Assessment of DNA Double Strand Break Repair Activity Using High-throughput and Quantitative Luminescence-based Reporter Assays.

The repair of DNA double strand breaks (DSBs) is crucial for the maintenance of genome stability and cell viability. DSB repair (DSBR) in cells is mediated through several mechanisms: homologous recombination (HR), non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and single strand annealing (SSA). Cellular assays are essential to measure the proficiency and modulation of these pathways in response to various stimuli. Here, we present a suite of extrachromosomal reporter assays that each measure the reconstitution of a nanoluciferase reporter gene by one of the four major DSBR pathways in cells. Upon transient transfection into cells of interest, repair of pathway-specific reporter substrates can be measured in under 24 h by the detection of Nanoluciferase (NanoLuc) luminescence. These robust assays are quantitative, sensitive, titratable, and amenable to a high-throughput screening format. These properties provide broad applications in DNA repair research and drug discovery, complementing the currently available toolkit of cellular DSBR assays.

A network analysis of self-compassion and burnout in a sample of nurses.

BACKGROUND: In the nursing profession, the concept of self-compassion has been associated with burnout. However, to date, the fine-grained relationships between different dimensions of self-compassion and symptoms of burnout have not been investigated. Network analysis provides a new avenue for exploring the fine-grained correlation paths of two related variables. AIM: To analyse the nuanced associations between self-compassion and burnout using network analysis in a large cohort of Chinese nurses. DESIGN: A cross-sectional multi-centre survey design study. METHODS: Participants were recruited from 30 hospitals in China between April and May 2022. These nurses completed the Chinese Maslach Burnout Inventory-General Survey (C-MBI-GS) and Self-Compassion Scale-Short Form (SCS-SF). Network analysis was performed to illustrate the complex nuanced relationships between self-compassion and burnout. RESULTS: A total of 1467 nurses (age 32.2 [18-56] years; 89.9% were female) participated in the study. Nodes Mindfulness and Isolation had the highest centralities measured by strength. Nodes Mindfulness, reduced personal accomplishment and Isolation were the most negative and positive influential nodes that bridged self-compassion and burnout. There were no differences in terms of gender, age, professional title and job tenure in the structure or connectivity of the self-compassion and burnout network. CONCLUSION: Different components of self-compassion were specifically associated with different dimensions of burnout in registered nurses. Among these, Mindfulness, Isolation and Reduced personal accomplishment were the three most important components of self-compassion for burnout symptoms. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPACT: Understanding the intricate connections between self-compassion and burnout will allow hospital administrators to prioritize the elements of Mindfulness and Isolation within self-compassion and the dimension of Reduced personal accomplishment within burnout when designing preventative measures and interventions aimed at reducing nurse burnout.

Antenatal glycemic management and postpartum cardiovascular disease risk screening.

OBJECTIVE: This study aims to evaluate the cardiovascular disease (CVD) risk profiles of patients referred to the maternal health clinic (MHC) with a history of gestational diabetes (GDM). METHODS: Eligible patients had their MHC appointment at 6 months postpartum between November 2011 and May 2022 and experienced GDM in their most recent pregnancy. Included participants were then divided into subgroups comparing methods of glycemic control: diet-controlled GDM and insulin-controlled GDM. Additionally, the MHC recruited 47 patients who have not experienced a complication in pregnancy to act as a comparator group in research studies. Demographics, medical and pregnancy history, and CVD risk scores were compared between the three groups. RESULTS: 344 patients with GDM were included in the analysis; 165 insulin-controlled and 179 diet-controlled. When measuring the median 30 year Framingham risk score based on both BMI and lipids, there was a significant stepwise increase seen from the unexposed group, the diet-controlled GDM, and the insulin-controlled groups, respectively (all P < 0.05). The presence of metabolic syndrome showed a stepwise increase in prevalence when comparing the unexposed group, diet exposure group, and the insulin exposure group, respectively (16.7%, 21.5%, 44.8%; P < 0.05). CONCLUSION: Our findings reinforce the prevalence of maternal CVD risk among GDM-diagnosed patients in the postpartum period and the necessity for screening. More specifically, our findings show how CVD risk may differ based on required interventions for glycemic control throughout pregnancy. Future research should aim to compare a more diverse patient population to optimize the generalizability of glycemic control-specific CVD outcomes.

Strategies for enhancing Chinese students' engagement in a large class learning environment: An interpretative phenomenological approach.

