Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response.

PCNA is a key component of DNA replication and repair machineries. DNA damage-induced PCNA ubiquitylation serves as a molecular mark to orchestrate postreplication repair. Here, we have identified and characterized Spartan, a protein that specifically recognizes ubiquitylated PCNA and plays an important role in cellular resistance to UV radiation. In vitro, Spartan engages ubiquitylated PCNA via both a PIP box and a UBZ domain. In cells, Spartan is recruited to sites of UV damage in a manner dependent upon the PIP box, the UBZ domain, and PCNA ubiquitylation. Furthermore, Spartan colocalizes and interacts with Rad18, the E3 ubiquitin ligase that modifies PCNA. Surprisingly, while Spartan is recruited by ubiquitylated PCNA, knockdown of Spartan compromised chromatin association of Rad18, monoubiquitylation of PCNA, and localization of Pol η to UV damage. Thus, as a "reader" of ubiquitylated PCNA, Spartan promotes an unexpected feed-forward loop to enhance PCNA ubiquitylation and translesion DNA synthesis.

ATR autophosphorylation as a molecular switch for checkpoint activation.

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master checkpoint regulator safeguarding the genome. Upon DNA damage, the ATR-ATRIP complex is recruited to sites of DNA damage by RPA-coated single-stranded DNA and activated by an elusive process. Here, we show that ATR is transformed into a hyperphosphorylated state after DNA damage, and that a single autophosphorylation event at Thr 1989 is crucial for ATR activation. Phosphorylation of Thr 1989 relies on RPA, ATRIP, and ATR kinase activity, but unexpectedly not on the ATR stimulator TopBP1. Recruitment of ATR-ATRIP to RPA-ssDNA leads to congregation of ATR-ATRIP complexes and promotes Thr 1989 phosphorylation in trans. Phosphorylated Thr 1989 is directly recognized by TopBP1 via the BRCT domains 7 and 8, enabling TopBP1 to engage ATR-ATRIP, to stimulate the ATR kinase, and to facilitate ATR substrate recognition. Thus, ATR autophosphorylation on RPA-ssDNA is a molecular switch to launch robust checkpoint response.

CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.

The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Set8 levels decline in S phase, but why and how this occurs is unclear. Here, we show that Set8 is targeted for proteolysis in S phase and in response to DNA damage by the E3 ubiquitin ligase, CRL4(Cdt2). Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4(Cdt2) leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Transient S phase expression of a Set8 mutant lacking the degron promotes premature H4K20me1 accumulation and chromatin compaction, and triggers a checkpoint-mediated G2 arrest. Thus, CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis.

TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.

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, 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. 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.

The ICN Leadership For Change™ Programme--20 years of growing influence.

AIM: The aim of this article was to present experiences from the field in the context of the International Council of Nurses' Leadership for Change™ programme, which celebrates 20 years of excellence in 2016 for developing the leadership and management capacity of nurses worldwide. BACKGROUND: The programme was launched in 1996 in order to boost nurse participation in the healthcare policy-making process, globally, and to foster within the nursing profession the requisite skills for nurses to lobby for and assume a greater responsibility in the leadership and management of health care services. INTRODUCTION: Over the course of two decades, the programme has been implemented in cooperation between ICN, national nurses associations, the World Health Organization, Ministries of Health and a variety of donor organizations such as the W.K. Kellogg Foundation and development agencies such as USAID and AUSAID. The programme has been implemented in more than 60 nations throughout Africa, Asia, Europe, the Middle East, Latin America and the Pacific Islands, to name a few regions. METHODS: This article offers an overview of the impact that certified ICN LFC nurse trainers and their colleagues have had in the United Arab Emirates, Vietnam and the United States of America and is affiliated islands and the North Pacific Islands. RESULTS: Twenty years of growth and empowerment are now the ongoing legacy of the ICN LFC Program, which has graduated and deployed nurse trainers around the world and achieved significant advances in the professional development of nurse leaders on an international scale. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nurse leaders can improve the health and well-being of their nations in collaboration with consumers and other key stakeholders. Nurse leaders are critical in improving health systems, their work places and broader societal challenges through sound nursing practice, education, research and evidence-based health and social policy change.

A statewide consortium's adoption of a unified nursing curriculum: evaluation of the first two years.

