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Telomere maintenance and elongation allows cells to gain replicative immortality and evade cellular senescence during cancer development. While most cancers use telomerase to maintain telomere lengths, a subset of cancers engage the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is present in 5%–10% of all cancers, although the prevalence is dramatically higher in certain cancer types, including complex karyotype sarcomas, isocitrate dehydrogenase-mutant astrocytoma (WHO grade II–IV), pancreatic neuroendocrine tumours, neuroblastoma and chromophobe hepatocellular carcinomas. ALT is maintained through a homology-directed DNA repair mechanism. Resembling break-induced replication, this aberrant process results in dramatic cell-to-cell telomere length heterogeneity, widespread chromosomal instability and chronic replication stress. Additionally, ALT-positive cancers frequently harbour inactivating mutations in either chromatin remodelling proteins (ATRX, DAXX and H3F3A) or DNA damage repair factors (SMARCAL1 and SLX4IP). ALT can readily be detected in tissue by assessing the presence of unique molecular characteristics, such as large ultrabright nuclear telomeric foci or partially single-stranded telomeric DNA circles (C-circles). Importantly, ALT has been validated as a robust diagnostic and prognostic biomarker for certain cancer types and may even be exploited as a therapeutic target via small molecular inhibitors and/or synthetic lethality approaches.

We integrate climatic niche models and dated phylogenies to characterize the evolution of climatic niches inOenotherasectionsAnograandKleinia(Onagraceae), and from that we make inferences on diversification in relation to climate. The evolution of climatic tolerances inAnogra+Kleiniahas been heterogeneous, across phylogenetic groups and across different dimensions of climate. All the extant taxa occur in semiarid to arid conditions (annual precipitation of 10.1–49.1 cm and high temperatures in the warmest month of 28.5°–40.1°C), but there is striking variation among taxa in their climatic tolerances, especially temperature (minimum temperatures in the coldest month of −14.0° to 5.3°C) and summer versus winter precipitation (precipitation in the warmest quarter of 0.6–19.4 cm). Climatic disparity is especially pronounced in two subclades (californica,deltoides) that radiated in the southwestern United States and California, apparently including both divergent and convergent evolution of climatic tolerances. This niche evolution is remarkable, given the probable timescale of the radiation (∼1 million years). We suggest that the spatiotemporal climatic heterogeneity of western North America has served as a driver of diversification. Our data are also consistent with Axelrod’s hypothesis that the spread of arid conditions in western North America stimulated diversification of arid‐adapted lineages.

POT1 and RPA go their separate ways Two single-stranded DNA binding proteins, POT1 and RPA, associate with the ends of DNA chromosomes, which are known as telomeres. Binding of RPA to telomeres can activate a DNA damage response, so it was suggested that POT1 might bind telomeres to prevent RPA association. Zou and colleagues unexpectedly find that POT1 and its partner TPP1 do not prevent RPA binding, but hnRNPA1 does. TERRA, a telomere-associated RNA, displaces hnRNPA1 and promotes POT1 binding after S phase, when replication is completed. Two single-stranded DNA-binding proteins, POT1 and RPA, associate with telomeres. Binding of RPA to telomeres can activate a DNA damage response, so it was previously proposed that POT1 binds telomeres to prevent RPA association. Here, it is found that POT1–TPP1 cannot prevent RPA binding, and hnRNPA1 is identified as having this activity instead. In addition, it is shown that TERRA, a telomere-associated RNA, displaces hnRNPA1 and promotes POT1 binding after S phase, when replication is completed. Maintenance of telomeres requires both DNA replication and telomere ‘capping’ by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres 1 , 2 , suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres 3 . Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.

Background Wheat production is increasingly challenged by the devastating damage caused by insect pests. The advent of global warming is further exacerbating this threat. Hessian fly ( Mayetiola destructor ), a dipteran gall midge, is a destructive pest of host wheat ( Triticum aestivum ) having severe economic consequences. Planting wheat cultivars harboring resistance genes is the most effective and economical Hessian fly management strategy. However, heat stress poses a challenge to this strategy, as elevated temperature often breaks down Hessian fly resistance in wheat. Our prior study identified temperature-independent resistant T. turgidum (durum wheat) accessions that maintained resistance to Hessian fly when challenged with an increased temperature of 30 °C. In this study, we carried out follow-up characterization of these durum lines to highlight molecular components involved during Hessian fly resistance or susceptibility in wheat following heat stress. Results Temperature-independent resistant durum lines were greater than 70% resistant to multiple Hessian fly biotypes at the elevated temperature of 30 °C. At the molecular level, these lines showed increased transcripts of Hfr-1 , a gene encoding an antinutrient lectin, unlike the heat-triggered susceptible durum wheat. The Hessian fly susceptibility-associated biomarker genes were significantly upregulated in the durum wheat with heat-triggered susceptibility at 30 °C, resembling the gene expression profile observed in susceptible wheat. None of these susceptibility-associated genes were differentially expressed in the temperature-independent resistant wheat. Genes involved in oxidative stress and jasmonic acid pathways did not reveal any specific expression pattern attributed to either heat stress or larval feeding. Neutral red staining revealed limited cell wall permeability in the temperature-independent resistant wheat, unlike the heat-triggered susceptible durum plants that were highly permeable similar to a wheat line susceptible to Hessian fly at 20 °C. Conclusions Temperature-independent resistant durum wheat lines provided robust resistance to multiple Hessian fly biotypes at higher temperatures. These lines offer a valuable resource for wheat producers for providing resistance following heat stress.

