ribose) (PAR) by PARP, removal of PAR by PARG is also thought to be required for repair of DNA strand breaks and for continued replication at perturbed forks. Here we use siRNA to show a synthetic lethal relationship between PARG and BRCA1, BRCA2, PALB2, FAM175A (ABRAXAS) and BARD1. In addition, we demonstrate that MCF7 cells depleted of these proteins are sensitive to Gallotannin and a novel and specific PARG inhibitor PDD00017273. We confirm that PARG inhibition increases endogenous DNA damage, stalls replication forks and increases homologous recombination, and propose that it is the lack of homologous recombination (HR) proteins at PARG inhibitor-induced stalled replication forks that induces cell death. Interestingly not all genes that are synthetically lethal with PARP result in sensitivity to PARG inhibitors, suggesting that although there is overlap, the functions of PARP and PARG may not be completely identical. These data together add further evidence to the possibility that single treatment therapy with PARG inhibitors could be used for treatment of certain HR deficient tumours and provide insight into the relationship between PARP, PARG and the processes of DNA repair.
This review seeks to provide a better understanding of energy used in the urban water system in China. Electricity is a major contributor to the environmental impact of water supply and wastewater ...treatment, particularly in countries like China where electricity is largely generated using coal and has a significant impact on greenhouse gas emissions. Electricity use can also constitute one of the main costs for water and wastewater companies. China is an important country for the study of energy for water, particularly in urban areas where population is rapidly increasing. China's daily wastewater treatment capacity has increased dramatically over the last decade and a half, and energy use for both wastewater treatment and potable water supply has grown significantly. This paper deals with the challenge of energy for water in China. It reviews the growing body of work on energy for conventional water supply and wastewater treatment in urban China. The review covers energy for all parts of conventional water supply and wastewater treatment, including energy for sourcing, treating and distributing groundwater and surface water, and energy for primary and secondary treatment and sludge treatment and disposal.
This review seeks to provide a better understanding of energy used in the urban water system in China. The review covers energy for sourcing, treating and distributing conventional water sources, and energy for treatment of wastewater and sludge. It draws conclusions on which areas should be the focus of efforts to reduce or recover energy.
This paper introduces a new method for learning algorithm evaluation and selection, with empirical results based on classification. The empirical study has been conducted among 8 ...algorithms/classifiers with 100 different classification problems. We evaluate the algorithms' performance in terms of a variety of accuracy and complexity measures. Consistent with the No Free Lunch theorem, we do not expect to identify the single algorithm that performs best on all datasets. Rather, we aim to determine the characteristics of datasets that lend themselves to superior modelling by certain learning algorithms. Our empirical results are used to generate rules, using the rule-based learning algorithm C5.0, to describe which types of algorithms are suited to solving which types of classification problems. Most of the rules are generated with a high confidence rating.
Seven human isoforms of importin α mediate nuclear import of cargo in a tissue- and isoform-specific manner. How nuclear import adaptors differentially interact with cargo harbouring the same nuclear ...localisation signal (NLS) remains poorly understood, as the NLS recognition region is highly conserved. Here, we provide a structural basis for the nuclear import specificity of W proteins in Hendra and Nipah viruses. We determine the structural interfaces of these cargo bound to importin α1 and α3, identifying a 2.4-fold more extensive interface and > 50-fold higher binding affinity for importin α3. Through the design of importin α1 and α3 chimeric and mutant proteins, together with structures of cargo-free importin α1 and α3 isoforms, we establish that the molecular basis of specificity resides in the differential positioning of the armadillo repeats 7 and 8. Overall, our study provides mechanistic insights into a range of important nucleocytoplasmic transport processes reliant on isoform adaptor specificity.
Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often ...modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H‐MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, 1H‐MRS–measured hepatic lipid saturation, or HOMA‐IR (homeostasis model assessment of insulin resistance; P > 0.05). Conclusion: These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss. (HEPATOLOGY 2009.)