AIM: It is common for Chinese students to sit quietly during classroom lectures, attentively following teachers' instructions without interacting or asking questions, viewed as passive engagement. This study aims to understand further the passive engagement of Chinese students in relation to classroom questioning, just-in-time feedback and collaborative activities. With objectives to formulate strategies to enhance Chinese students' engagement in a large class learning environment without undermining the cultural dimension of "face". BACKGROUND: Engaging in collaborative educational activities between teachers and students can be challenging in a large classroom learning environment. Within the Chinese context, Confucian-heritage culture may further exacerbate the challenges teachers face. Chinese students often appear passive when responding to questions. In this situation, educators may receive insufficient student feedback to modify and optimise their teaching and learning approaches. DESIGN: A qualitative research method, with an interpretative phenomenological approach was employed in a self-financed institute of higher education in Hong Kong. METHODS: Eight nursing graduates were invited to participate in two focus group interviews to generate teaching and learning strategies. In addition, individual in-depth interviews were conducted with twelve nursing teachers recruited through a snowballing sampling strategy. The narratives were coded, categorised, themed, analysed and interpreted through thematic analysis. RESULTS: Chinese students are concerned with "losing face" and the fear of being teased by their peers in a collectivist culture. Based on these findings, three teaching and learning strategies for engaging students in classroom questioning and collaborative activities were generated. These strategies include using digital learning platforms, the promotion of communication and fostering interpersonal relationships. CONCLUSIONS: In higher education, academic managers and teachers must critically reflect on teaching and learning strategies tailor-made to different cultural and contextual settings. Collaborating on pedagogical reforms can provide solid guidance and insight on implementing student-centred learning for Chinese students in large class learning environments while respecting the cultural dimension of "face".

Ten-Year Review of the Postpartum Maternal Health Clinic at the Kingston Health Sciences Centre.

OBJECTIVES: The postpartum Maternal Health Clinic (MHC) sees patients who have experienced pregnancy complications identified as pregnancy-related cardiovascular disease (CVD) risk indicators (hypertensive disorders of pregnancy, gestational diabetes, placental abruption, idiopathic preterm delivery, and intrauterine growth restriction) at 6 months postpartum for CVD risk screening. This project aimed to summarise the past 10 years of the MHC and identify trends in patient characteristics, patient CVD risk assessments, and clinic attendance over time. METHODS: Patients included in this study have experienced 1 or more pregnancy-related CVD risk indicator(s) and have delivered between April 2011 and April 2021. MHC patient data and the Better Outcomes Registry Network database were utilised to compare eligible and participating patient data during clinically significant time periods. RESULTS: The clinic has seen 1030 patients in the last 10 years and their characteristics have remained largely consistent. However, there has been an increase in the proportion of patients seen because of a hypertensive disorder and an increase in the proportion of patients with obesity, abnormal total cholesterol, and elevated fasting glucose. Additionally, CVD risk scores and the prevalence of metabolic syndrome have remained consistent over the years. Regarding the clinic's outreach, patient eligibility for the MHC has been increasing while attendance has been decreasing over time. CONCLUSIONS: Overall, there remains a need to screen these patients for CVD risk and counsel them on risk reduction. There is also an opportunity to increase patient recruitment to improve attendance and to address the increased need for CVD risk screening and counselling in the community.

Research of Arithmetic and Drawing Writing in Improving Communication and Cognitive Function in Patients with Mild-to-Moderate Dementia: A Cluster Randomized Controlled Trial.