Background In 2012, the Saskatchewan Ministry for Health mandated a system-wide Lean transformation. Research has been conducted on the implementation processes of this system-wide Lean implementation. However, no research has been done on the sustainability of these Lean efforts. We conducted a realist evaluation on the sustainability of Lean in pediatric healthcare. We used the context (C) + mechanism (M) = outcome (O) configurations (CMOcs) heuristic to explain under what contexts, for whom, how and why Lean efforts are sustained or not sustained in pediatric healthcare. Methods We employed a case study research design. Guided by a realist evaluation framework, we conducted qualitative realist interviews with various stakeholder groups across four pediatric hospital units ‘cases’ at one acute hospital. Interview data was analyzed using an integrated approach of CMOc categorization coding, CMOc connecting and pattern matching. Results We conducted thirty-two interviews across the four cases. Five CMOcs emerged from our realist interview data. These configurations illustrated a ‘ripple-effect’ from implementation outcomes to contexts for sustainability. Sense-making and staff engagement were prominent mechanisms to the sustainment of Lean efforts. Failure to trigger these mechanisms resulted in resistance. The implementation approach used influenced mechanisms and outcomes for sustainability, more so than Lean itself. Specifically, the language, messaging and training approaches used triggered mechanisms of innovation fatigue, poor ‘sense-making’ and a lack of engagement for frontline staff. The mandated, top-down, externally led nature of implementation and lack of customization to context served as potential pitfalls. Overall, there was variation between leadership and frontline staff’s perceptions on how embedded Lean was in their contexts, and the degree to which participants supported Lean sustainability. Conclusions This research illuminates important contextual factors and mechanisms to the process of Lean sustainment that can be applicable to those implementing systems changes. Future work is needed to continue to develop the science on the sustainability of interventions for healthcare improvement.

The current feasibility study examined the adherence, reliability, and assessment potential of an evidence-based game-like mobile Monitoring Tool (Akili Interactive Labs), to monitor 100 participants’ cognition for eight sessions at a summer camp for children with special needs. A validated measure of attention was administered at baseline. In the last session, participants completed an exit questionnaire. The Monitoring Tool was found to be enjoyable, and showed a high rate of adherence. No Monitor-related adverse events were reported. Monitor metrics showed good reliability across repeated measurements, indicating it is stable over long-term cognitive monitoring. There was evidence that the Monitoring Tool was able to detect differences in cognition between the children diagnosed with attention deficit hyperactivity disorder and autism spectrum disorders.

Aim Patient engagement (PE) in pediatric health services research is challenging due to contextual factors such as busyness of parenting, work schedules, and diverse family structures. This scoping review seeks to comprehensively map current PE strategies with parents and families across existing published pediatric health research literature. Methods We followed Arksey and O’Malley (2005) and Levac et al., (2010) six-stage scoping review process. We conducted the search strategy in Medline, Embase, CINAHL, and Psychinfo databases. Data were extracted from included articles; evidence tables were developed and narrative synthesis was completed. Results Of 3925 retrieved records, seventeen articles were included in the review. Patient engagement primarily occurred through strategies such as advisory groups, meetings, focus groups and interviews. Strategies were used to engage patients at various levels, for different purposes (e.g., to inform, participate, consult, involve collaborate and/or lead). These strategies were also used at various stages of the research process. Navigating power differences, time and money were commonly reported challenges. Inconsistent terminology plagued (e.g., stakeholder engagement, consumer participation, patient and public involvement, participatory research) this body of literature and clarity is urgently needed. Conclusions This review offers insights into current PE strategies used in pediatric health services research and offers insight for researchers considering employing PE in the future.