The MERS coronavirus (MERS-CoV) is a highly pathogenic, emerging virus that produces accessory proteins to antagonize the host innate immune response. The MERS-CoV ORF4b protein has been shown to ...bind preferentially to the nuclear import adapter IMPα3 in infected cells, thereby inhibiting NF-κB-dependent innate immune responses. Here, we report high-resolution structures of ORF4b bound to two distinct IMPα family members. Each exhibit highly similar binding mechanisms that, in both cases, lack a prototypical Lys bound at their P2 site. Mutations within the NLS region dramatically alter the mechanism of binding, which reverts to the canonical P2 Lys binding mechanism. Mutational studies confirm that the novel binding mechanism is important for its nuclear import, IMPα interaction, and inhibition of innate immune signaling pathways. In parallel, we determined structures of the nuclear binding domain of NF-κB component p50 bound to both IMPα2 and α3, demonstrating that p50 overlaps with the ORF4b binding sites, suggesting a basis for inhibition. Our results provide a detailed structural basis that explains how a virus can target the IMPα nuclear import adapter to impair immunity, and illustrate how small mutations in ORF4b, like those found in closely related coronaviruses such as HKU5, change the IMPα binding mechanism.
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•PARG and PARP inhibition both radiosensitize.•PARP and PARG inhibition both alter the DNA damage response following irradiation (IR).•PARP and PARG inhibition both alter homologous ...recombination following IR.•Only PARG inhibition induces rapid activation of non-homologous end-joining post-IR.•Only inhibition of PARG causes accumulation of cells in metaphase post-IR.
Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize. Further, PDD00017273 is compared with the PARP1/2/3 inhibitor olaparib. Both olaparib and PDD00017273 altered the repair of IR-induced DNA damage, resulting in delayed resolution of RAD51 foci compared with control cells. However, only PARG inhibition induced a rapid increase in IR-induced activation of PRKDC (DNA-PK) and perturbed mitotic progression. This suggests that PARG has additional functions in the cell compared with inhibition of PARP1/2/3, likely via reversal of tankyrase activity and/or that inhibiting the removal of poly(ADP-ribose) (PAR) has a different consequence to inhibiting PAR addition. Overall, our data are consistent with previous genetic findings, reveal new insights into the function of PAR metabolism following IR and demonstrate for the first time the therapeutic potential of PARG inhibitors as radiosensitizing agents.
The East India Company at Home, 1757–1857 explores how empire in Asia shaped British country houses, their interiors and the lives of their residents. It includes chapters from researchers based in a ...wide range of settings such as archives and libraries, museums, heritage organisations, the community of family historians and universities. It moves beyond conventional academic narratives and makes an important contribution to ongoing debates around how empire impacted Britain. The volume focuses on the propertied families of the East India Company at the height of Company rule. From the Battle of Plassey in 1757 to the outbreak of the Indian Uprising in 1857, objects, people and wealth flowed to Britain from Asia. As men in Company service increasingly shifted their activities from trade to military expansion and political administration, a new population of civil servants, army officers, surveyors and surgeons journeyed to India to make their fortunes. These Company men and their families acquired wealth, tastes and identities in India, which travelled home with them to Britain. Their stories, the biographies of their Indian possessions and the narratives of the stately homes in Britain that came to house them, frame our explorations of imperial culture and its British legacies.
Aged-care programs that are based in First Nations worldviews are believed to translate to improved quality of life for First Nations Elders. First Nations perspectives of health and well-being ...incorporates social and cultural determinants in addition to traditional Western biomedical approaches. This is exemplified by the Good Spirit Good Life (GSGL) framework, which comprises 12 strength-based factors determined by First Nations Elders as constituting culturally appropriate ageing. Our objective was to conduct a systematic review of existing aged care models of practice to determine the degree of alignment with the GSGL framework. Recommendations of the national Australian Royal Commission into Aged Care Quality and Safety informed this work.
We conducted a systematic search of academic and grey literature in the PubMed, Scopus, Ovid Embase, and Informit online databases. Inclusion criteria comprised English language, original research describing the implementation of First Nations culturally appropriate aged care models, published before August 2022. Research that was not focused on First Nations Elders' perspectives or quality of life was excluded. We subsequently identified, systematically assessed, and thematically analyzed 16 articles. We assessed the quality of included articles using the Aboriginal and Torres Strait Islander Quality Assessment Tool (ATSIQAT), and the Joanna Briggs Institute (JBI) critical appraisal tool for qualitative research.
Most studies were of medium to high quality, while demonstrating strong alignment with the 12 GSGL factors. Nine of the included studies detailed whole service Models of care while 7 studies described a single program or service element. Thematic analysis of included studies yielded 9 enablers and barriers to implementing models of care.
Best-practice First Nations aged care requires a decolonizing approach. Programs with strong adherence to the 12 GSGL factors are likely to improve Elders' quality of life.
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