AIM: This article provides an evaluation of the first two years of implementation of a statewide nursing consortium (SNC) curriculum on nursing faculty work life, teaching productivity, and quality of education. BACKGROUND: In response to the call for nursing education reform, the SNC incorporated new approaches to competency-based, student-centered learning and clinical education. METHOD: Faculty and two cohorts of students were measured at three points over the first two years of the curriculum implementation. RESULTS: The expected positive impact of the SNC was documented at the start of the first year, but not sustained. Students reported having more confidence in their clinical skills at the start of the first year, yet demonstrated significantly less confidence in their ability after two years. CONCLUSION: Faculty indicated that the SNC allowed greater opportunity for collaboration, but that the experience did not alter their classroom performance or satisfaction beyond the first year.

Identification of erythropoietin mimetic peptide 1 linear form in a sealed vial and its administration study in horses for doping control purpose.

The erythropoietin mimetic peptide 1 linear form (EMP1-linear), GGTYSCHFGPLTWVCKPQGG-NH2 , was identified in an unknown preparation consisting of white crystalline powder contained in sealed glass vials using ultrahigh performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). The white crystalline powder, allegedly used for doping racehorses, was found to contain around 2% (w/w) of EMP1-linear. EMP1-linear can be cyclised in equine plasma at physiological temperature of 37°C by forming an intramolecular disulfide bond to give EMP1, which is a well-known erythropoiesis stimulating agent that can bind to and activate the receptor for cytokine erythropoietin (EPO). Thus, EMP1-linear is a prodrug of EMP1, which is a performance-enhancing doping agent that can be misused in equine sports. In order to identify potential target(s) for detecting the misuse of EMP1-linear in horses, an in vitro metabolic study using horse liver S9 fraction was performed. After incubation, EMP1-linear mainly existed in its cyclic form as EMP1, and four N-terminus truncated in vitro metabolites TYSCHFGPLTWVCKPQGG-NH2 (M1), SCHFGPLTWVCKPQGG-NH2 (M2), WVCKPQGG-NH2 (M3) and VCKPQGG-NH2 (M4) were identified. An intravenous administration study with the preparation of white crystalline powder containing EMP1-linear was also conducted using three retired thoroughbred geldings. EMP1 was detectable only in the postadministration plasma samples, whereas the four identified in vitro metabolites were detected in both postadministration plasma and urine samples. For controlling the misuse of EMP1-linear in horse, its metabolite M3 gave the longest detection time in both plasma and urine and could be detected for up to 4 and 27 h postadministration, respectively.

Activation of feedforward wiring in adult hippocampal neurons by the basic-helix-loop-helix transcription factor Ascl4.

Although evidence indicates that the adult brain retains a considerable capacity for circuit formation, adult wiring has not been broadly considered and remains poorly understood. In this study, we investigate wiring activation in adult neurons. We show that the basic-helix-loop-helix transcription factor Ascl4 can induce wiring in different types of hippocampal neurons of adult mice. The new axons are mainly feedforward and reconfigure synaptic weights in the circuit. Mice with the Ascl4-induced circuits do not display signs of pathology and solve spatial problems equally well as controls. Our results demonstrate reprogrammed connectivity by a single transcriptional factor and provide insights into the regulation of brain wiring in adults.

Application of guided imagery to facilitate the transition of new graduate registered nurses.

Traditionally, the new graduate registered nurse (RN) transition has included a didactic and skills-based orientation accompanied by a period of preceptored practice. However, these methods do not ensure that new RNs are in a state of reduced anxiety to fully interact with their new environment. Transition to practice may cause anxiety, and the new graduate RN may perceive moderate to severe stress. One method of stress reduction is the use of guided imagery, which has shown strong potential with a variety of populations undergoing stressful events. Today, new graduate RNs expect institutions to facilitate orientation to their new employment settings and assist in the transition to their role as a professional nurse. This article proposes a model that incorporates guided imagery for refining the new graduate RN transition process. The model can be adapted for use in the context of orienting other adult learners to unfamiliar practice situations.

Dietary issues inpatients face with being vegetarian: an integrative review.

This article reviews the literature from 1985 through 2010 on research related to the dietary issues vegetarian inpatients may encounter in the acute care setting. A thematic portrayal of vegetarianism in the context of the inpatient setting is described. Implications for future research and nursing practice are identified.