Background In 2012, Alberta Health Services created Strategic Clinical Networks TM (SCNs) to develop and implement evidence-informed, clinician-led and team-delivered health system improvement in Alberta, Canada. SCNs have had several provincial successes in improving health outcomes. Little research has been done on the sustainability of these evidence-based implementation efforts. Methods We conducted a qualitative realist evaluation using a case study approach to identify and explain the contextual factors and mechanisms perceived to influence the sustainability of two provincial SCN evidence-based interventions, a delirium intervention for Critical Care and an Appropriate Use of Antipsychotics (AUA) intervention for Senior’s Health. The context (C) + mechanism (M) = outcome (O) configurations (CMOcs) heuristic guided our research. Results We conducted thirty realist interviews in two cases and found four important strategies that facilitated sustainability: Learning collaboratives, audit & feedback, the informal leadership role, and patient stories. These strategies triggered certain mechanisms such as sense-making, understanding value and impact of the intervention, empowerment, and motivation that increased the likelihood of sustainability. For example, informal leaders were often hands-on and influential to front-line staff. Learning collaboratives broke down professional and organizational silos and encouraged collective sharing and learning, motivating participants to continue with the intervention. Continual audit-feedback interventions motivated participants to want to perform and improve on a long-term basis, increasing the likelihood of sustainability of the two multi-component interventions. Patient stories demonstrated the interventions’ impact on patient outcomes, motivating staff to want to continue doing the intervention, and increasing the likelihood of its sustainability. Conclusions This research contributes to the field of implementation science, providing evidence on key strategies for sustainability and the underlying causal mechanisms of these strategies that increases the likelihood of sustainability. Identifying causal mechanisms provides evidence on the processes by which implementation strategies operate and lead to sustainability. Future work is needed to evaluate the impact of informal leadership, learning collaboratives, audit-feedback, and patient stories as strategies for sustainability, to generate better guidance on planning sustainable improvements with long term impact.

Background Knowledge translation (KT) strategies are widely used to facilitate the implementation of EBIs into healthcare practices. However, it is unknown what and how KT strategies are used to facilitate the sustainability of EBIs in institutional healthcare settings. Objectives This scoping review aimed to consolidate the current evidence on (i) what and how KT strategies are being used for the sustainability of EBIs in institutional healthcare settings; (ii) the reported KT strategy outcomes (e.g., acceptability) for EBI sustainability, and (iii) the reported EBI sustainability outcomes (e.g., EBI activities or component of the intervention continue). Methods We conducted a scoping review of five electronic databases. We included studies describing the use of specific KT strategies to facilitate the sustainability of EBIs (more than 1-year post-implementation). We coded KT strategies using the clustered ERIC taxonomy and AIMD framework, we coded KT strategy outcomes using Tierney et al.’s measures, and EBI sustainability outcomes using Scheirer and Dearing’s and Lennox’s taxonomy. We conducted descriptive numerical summaries and a narrative synthesis to analyze the results. Results The search identified 3776 studies for review. Following the screening, 25 studies (reported in 27 papers due to two companion reports) met the final inclusion criteria. Most studies used multi-component KT strategies for EBI sustainability ( n = 24). The most common ERIC KT strategy clusters were to train and educate stakeholders ( n = 38) and develop stakeholder interrelationships ( n = 34). Education was the most widely used KT strategy ( n = 17). Many studies ( n = 11) did not clearly report whether they used different or the same KT strategies between EBI implementation and sustainability. Seven studies adapted KT strategies from implementation to sustainability efforts. Only two studies reported using a new KT strategy for EBI sustainability. The most reported KT strategy outcomes were acceptability ( n = 10), sustainability ( n = 5); and adoption ( n = 4). The most commonly measured EBI sustainability outcome was the continuation of EBI activities or components ( n = 23), followed by continued benefits for patients, staff, and stakeholders ( n = 22). Conclusions Our review provides insight into a conceptual problem where initial EBI implementation and sustainability are considered as two discrete time periods. Our findings show we need to consider EBI implementation and sustainability as a continuum and design and select KT strategies with this in mind. Our review has emphasized areas that require further research (e.g., KT strategy adaptation for EBI sustainability). To advance understanding of how to employ KT strategies for EBI sustainability, we recommend clearly reporting the dose, frequency, adaptations, fidelity, and cost of KT strategies. Advancing our understanding in this area would facilitate better design, selection, tailored, and adapted use of KT strategies for EBI sustainability, thereby contributing to improved patient, provider, and health system outcomes.

• Large structural variations frequently occur in higher plants; however, the impact of such variations on plant diversification, adaptation and domestication remains elusive. • Here, we mapped and characterised a reciprocal chromosomal translocation in soybeans and assessed its effects on diversification and adaptation of wild (Glycine soja) and semiwild (Glycine gracilis) soybeans, and domestication of cultivated soybean (Glycine max), by tracing the distribution of the translocation in the USDA Soybean Germplasm Collection and population genetics analysis. • We demonstrate that the translocation occurred through CACTA transposon-mediated chromosomal breakage in wild soybean c. 0.34 Ma and is responsible for semisterility in translocation heterozygotes and reduces their reproductive fitness. The translocation has differentiated Continental (i.e. China and Russia) populations from Maritime (i.e. Korea and Japan) populations of G. soja and predominately adapted to cold and dry climates. Further analysis revealed that the divergence of G. max from G. soja predates the translocation event and that G. gracilis is an evolutionary intermediate between G. soja and G. max. • Our results highlight the effects of a chromosome rearrangement on the processes leading to plant divergence and adaptation, and provides evidence that suggests G. gracilis, rather than G. soja, as the ancestor of cultivated soybean.