The cellular impact of diminished DNA origin licensing capacity and its potential therapeutic exploitation

Genomic instability underlies various diseases including cancer. The maintenance of genomic stability requires accurate replication of the genome, proper segregation of duplicated DNA to progeny cells, and the capacity to respond effectively to DNA damage. Early sections of this thesis focus on the response to DNA double-strand breaks (DSBs) within compact regions of chromatin (heterochromatin). Here, methodology was optimised for monitoring the repair of site-specific DSBs within regions likely to be enriched for heterochromatin. This system was exploited to examine the function of the Artemis endonuclease in heterochromatic DSB repair. Later sections focus on factors involved in DNA replication and the response to replication stress. Among the various mechanisms involved in the DNA damage response (DDR) to replication stress, the licensing of excess origins of replication has been proposed to safeguard against replication failure. Here, the impact of diminished origin licensing capacity on the response to replication stress was compared in tumour and non-tumour cell lines. I present findings demonstrating that depletion of origin licensing factors causes hypersensitisation of tumour-derived but not non-tumour cell lines to replication stress-inducing agents. Further, combining diminished origin licensing capacity with depletion of the tumour suppressor, p53, or overexpression of the c-Myc oncogene impairs viability under conditions of replication stress in non-tumour fibroblasts. These findings suggest that tumour cells have a greater reliance on origin licensing capacity, raising the possibility that licensing factors might represent suitable targets for drugbased cancer therapy. Factors involved in replication origin licensing have also been implicated in the establishment of heterochromatin. Here, I examined higher-order chromatin structure and the ionizing radiation (IR)-induced DDR in cells from patients harbouring mutations in origin licensing factors. Findings from these studies provide evidence for the first time that origin licensing complex (ORC)-deficient Meier-Gorlin Syndrome (MGS) may be classified as a disordered chromatin syndrome

Chapter Sign language ideologies: Practices and politics

This book focuses on how sign language ideologies influence, manifest in, and are challenged by communicative practices. Sign languages are minority languages using the visual-gestural and tactile modalities, whose affordances are very different from those of spoken languages using the auditory-oral modality

Nephrotoxicity of gadolinium-based contrast in the setting of renal artery intervention: retrospective analysis with 10-year follow-up

PURPOSE:We aimed to determine the incidence rate and potential risk factors for postcontrast acute kidney injury (PC-AKI) as well as the long-term clinical implications on dialysis and mortality in patients with chronic kidney disease (CKD) who underwent renal artery stent placement exclusively with gadolinium-based contrast agents.METHODS:This retrospective study reviewed 412 patients with CKD who underwent renal artery stent placement. Sixty-eight patients underwent intervention exclusively with gadolinium-based contrast agents and were analyzed. Criteria for PC-AKI included either an absolute serum creatinine increase >0.3 mg/dL or percentage increase in serum creatinine >50% within 48 hours of intervention. Logistic regression analysis was performed to identify risk factors for PC-AKI. The cumulative proportion of patients who died or went on to hemodialysis was determined using Kaplan-Meier survival analysis.RESULTS:The incidence of PC-AKI was 14.7%. The rate of AKI decreased for every 1 unit increase in glomerular filtration rate ( GFR, odds ratio [OR]=0.91, P = 0.047). Prehydration was associated with a lower PC-AKI rate (OR=0.17; P = 0.015). Acute kidney injury after intervention was associated with an increased rate of dialysis (Hazard ratio [HR]=4.51, P = 0.002) and mortality (HR=2.52; P = 0.027).CONCLUSION:Gadolinium-based contrast agents are potentially nephrotoxic when used for endovascular intervention in patients with CKD. The risk of PC-AKI increased with lower GFR and decreased with prehydration. Dialysis and mortality risk were increased in patients who developed PC-AKI

Understanding and application of daptomycin-susceptible dose-dependent category for Enterococcus: A mixed-methods study

Background: In 2018, the Clinical Microbiology Laboratory at our institution adopted updated daptomycin Methods: This mixed-methods study combined a clinician survey with a retrospective pre-post prescribing analysis. An 8-question survey was distributed to infectious diseases (ID) and internal medicine (IM) clinicians. A retrospective chart review of hospitalized adults with infections due to Results: Survey response rates were 40 of 98 (41%) for IM and 22 of 34 (65%) for ID clinicians. ID clinicians scored significantly higher than IM clinicians in knowledge of SDD. Chart review of 474 patients (225 pre- vs 249 post-SDD) showed that daptomycin dosage following susceptibility testing was significantly higher post-SDD compared with pre-SDD (8.5 mg/kg vs 6.4 mg/kg; Conclusions: The survey revealed that ID clinicians placed more importance on and had more confidence in the SDD category over IM clinicians. SDD reporting was associated with a change in definitive daptomycin dosing. ID specialist involvement is recommended in the care of infections due to enterococci for which daptomycin is reported as SDD given their expertise

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Report on SHAFE policies, strategies and funding

The objective of Working Group (WG) 4 of the COST Action NET4Age-Friendly is to examine existing policies, advocacy, and funding opportunities and to build up relations with policy makers and funding organisations. Also, to synthesize and improve existing knowledge and models to develop from effective business and evaluation models, as well as to guarantee quality and education, proper dissemination and ensure the future of the Action. The Working Group further aims to enable capacity building to improve interdisciplinary participation, to promote knowledge exchange and to foster a cross-European interdisciplinary research capacity, to improve cooperation and co-creation with cross-sectors stakeholders and to introduce and educate students SHAFE implementation and sustainability (CB01, CB03, CB04, CB05). To enable the achievement of the objectives of Working Group 4, the Leader of the Working Group, the Chair and Vice-Chair, in close cooperation with the Science Communication Coordinator, developed a template (see annex 1) to map the current state of SHAFE policies, funding opportunities and networking in the COST member countries of the Action. On invitation, the Working Group lead received contributions from 37 countries, in a total of 85 Action members. The contributions provide an overview of the diversity of SHAFE policies and opportunities in Europe and beyond. These were not edited or revised and are a result of the main areas of expertise and knowledge of the contributors; thus, gaps in areas or content are possible and these shall be further explored in the following works and reports of this WG. But this preliminary mapping is of huge importance to proceed with the WG activities. In the following chapters, an introduction on the need of SHAFE policies is presented, followed by a summary of the main approaches to be pursued for the next period of work. The deliverable finishes with the opportunities of capacity building, networking and funding that will be relevant to undertake within the frame of Working Group 4 and the total COST Action. The total of country contributions is presented in the annex of this deliverable