Objective: The aim of the study was to investigate the effectiveness of arithmetic and drawing writing on communication skills, quality of life, and cognitive impairment among people with mild and moderate dementia. Methods: We recruited 45 patients diagnosed with mild-to-moderate dementia into this study. The participants were randomly divided into arithmetic group (n = 14), drawing writing group (n = 16), and control group (n = 15). The arithmetic group was educated to understand the addition and subtraction formulas, then wrote down the correct answers between the number of 20 and 100. The drawing writing group was guided to name, draw, and write a given object. Both were trained by therapist for 12 weeks (40 minutes per week). Blinded assessors measured global cognitive function, communication skills, and quality of life using Mini-Mental State Examination (MMSE) scale, the subscales of Functional Assessment of Communication Skills scale and Quality of Life-Alzheimer's Disease scale at baseline and after 12 weeks' intervention. Results: After the 12-week intervention, the participants with mild-to-moderate dementia of the arithmetic writing group and the drawing writing group showed statistically significant improvement in communication skills and quality of life compared with the control group (social communication: 6.00 ± 0.69 vs. 6.06 ± 0.92 vs. 3.98 ± 1.33; basic needs communication: 6.32 ± 0.48 vs. 6.42 ± 0.53 vs. 4.25 ± 1.49; quality of life: 33.23 ± 5.34 vs. 34.07 ± 3.49 vs. 25.07 ± 2.60). In addition, MMSE scores of the arithmetic group tended to improve after the 12-week intervention (14.77 ± 3.06 vs. 17.31 ± 4.80, P < .01), but stabled in drawing writing group (14.27 ± 4.28 vs. 14.53 ± 5.26, P > .05) and significant decreased in the control group (13.73 ± 2.58 vs. 10.13 ± 3.23, P < .01). Conclusion: Arithmetic, drawing, and writing are effective in improving communication skills and quality of life; arithmetic also could delay the decline of cognitive function in people with mild-to-moderate dementia.

Latent profiles of academic resilience in undergraduate nursing students and their association with resilience and self-efficacy.

AIM: This study aimed to investigate the heterogeneity of academic resilience among nursing students using latent profile analysis and its associated influencing factors. BACKGROUND: Nursing students experience higher levels of stress compared to their peers in other professions, and the cultivation of academic resilience plays a pivotal role in their ability to effectively cope with this stress. Academic resilience not only facilitates success in the face of academic adversity but also contributes to the promotion of mental well-being among nursing students. However, the current research on the academic resilience of nursing students has predominantly focused on a scale-centered total score approach, disregarding individual variability, and hindering the development to inform personalized interventions for enhancing academic resilience. DESIGN: A cross-sectional study. METHODS: A convenience sampling method was used to collect a total of 644 nursing students from two medical schools in Guangzhou City. The participants were recruited through an online survey conducted from January to March 2023. The questionnaires consisted of a general information form, the Chinese version of the Academic Resilience Scale-30 (C-ARS-30), the 10-item Connor Davidson Resilience Scale (CD-RISC-10), and the General Self-Efficacy Scale (GSES). Latent profile analysis was used to identify distinct categories of academic resilience among nursing students, and influencing factors were examined through ordinal logistic regression analysis. RESULTS: The academic resilience levels of nursing students can be divided into three potential categories: 'low academic resilience' (13.0%), 'moderate academic resilience' (70.0%), and 'high academic resilience' (17.0%). Level of grade, GPA, self-reported physical health level, resilience and self-efficacy were significantly influenced the different categories of academic resilience of nursing students (P<0.05). CONCLUSIONS: The majority of undergraduate nursing students were placed in the moderate academic resilience group, however, educational institutions should pay special attention to nursing students demonstrating low levels. Regular assessments of academic resilience are recommended, and personalized interventions should be tailored to address specific academic resilience characteristics across different grades of nursing students. Strategies aimed at enhancing academic resilience among nursing students may include improvements in GPA performance, attention to physical health, and the reinforcement of resilience and self-efficacy.

Women's Knowledge of Future Cardiovascular Risk Associated With Complications of Pregnancy: A Systematic Review.

Background: Several common pregnancy conditions significantly increase a woman's risk of future cardiovascular diseases (CVD). Patient education and interventions aimed at awareness and self-management of cardiovascular risk factors may help modify future cardiovascular risk. The aim of this systematic review was to examine education interventions for cardiovascular risk after pregnancy, clinical measures/scales, and knowledge outcomes in published qualitative and quantitative studies. Methods: Five databases were searched (from inception to June 2023). Studies including interventions and validated and nonvalidated measures of awareness/knowledge of future cardiovascular risk among women after complications of pregnancy were considered. Quality was rated using the Mixed Methods Appraisal Tool. Results were analyzed using the Synthesis Without Meta-analysis reporting guideline. Characteristics of interventions were reported using the Template for Intervention Description and Replication. Fifteen studies were included; 3 were randomized controlled trials. Results: In total, 1623 women had a recent or past diagnosis of hypertensive disorders of pregnancy, gestational diabetes mellitus, and/or premature birth. Of the 7 studies that used online surveys or questionnaires, 2 reported assessing psychometric properties of tools. Four studies used diverse educational interventions (pamphlets, information sheets, in-person group sessions, and an online platform with health coaching). Overall, women had a low level of knowledge about their future CVD risk. Interventions were effective in increasing this knowledge. Conclusions: In conclusion, women have a low level of knowledge of risk of CVD after pregnancy complications. To increase this level of knowledge and self-management, this population has a strong need for psychometrically validated tailored education interventions.

