CONSERVED NOVEL INTERACTIONS BETWEEN POST-REPLICATIVE REPAIR AND MISMATCH REPAIR PROTEINS HAVE DIFFERENTIAL EFFECTS ON DNA REPAIR PATHWAYS

DNA mismatch repair (MMR) is the DNA repair mechanism that repairs base-base mispairs and small insertions and deletions remaining after replication. MMR is also required for apoptosis after certain types of exogenous DNA damage that result in damage-associated mispairs. The basic MMR mechanism is well understood; however, proteins associated with MMR continue to be identified. The roles of these interacting proteins in MMR are largely unknown. We have identified the yeast protein Rad5 as a novel interactor of the critical MMR proteins Msh2 and Mlh1. Rad5 is a DNA helicase and E3 ubiquitin ligase involved in post-replicative repair. However, to date, Rad5 has no known role in MMR despite interacting with both MMR factors. We show that the deletion of yeast RAD5 does not have the mutation rate or mutation spectrum associated with defective canonical MMR. Rad5’s interactions with MMR are conserved throughout evolution and split between its human homologs, HLTF and SHPRH. Human MSH2 interacts with HLTF regardless of damage, whereas human MLH1 interacts with SHPRH in an MMR-specific damage-dependent manner. Loss of HLTF or SHPRH, alone or in tandem, does not affect canonical MMR. SHPRH knockdown or knockout induces a moderate resistance to MMR-mediated apoptosis; however, loss of HLTF does not affect MMR-mediated apoptosis. We recently confirmed that our HLTF and SHPRH knockout cells affect survival after exposure to DNA-damaging agents that are substrates for post-replicative repair. Loss of MSH2, but not MLH1, also confers a resistance to apoptosis when treated with DNA damage related to post-replicative repair. This study defines a novel accessory factor that binds with MMR proteins and is conserved from yeast to humans. This study also provides a deeper understanding of how MMR accessory factors may provide a mechanistic distinction between canonical and non-canonical MMR and how MMR influences post-replicative repair pathways. Understanding the interplay between MMR and other repair pathways is essential for cancer development and treatment implications

Exploring heritage through time and space : Supporting community reflection on the highland clearances

On the two hundredth anniversary of the Kildonan clearances, when people were forcibly removed from their homes, the Timespan Heritage centre has created a program of community centred work aimed at challenging pre conceptions and encouraging reflection on this important historical process. This paper explores the innovative ways in which virtual world technology has facilitated community engagement, enhanced visualisation and encouraged reflection as part of this program. An installation where users navigate through a reconstruction of pre clearance Caen township is controlled through natural gestures and presented on a 300 inch six megapixel screen. This environment allows users to experience the past in new ways. The platform has value as an effective way for an educator, artist or hobbyist to create large scale virtual environments using off the shelf hardware and open source software. The result is an exhibit that also serves as a platform for experimentation into innovative ways of community co-creation and co-curation.Postprin

What Is the Storage Effect, Why Should It Occur in Cancers, and How Can It Inform Cancer Therapy?

Intratumor heterogeneity is a feature of cancer that is associated with progression, treatment resistance, and recurrence. However, the mechanisms that allow diverse cancer cell lineages to coexist remain poorly understood. The storage effect is a coexistence mechanism that has been proposed to explain the diversity of a variety of ecological communities, including coral reef fish, plankton, and desert annual plants. Three ingredients are required for there to be a storage effect: (1) temporal variability in the environment, (2) buffered population growth, and (3) species-specific environmental responses. In this article, we argue that these conditions are observed in cancers and that it is likely that the storage effect contributes to intratumor diversity. Data that show the temporal variation within the tumor microenvironment are needed to quantify how cancer cells respond to fluctuations in the tumor microenvironment and what impact this has on interactions among cancer cell types. The presence of a storage effect within a patient’s tumors could have a substantial impact on how we understand and treat cancer

Flow Equations for Non-BPS Extremal Black Holes

We exploit some common features of black hole and domain wall solutions of (super)gravity theories coupled to scalar fields and construct a class of stable extremal black holes that are non-BPS, but still can be described by first-order differential equations. These are driven by a "superpotential'', which replaces the central charge Z in the usual black hole potential. We provide a general procedure for finding this class and deriving the associated "superpotential''. We also identify some other cases which do not belong to this class, but show a similar behaviour.Comment: LaTeX, 21 pages, 2 figures. v2: reference added, JHEP versio

High-flow nasal cannula implementation has not reduced intubation rates for bronchiolitis in Canada

