RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

Parental ethnic identity and child test scores

We examine the relationship between parental ethnic identity and the test scores of ethnic minority children. We use standard survey measures of the strength of parental identity alongside validated cognitive test scores in a rich British cohort study. We show that children whose mothers report either an adoption or an active rejection of the majority identity tend to score lower in cognitive tests at age 7, compared to those children whose mothers report neutral feelings about the majority identity. We find no consistent differences in test scores according to mothers’ minority identity. Our findings provide no support for education or citizenship policies which promote the adoption of the majority identity or discourage the maintenance of separate identities in ethnic minority communities

RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death

2007 AAPP Monograph Series

The African American Professors Program (AAPP) at the University of South Carolina is proud to publish the seventh edition of its annual monograph series. Furthermore, it is an honor to celebrate the remarkable tenth anniversary of AAPP through these manuscripts. The program recognizes the significance of offering its scholars a venue to engage actively in research and publish papers related thereto. Parallel with the publication of their refereed manuscripts is the opportunity to gain visibility among scholars throughout institutions worldwide. Scholars who have contributed papers for this monograph are to be commended for adding this responsibility to their academic workload. Writing across disciplines adds to the intellectual diversity of these papers. From neophytes, relatively speaking, to an array of very experienced individuals, the chapters have been researched and comprehensively written. Founded in 1997 through the Department of Educational Leadership and Policies in the College of Education, AAPP was designed to address the underrepresentation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored by the University of South Carolina, the W.K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits doctoral students for disciplines in which African Americans currently are underrepresented among faculty in higher education. The continuation of this monograph series is seen as responding to a window of opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, at the same time, one that allows for the dissemination of products to a broader community. The importance of this monograph series has been voiced by one of our 2002 AAPP graduates, Dr. Shundele LaTjuan Dogan, formerly an Administrative Fellow at Harvard University and a Program Officer for the Southern Education Foundation. She is currently a Program Officer for the Arthur M. Blank Foundation in Atlanta. Dr. Dogan wrote: One thing in particular that I want to thank you for is having the African American Professors Program scholars publish articles for the monograph. have to admit that writing the articles seemed like extra work at the time. However, in my recent interview process, organizations have asked me for samples of my writing. Including an article from a published monograph helped to make my portfolio much more impressive. You were \u27right on target\u27 in having us do the monograph series. (AAPP 2003 Monograph, p. xi) The African American Professors Program dedicates this 2007 tenth anniversary publication as a special contribution to its readership and hopes that each will be inspired by this interdisciplinary group of manuscripts. John McFadden, Ph.D. The Benjamin Elijah Mays Distinguished Professor Emeritus Director, African American Professors Program University of South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1009/thumbnail.jp

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report.

The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state-of-the-art, clinical diagnostics literature by experts in the field and an open public forum in a face-to-face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design

Ensuring Quality in AFRINEST and SATT: Clinical Standardization and Monitoring

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results

The role of fortitude in relation to exposure to violence among adolescents living in lower socio-economic areas in South Africa

OBJECTIVE: There is compelling evidence that a significant proportion of adolescents exposed to violence do not develop trauma-related symptoms, but adapt successfully. This differential vulnerability has propelled research into identifying factors that promote coping. This study focused on the role of fortitude in the relationship between violence and trauma-related symptoms among South African adolescents living in two low-income communities. Fortitude is derived from positive cognitive appraisals of the self, the family and external sources of support. METHOD: Adolescents (n = 498) completed an adapted version of the Harvard Trauma Scale (HTS) and the Fortitude Questionnaire (FORQ). RESULTS: Moderated regression analysis demonstrated that fortitude had a health-sustaining and stress- buffering role. Adolescents who displayed high levels of fortitude had lower levels of trauma symptoms in relation to exposure to violence (stress-buffering) and were able to maintain their levels of wellbeing irrespective of the nature and extent of such exposure (health-sustaining). CONCLUSION: The study provides evidence for fortitude as a protective factor by highlighting the role of specific cognitive appraisals related to fortitude in facilitating adaptation in relation to trauma. The study also underscores the relevance of using clinical interventions that target problematic cognitive appraisals and strengthen perceptions of coping.DHE