Contexte: Plusieurs problèmes médicaux liés à la grossesse augmentent significativement le risque d'une maladie cardiovasculaire (MCV) ultérieure chez les femmes. L'éducation des patients et les interventions axées sur la sensibilisation aux facteurs de risques cardiovasculaire et sur l'autoprise en charge pourraient aider à limiter le risque de MCV. La présente analyse des études qualitatives et quantitatives publiées visait à examiner les interventions éducatives au sujet des risques cardiovasculaires après la grossesse, les mesures et échelles cliniques qui y sont associées, et les résultats de ces interventions sur le plan des connaissances. Méthodologie: Des recherches ont été réalisées dans cinq bases de données (de leur date de création jusqu'à juin 2023). Les études considérées incluaient des interventions et des mesures validées ou non de la sensibilisation des femmes au sujet des risques de MCV après des complications liées à la grossesse ou de leurs connaissances à ce sujet. La qualité des études a été évaluée avec l'Outil d'évaluation de la qualité méthodologique des études incluses dans une revue mixte, et les résultats ont été évalués à l'aide de la méthodologie Synthesis Without Meta-analysis. Les caractéristiques des interventions ont été relevées selon le modèle Template for Intervention Description and Replication. Quinze études ont été retenues, dont 3 essais contrôlés randomisés. Résultats: Au total, 1623 femmes avaient reçu récemment ou auparavant un diagnostic de trouble hypertensif lié à la grossesse, de diabète gestationnel et/ou de travail prématuré. Parmi les 7 études ayant eu recours à des questionnaires ou des sondages en ligne, 2 mentionnaient l'évaluation des propriétés psychométriques des outils. Dans 4 études, plusieurs interventions éducatives ont été utilisées (dépliants, feuillets informatifs, séances de groupe en personne et plateforme en ligne offrant un accompagnement en matière de santé). De manière générale, le niveau de connaissance des femmes au sujet de leur risque de MCV était faible, mais les interventions se sont révélées efficaces pour améliorer ces connaissances. Conclusions: En conclusion, les femmes ne connaissent pas bien les risques de MCV associés aux complications survenues au cours de la grossesse. Pour améliorer le niveau des connaissances et l'autoprise en charge, des interventions conçues pour cette population et validées sur le plan psychométrique sont indispensables.

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Assessing cardiovascular disease risk in women with a history of hypertensive disorders of pregnancy: A guidance paper for studies using administrative data.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality, and their association with increased cardiovascular disease (CVD) risk represents a major public health concern. However, assessing CVD risk in women with a history of these conditions presents unique challenges, especially when studies are carried out using routinely collected data. OBJECTIVES: To summarise and describe key challenges related to the design and conduct of administrative studies assessing CVD risk in women with a history of HDP and provide concrete recommendations for addressing them in future research. METHODS: This is a methodological guidance paper. RESULTS: Several conceptual and methodological factors related to the data-generating mechanism and study conceptualisation, design/data management and analysis, as well as the interpretation and reporting of study findings should be considered and addressed when designing and carrying out administrative studies on this topic. Researchers should develop an a priori conceptual framework within which the research question is articulated, important study variables are identified and their interrelationships are carefully considered. CONCLUSIONS: To advance our understanding of CVD risk in women with a history of HDP, future studies should carefully consider and address the conceptual and methodological considerations outlined in this guidance paper. In highlighting these challenges, and providing specific recommendations for how to address them, our goal is to improve the quality of research carried out on this topic.

Reconsidering Routine Repeat Group and Screens During Pregnancy-Personalizing Pregnancy Care.

The group and screen (G&S) are performed in early pregnancy to identify clinically significant antibodies (CSA) that may necessitate fetal monitoring for hemolysis/anemia or affect RhIg eligibility. Guidelines vary, including differences between RhD-positive and negative patients, but typically, the G&S is repeated at 28 weeks, and sometimes pre-delivery. We reviewed data showing a low risk (0.01%-0.43%) of detecting a new CSA in late gestation (late alloimmunization) and the risk of late alloimmunization causing severe hemolysis/anemia is even lower at <0.01%. Routinely repeating a G&S at 28 weeks and delivery may not be necessary for healthy, low-risk pregnancies.