Background and Objective: Bronchiolitis is the most common reason for admission to hospital in the first year of life, with increasing hospitalization rates in Canada. Respiratory support with high-flow nasal cannula (HFNC) is being routinely used in paediatric centres, though the evidence of efficacy is continuing to be evaluated. We examined the impact of HFNC on intubation rates, hospital and paediatric critical care unit (PCCU) length of stay (LOS), and PCCU admission rates in paediatric tertiary centres in Canada. Methods: We conducted a multicentre, interrupted time series analysis to examine intubation rates pre- to postimplementation of HFNC for bronchiolitis. Data were obtained from the Canadian Institute for Health Information database. Paediatric tertiary centres that introduced HFNC between 2009 and 2014 were included, and data were collected from April 2005 to March 2017. Results: A total of 17,643 patients met inclusion criteria. There was no significant change in intubation rates after the introduction of HFNC. There was a significant increase in PCCU admission, with a decrease in the PCCU LOS following the introduction of HFNC. There was no significant change in average hospital LOS after HFNC was introduced. Conclusions: This study adds to the evolving evidence showing that overall disease course is not modified by the use of HFNC. The initiation of HFNC in Canadian paediatric centres resulted in no significant change in intubation rates or average LOS in hospital, but had an increase in PCCU admissions. Careful monitoring of new technologies on their clinical impact as well as health care resource utilization is warranted

Interventions for Infection and Inflammation-Induced Preterm Birth: a Preclinical Systematic Review

Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: "animal models", "preterm birth", "inflammation", and "therapeutics". We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectious agent serotype, dose, and route of delivery. Gestational length was significantly prolonged in 20/24 interventions (83%) and markers of maternal inflammation were reduced in 20/23 interventions (87%). Interventions targeting interleukin-1, interleukin-6, and toll-like receptors show particular therapeutic potential. However, due to the heterogeneity of the methodology of the included studies, meta-analysis was impossible. All studies were assigned an unclear risk of bias using the SYRCLE risk of bias tool. Interventions targeting inflammation demonstrate therapeutic potential for the prevention of preterm birth. However, better standardisation of preterm birth models, including the dose, serotype, timing of administration and pathogenicity of infectious agent, and outcome reporting is urgently required to improve the reproducibility of preclinical studies, allow meaningful comparison of intervention efficacy, and aid clinical translation

An exploration of the experiences and utility of functional electrical stimulation for foot drop in people with multiple sclerosis

Purpose: Functional electrical stimulation (FES) is effective in improving walking in people with multiple sclerosis (MS) with foot drop. There is limited research exploring people’s experiences of using this device. This study aims to explore the utility, efficacy, acceptability, and impact on daily life of the device in people with MS. Methods: An interpretative phenomenological approach was employed. Ten participants who had used FES for 12 months were interviewed. Transcripts were analysed, and emergent themes identified. Results: Nine participants continued to use the device. Three relevant super-ordinate themes were identified; impact of functional electrical stimulation, sticking with functional electrical stimulation, and autonomy and control. Participants reported challenges using the device; however, all reported positive physical and psychological benefits. Intrinsic and external influences such as; access to professional help, the influence of others, an individual’s ability to adapt, and experiences using the device, influenced their decisions to continue with the device. A thematic model of these factors was developed. Conclusions: This study has contributed to our understanding of people with MS experiences of using the device and will help inform prescribing decisions and support the continued, appropriate use of FES over the longer term

Development and initial testing of the self‐care of chronic illness inventory

Aim The aim was to develop and psychometrically test the self‐care of chronic illness Inventory, a generic measure of self‐care. Background Existing measures of self‐care are disease‐specific or behaviour‐specific; no generic measure of self‐care exists. Design Cross‐sectional survey. Methods We developed a 20‐item self‐report instrument based on the Middle Range Theory of Self‐Care of Chronic Illness, with three separate scales measuring Self‐Care Maintenance, Self‐Care Monitoring, and Self‐Care Management. Each of the three scales is scored separately and standardized 0–100 with higher scores indicating better self‐care. After demonstrating content validity, psychometric testing was conducted in a convenience sample of 407 adults (enrolled from inpatient and outpatient settings at five sites in the United States and ResearchMatch.org). Dimensionality testing with confirmatory factor analysis preceded reliability testing. Results The Self‐Care Maintenance scale (eight items, two dimensions: illness‐related and health‐promoting behaviour) fit well when tested with a two‐factor confirmatory model. The Self‐Care Monitoring scale (five items, single factor) fitted well. The Self‐Care Management scale (seven items, two factors: autonomous and consulting behaviour), when tested with a two‐factor confirmatory model, fitted adequately. A simultaneous confirmatory factor analysis on the combined set of items supported the more general model. Conclusion The self‐care of chronic illness inventory is adequate in reliability and validity. We suggest further testing in diverse populations of patients with chronic illnesses