Are Emoji Processed Like Words? An Eye-Tracking Study.

In this study, we investigate the processing of object-denoting emoji in sentences using eye tracking. We hypothesize that (a) such emoji are more difficult to process when used as word replacement; and (b) their processing is subject to ambiguity constraints similarly to what happens with words. We conduct two experiments in which participants have to read sentences in which an emoji either follows or replaces a word. Control stimuli not containing emoji are also tested. In the second experiment, the emoji are presented in two different disambiguating contexts. First fixation duration, total visit duration, and total revisit duration are modeled in the various conditions using linear mixed models. Both our hypotheses are supported. We observe longer total visit time for non-redundant emoji, and higher values for all three measures for ambiguous emoji. We conclude that lexical access may be more difficult for emoji especially when they are used as word replacements and their meaning is not immediately clear. Furthermore, we also conclude that non-redundant emoji are more difficult to integrate in the processing of the sentence than the equivalent words, or emoji used in a redundant way. In turn, our results indicate that emoji may not always be as immediate and easy to process for readers in spite of their popularity.

Consultation patterns and frequent attenders in UK primary care from 2000 to 2019: a retrospective cohort analysis of consultation events across 845 general practices.

OBJECTIVE: To describe the distribution of consultations at the practice level and examine whether increases are uniform or driven by people who consult more frequently. DESIGN: Retrospective cohort study. SETTING: UK general practice data from the Clinical Practice Research Datalink (CPRD) GOLD database. PARTICIPANTS: 1 699 709 314 consultation events from 12 330 545 patients, in 845 general practices (1 April 2000 to 31 March 2019). METHODS: Consultation information was aggregated by financial year into: all consultations/all staff; all consultations/general practitioners (GPs); face-to-face consultations/all staff; face-to-face consultations/GPs. Patients with a number of consultations above the 90th centile, within each year, were classified as frequent attenders. Negative binomial regressions examined the association between available practice characteristics and consultation distribution. RESULTS: Among frequent attenders, all consultations by GPs increased from a median (25th and 75th centile) of 13 (10 and 16) to 21 (18 and 25) and all consultations by all staff increased from 27 (23-30) to 60 (51-69) over the study period. Approximately four out of ten consultations of any type concerned frequent attenders and the proportion of consultations attributed to them increased over time, particularly for face-to-face consultations with GPs, from a median of 38.0% (35.9%-40.3%) in 2000-2001 to 43.0% (40.6%-46.4%) in 2018-2019. Regression analyses indicated decreasing trends over time for face-to-face consultations and increasing trends for all consultation types, for both GPs and all staff. Frequent attenders consulted approximately five times more than the rest of the practice population, on average, with adjusted incidence rate ratios ranging between 4.992 (95% CI 4.917 to 5.068) for face-to-face consultations with all staff and 5.603 (95% CI 5.560 to 5.647) for all consultations with GPs. CONCLUSIONS: Frequent attenders progressively contributed to increased workload in general practices across the UK from 2000 to 2019. Important knowledge gaps remain in terms of the demographic, social and health characteristics of frequent attenders and how UK general practices can be prepared to meet the needs of these patients.

Use of complementary and alternative medical interventions for the management of procedure-related pain, anxiety, and distress in pediatric oncology: an integrative review.

This integrative review aims to identify evidence in four electronic databases (MEDLINE, CINAHL, PsyINFO, and COCHRANE) regarding the effectiveness of complementary and alternative medical interventions, either alone or as an adjunct to pharmacological therapy, in alleviating procedure-related pain, anxiety, and distress in children and adolescents with cancer. A total of 32 articles met inclusion criteria. Results suggest that mind-body interventions, including hypnosis, distraction, and imagery, may be effective, alone or as adjuncts to pharmacological interventions, in managing procedure-related pain, anxiety, and distress in pediatric oncology.

Becoming an Air Force Nurse: The Experience of Transition A New Perspective of a Known Phenomenon.