Navigating changes: A qualitative study exploring the health-related quality of life of breast cancer survivors during the coronavirus disease 2019 pandemic.

AIMS: To explore the impact of the coronavirus disease 2019 pandemic on the health-related quality of life (HRQoL) of breast cancer survivors. DESIGN: We utilized a qualitative descriptive approach to facilitate interviews among 25 participants, all of whom are survivors of breast cancer and have received treatment in Hong Kong within the preceding 3 years. METHODS: Content analysis was performed to understand how patients' HRQoL views and experiences changed during coronavirus disease 2019 pandemic. RESULTS: The results included six themes delineating the impact of the coronavirus disease 2019 pandemic: (i) survivor sensitivities in pandemic times, (ii) coping and conditioning in pandemic times, (iii) transforming work and home dynamics in pandemic times, (iv) cognitive resilience and adaptation to the COVID-19 protective measures, (v) social resilience in pandemic times and (vi) healthcare adaptation and coping in pandemic times. CONCLUSION: This study provides insights into the experiences and challenges of breast cancer survivors during the coronavirus disease 2019 pandemic. Some survivors had new physical and psychological symptoms, including fear and anxiety, isolation, pain, lymphoedema and burnout, which potentially have long-term impact upon HRQoL. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study highlights the unique challenges faced by breast cancer survivors during the coronavirus disease 2019 pandemic, including accessing healthcare services and the impact of social isolation. Healthcare providers should consider the holistic needs of breast cancer survivors in the provision of health care and develop supportive interventions, including telehealth services and online support groups, to address these challenges and improve their HRQoL. IMPACT: Surgery aimed at treating breast cancer or reducing its risk generally influences the appearance of breast areas and donor sites. The continuing effects of these changes on body image and HRQoL are well-reported, although studies have ineffectively examined the initial experiences of women regarding their postoperative appearance, particularly during the pandemic. REPORTING METHOD: The checklist of consolidated criteria for reporting qualitative research (COREQ) was utilized. PATIENT OR PUBLIC CONTRIBUTION: A small selection on breast cancer survivors contributed to the design of this study, in particular the content of the semi-structured interviews.

Pregnancy-associated cardiovascular risks and postpartum care; an opportunity for interventions aiming at health preservation and disease prevention.

Cardiovascular disease (CVD) is the leading cause of premature death and disability for female individuals around the world and the rates are increasing in those aged 35-44 years. Certain pregnancy complications (Pregnancy-associated Cardiovascular Risks (P-CVR))are linked to an increased risk of future CVD making pregnancy and the postpartum period as an ideal time to screen individuals for underlying, often unrecognized, cardiovascular risk factors. Pregnancy complications associated with an increased risk of future CVD including the hypertensive disorders of pregnancy, gestational diabetes, idiopathic preterm birth, delivery of a growth restricted baby and a placental abruption that leads to delivery. A number of guidelines and research groups recommend postpartum CVR screening, counseling and lifestyle intervention for all those who have had one or more of P-CVRs starting within the first six months postpartum. An individualized plan for postpartum screening should be created with the individual and lifestyle interventions discussed.

Quantitative, titratable and high-throughput reporter assays to measure DNA double strand break repair activity in cells.

Repair of DNA damage is essential for the maintenance of genome stability and cell viability. DNA double strand breaks (DSBs) constitute a toxic class of DNA lesion and multiple cellular pathways exist to mediate their repair. Robust and titratable assays of cellular DSB repair (DSBR) are important to functionally interrogate the integrity and efficiency of these mechanisms in disease models as well as in response to genetic or pharmacological perturbations. Several variants of DSBR reporters are available, however these are often limited by throughput or restricted to specific cellular models. Here, we describe the generation and validation of a suite of extrachromosomal reporter assays that can efficiently measure the major DSBR pathways of homologous recombination (HR), classical nonhomologous end joining (cNHEJ), microhomology-mediated end joining (MMEJ) and single strand annealing (SSA). We demonstrate that these assays can be adapted to a high-throughput screening format and that they are sensitive to pharmacological modulation, thus providing mechanistic and quantitative insights into compound potency, selectivity, and on-target specificity. We propose that these reporter assays can serve as tools to dissect the interplay of DSBR pathway networks in cells and will have broad implications for studies of DSBR mechanisms in basic research and drug discovery.