PROBLEM: Transitions in nursing have consistently been described as complex and stressful. While the literature is replete with studies investigating role transitions in civilian healthcare settings, there is no known research that explores the role transition of experienced nurses who move from civilian to military nursing practice. Using nurses in the U.S. Air Force as an exemplar, this study serves as a starting point to understand the transition process and challenges likely encountered by nurses new to the military. The outcomes of this study could influence future efforts to recruit and retain qualified nurses. METHODS: A hermeneutic, phenomenologic approach was used to explore and describe the lived experience of transition from civilian staff nurse to Air Force staff nurse. FINDINGS: The results indicated that new Air Force nurses encounter challenges related to a lack of knowledge and role preparedness, which led to feelings of stress and frustration. Support from peers, mentors, and managers helped the new Air Force nurses bridge the gap in knowledge and successfully integrate into the military culture. IMPLICATIONS: Efforts to reduce the perceived lack of knowledge through improvements to the Commissioned Officer Training program and the clinical orientation period are recommended.

Facilitating Community Participants' Research Engagement: Community Members' Perceptions of Community-based Research.

OBJECTIVES: To describe the perspectives of community participants about engaging in community-based participatory research, and then to use the information to develop a model to depict the community participants' perceptions of interfacing with academic researchers. METHOD: A diverse group of Native Hawaiian community-dwelling participants engaged in open-ended and semi-structured focus group interviews, addressing community members' perceptions of community-based participatory research. RESULTS: Three key areas were identified: (1) reciprocal trustable is needed; (2) perceptions about the purpose, research intent and expectations; (3) expectations of roles and responsibilities of the researcher(s). A model showing the reciprocity between the academic partner and the community partner is needed to establish the full CBPR process is proposed. CONCLUSION: The three themes implied the community participants' expectations of reciprocal relationships. The dimensions influencing community members' perceptions of community-based research need to be taken into account when academic researchers interface with community participants. Successful community-based participatory research approaches for addressing the challenges of translating research findings into community actions is enhanced when the expectations of community members are taken into account.

Medically fragile children: an integrative review of the literature and recommendations for future research.

The literature related to medically fragile children (MFC) is analyzed, and a model is generated to improve quality of care and cost effectiveness. The sources of stress for families include home care professionals, respite care, financial concerns, and limited community resources. Children cared for in hospitals often experience less than desirable quality outcomes. Community-based pediatric extended care facilities may be a means of reducing family stress, improving physiologic and developmental outcomes, and reducing cost. Case management may significantly reduce parental stress and improve the quality of life for these children. Additional systematic study of care options for MFC is essential.

Stress in families with medically fragile children.

The literature related to the stress experienced by families who care for medically fragile children is analyzed. A model is generated from themes identified in the research literature. Four core themes were identified under which most of the stressors identified in the literature could be grouped. These are role conflict, financial burden, care burden, and independence. These are in turn arranged as a matrix in which the family, the child, the care professional, and health care system interact dynamically with the four core themes. The Family Stress/Task Matrix has the potential for facilitating research related to models that include a family-centered view among health professional and systems.

Care delivery for Filipino Americans using the Neuman systems model.

Filipino Americans are at risk of coronary heart disease due to the presence of multiple cardiometabolic factors. Selecting a framework that addresses the factors leading to coronary heart disease is vital when providing care for this population. The Neuman systems model is a comprehensive and wholistic framework that offers an innovative method of viewing clients, their families, and the healthcare system across multiple dimensions. Using the Neuman systems model, advanced practice nurses can develop and implement interventions that will help reduce the potential cardiovascular problems of clients with multiple risk factors. The authors in this article provides insight into the cardiovascular health of Filipino Americans and has implications for nurses and other healthcare providers working with various Southeast Asian groups in the United States.

Evaluating the impact of a school-based prevention program on self-esteem, body image, and risky dieting attitudes and behaviors among Kaua'i youth.

Eating disorders and obesity (EDO) are increasing among youth, having serious long-term physical and psychological consequences. The purpose of this study was to determine if significant differences exist in EDO risk factors following participation of 4-6th grade students in a school-based EDO prevention curriculum. This community-based research project assessed students at baseline and one week following EDO intervention. Primary outcome variables measured self-esteem, body dissatisfaction, and high risk eating attitudes and behaviors. Pre and post-test differences were calculated using mixed models, correcting for clustering within schools and teachers. This study found mean changes in all scores in healthy directions, as well as movement of students into lower risk groups post-intervention. This program demonstrated that a classroom curriculum is associated with decreased risks of EDO in boys and girls, supporting prevention programs at an early age for both sexes. Studies to determine long term benefit and guide booster interventions are warranted.